Cardiologia Croatica. 2016;11(7)

Jan Steffel, Pierre Jais, Gerhard Hindricks

## Preamble The year 2015 was once more filled with exciting and important novel developments in the field of invasive electrophysiology and implantable cardiac devices. These include technical innovation, novel molecular and cellular insights, and presentation of large randomized clinical trials as well as important ‘real-world’ registries. In addition, several new guidelines surfaced in 2015, including those for the treatment of ventricular arrhythmias and prevention of sudden cardiac death. It is virtually impossible to cover all novel developments that would merit discussion in this type of overview; as a result, the authors had to make a selection, focusing on several important developments with direct implications for daily clinical practice. ## Cardiac arrhythmias and catheter ablation ## Atrial fibrillation Catheter ablation of atrial fibrillation (AF) remained in focus of clinical studies and large-scale trials. The use of force-sensing ablation catheter technologies seems to improve the induction of durable atrial lesions and was shown to significantly reduce AF recurrence rate after catheter ablation in a meta-analysis mainly made of non-randomized trials. (1) This technology will become standard for AF catheter ablation in the future. A word of caution: there is growing evidence that more extensive ablation in the atria does not per se improve the rhythm outcome after AF catheter ablation. The Minimax Trial compared two ablation strategies for pulmonary vein isolation (PVI) in 234 patients who underwent catheter ablation of paroxysmal AF: circumferential antral PVI alone (‘minimal’) vs. PVI with intravenous ridge ablation to achieve individual PVI (‘maximal’). After a mean follow-up of 17 ± 8 months, freedom from AF after limited ‘minimal’ ablation was not worse compared with more extensive ‘maximal’ ablation (70 vs. 62%; P = 0.25). (2) Previous data indicated that adenosine-guided detection of dormant pulmonary vein re-conduction and subsequent re-isolation of the veins can be successfully applied to improve outcome of AF catheter ablation. (3) However, a much bigger randomized trial published in European Heart Journal now questioned the usefulness of adenosine testing: in the Japanese UNDER anti-tachycardia pacing (ATP) Trial, 2113 patients were randomized to either adenosine challenge or control and no difference in AF recurrence rate was shown at 1 year. (4) The reasons for the contradictory results reported from these two multi-centre, randomized trials are unclear at present and deserve further investigation. Treatment with anti-arrhythmic drugs after catheter ablation was shown to reduce the AF recurrence 90 days after catheter ablation in the EAST AF trial, however, at 1 year there was no difference in arrhythmia recurrence between treatment and control group. (5) These results are quite in line with the data of the AmioCat Trial. (6) In AmioCat patients were randomized to amiodarone or placebo for 8 weeks after AF catheter ablation. While amiodarone treatment reduced hospitalizations and cardioversions in the 3-month post-ablation blanking period, there was no difference in AF recurrence rate at 6-month follow-up (39 vs., 48%; P = 0.18). Thus, anti-arrhythmic drugs may prevent early AF recurrences after ablation but may not promote a better atrial re-modelling resulting in a higher sinus rhythm rate during follow-up. The 5-year follow-up data of the MANTRA-PAF Trial were reported during the ESC Congress in London: MANTRA-PAF evaluated the comparative effects of first-line radiofrequency catheter ablation of AF with anti-arrhythmic drug therapy. At 2-year follow-up, there was no difference in cumulative AF burden between the ablation and anti-arrhythmic drug group, while the burden of AF was significantly lower in the ablation group (90th percentile, 9 vs. 18%; P = 0.007). (7) However, at 5-year follow-up, there was a significantly higher rate of AF-free patients in the ablation compared the anti-arrhythmic drug treatment group (86 vs. 71%; P = 0.001). Also, AF burden was lower in the ablation compared with the drug group (P = 0.003). Interestingly, the effects on quality of life were similar in both groups. These data indicate that the rhythm benefit resulting from catheter ablation may increase over time; however, it is important to understand that MANTRA-PAF was too small to evaluate any effect of ablation or anti-arrhythmic drugs on hard outcome parameters such as stroke and/or mortality. These questions will be open until data from the EAST Trial (endpoint: composite of death, stroke, and heart failure) and CABANA Trial (endpoint: composite of death, serious bleeding, disabling stroke, and cardiac arrest) are available. (8, 9) Persistent AF ablation strategy has never been mature enough for a consensus to emerge, neither in the past nor in 2015. Rotor ablation using contact phase mapping has been questioned, (10) and CAFÉ ablation is not specific enough to be convincing as demonstrated by a large meta-analysis. (11) In contrast, lifestyle modification such as weight loss is remarkably effective in reducing AF burden (10% loss translates into a six-fold AF burden reduction) and in inducing reverse remodelling on left atrial size and left ventricular septal thickness. (12) ## Stroke prevention Due to the results from large-scale clinical trials, the non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred treatment for stroke prevention in non-valvular AF, as reflected in current ESC guidelines. (13) As the fourth NOAC, edoxaban has been approved in 2015 in many countries including the USA, Switzerland, and Europe based on the results of the ENGAGE AF-TIMI 48 trial. (14) During the year 2015, several subgroup analyses of the large NOAC trials have surfaced, including bleeding management and outcome with apixaban, (15) the management of rivaroxaban around catheter ablation for AF (VENTURE-AF), (16) and the outcome of amiodarone co-medication in patients receiving edoxaban, (17) to name just a few. Virtually, all subgroups of the large NOAC trials indicate a consistent benefit and safety of these drugs compared with warfarin, further underlining their overall superiority. This is supported by important real-world data (including those from a prospective registry with rivaroxaban, XANTUS) (18) indicating efficacy and safety, which is in line with that observed in the randomized clinical trials. Arguably, the most exciting novelty in the field of NOACs comes from the development of specific reversal agents (‘antidotes’). In a Phase 1 study in healthy men, the monoclonal antibody idarucizumab (specific for dabigatran) was well tolerated with no unexpected or clinically relevant safety concerns, and was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation. (19) Moreover, in a Phase 3 study, idarucizumab was demonstrated to effectively and immediately reverse the anticoagulant effect of dabigatran in patients presenting with serious bleeding or requiring an urgent procedure. (20) As a result, the US Food and Drug Administration has approved the drug in October 2015; the Committee for Medicinal Products for Human Use of the European Medicines Agency has also recently issued a positive opinion, and approval is expected by the end of this year or early 2016. Importantly, idarucizumab is ineffective against Xa-inhibitors; instead, different directly acting antidotes are being developed, including andexanet alfa and PER977. First results are also positive with these agents, and larger-scale clinical trials are anticipated within the year 2016. While these drugs clearly represent an important addition to our portfolio, many aspects in the practical use remain to be determined, including the type of patients and conditions requiring reversal and the time of reinstitution of anticoagulation. These and other issues are elegantly described in the 2015 updated version of the European Heart Rhythm Association practical guide, (21) following the great success of its first version published in 2013. (22) Will catheter ablation of AF have an impact on stroke risk? Novel data from a large Danish registry suggest a very low risk of stroke for patients after catheter ablation. (23) However, these data do require validation in a prospective randomized trial before clinical practice for oral anticoagulation after catheter ablation may be changed. (24) ## Ventricular arrhythmias and sudden cardiac death Catheter ablation of ventricular tachycardia (VT) is one of the fastest growing fields in interventional electrophysiology (25); the importance of diagnosing and correctly triaging VTs, particularly those easily amenable to catheter ablation (**Figure 1**), is a challenge faced by cardiologists on a regular basis. Multiple important studies have been reported within the last 12 months documenting the importance and increased utilization of VT ablation. Despite several remarkable technical and technological improvements and innovations such as use of image integration, (26) novel ablation electrodes, (27, 28) force-sensing technologies, (29) or ultra-high density mapping, (30) the relatively high recurrence rate of any VT after catheter ablation in patients with VT and structural heart disease remains a key challenge. As evident from recent multi-centre data, non-inducibility of any VT at the end of the ablation is probably the best endpoint for the procedure and should be targeted. (31) In addition, non-inducibility when supported by elimination of abnormal potentials may also have an impact on survival as well. (32, 33) Most fascinating is the report of successful ‘ablation’ of Brugada syndrome. The idea to treat Brugada patients at risk of sudden cardiac death with an interventional ablation procedure is further advanced by a recent report from Brugada et al. (34) In their series, 13 patients underwent epicardial mapping and right ventricular abnormal electrograms were identified in all of them. Catheter ablation normalized the ECG and abolished pre-existing typical ECG changes induced by flecainide. However, despite all enthusiasm, it is unclear whether or not these ablation effects have an impact on spontaneous VT/ventricular fibrillation (VF) and/or risk of sudden cardiac death. The new ESC Guidelines for the treatment of ventricular arrhythmias and prevention of sudden cardiac death were presented during the ESC congress in London. (35) These guidelines provide up-to-date state-of-the-art summary of current knowledge and best practice treatment in this field. Figure 1. Twelve-lead electrocardiogram morphology of different sites of origin in idiopathic ventricular tachycardia. RVOT = right ventricular outflow tract; RCC = right coronary cusp; R–L com = right–left coronary cusp commissure; LCC = left coronary cusp; AMC = aortomitral continuity; TV = tricuspid annulus; MV = mitral annulus; APM = anterior PAP; PPM = posterior PAP; LPF = left posterior fascicle; LAF = left anterior fascicle; GCV = greater cardiac vein; AIV = anterior inter-ventricular vein. Reproduced from Tanawuttiwat *et al*., reprinted with kind permission from Tanawuttiwat *et al.* (25) ## Cardiac electronic devices ## Leadless pacemakers One of the main trends for cardiac devices in the year 2015 was the continued movement towards the abandonment of intravascular leads. After an initially tedious start, leadless single-chamber pacemakers have finally arrived in daily clinical practice. Early results from the 140 patients receiving the Medtronic MICRA leadless pacemaker system demonstrated a favourable efficacy and safety profile. (36) During a mean follow-up of 1.9 ± 1.8 months (i.e. covering primarily the perioperative and early postoperative period), no unanticipated serious adverse device events were observed, including no device dislodgement and only one pericardial effusion without tamponade (resulting in prolonged hospitalization). Of note, the latter occurred in a patient in whom the device needed to be repeatedly repositioned (18×). In the majority of patients (81%), however, the device was properly placed with no or only one repositioning. During follow-up, electrical values including pacing thresholds, impedance, and sensing remained stable and favourable, resulting in an anticipated battery longevity of 12.6 years (range 8.6–14.4). (36) As a result of these findings, the MICRA system received CE mark in the summer of 2015, followed by careful rollout to selected centres and operators after undergoing comprehensive in vivo and ex vivo training. These positive initial results were mirrored in a larger group of 725 patients, of whom 719 (99.2%) underwent successful implantation. (37) Electrical values (threshold, sensing, and impedance) were favourable in 292 of 297 patients with paired 6-month data. There were 28 major complications in 25 of 725 patients [4.0%, including 11 (1.9%) traumatic cardiac perforation or effusion and 1 death (0.1%)]. These numbers compared favourably with historic controls undergoing transvenous pacemaker implantation. Importantly, no device dislodgements were observed. (37) Results of the second available single-chamber transcatheter pacing system, the Nanostim (St Jude Medical), were equally presented and published this year. (38) In the first 526 patients undergoing implantation, the system was successfully implanted in 504 (95.8%). Of the 300 patients who completed 6-month follow-up, the primary efficacy outcome (acceptable electrical values) was reached in 90%. Of the total cohort of 526 patients, serious device-related adverse events occurred in 6.5% of patients, including cardiac tamponade in 5 (1.0%), device dislodgement in 6 (in 1.5%), and device migration during implantation owing to inadequate fixation in 2 patients (0.4%). Further experience with both leadless pacing systems will show how they compare in even larger populations and in daily clinical practice. Patients with a typical single-chamber pacemaker indication currently represent the primary population for leadless pacers, i.e. permanent AF with symptomatic bradycardia and/or AV block. Future studies and real-world experience will show how these device behave long term (including the novel rate-adaptive sensor system); first personal experiences are encouraging. The development for more advanced systems is ongoing, including dual-chamber pacemakers, cardiac resynchronization therapy, and communication with the subcutaneous implantable cardioverter defibrillator (ICD). ## Implantable cardioverter defibrillator therapy and implant-based telemonitoring Implantable cardioverter defibrillator testing is no longer necessary during routine and uncomplicated ICD implantation: in the Nordic ICD Trial, 1077 patients were randomly assigned to first time ICD implantation with (n = 540) or without (n = 537) testing of defibrillation threshold. (39) Defibrillation efficacy was not different between both groups during follow-up. Similarly, in the SIMPLE trial of 2500 patients, routine defibrillation testing did not result in a reduction in arrhythmic deaths during a mean follow-up of 3.1 years. (40) Almost all pacemakers and defibrillators that are currently available have the technical option for remote monitoring. (41) Previous results from randomized clinical trials and analysis from big data sets indicated that these technologies may have beneficial effects when applied appropriately. (42) However, recent data from the Optilink HF Trial reported at the ESC Congress in London showed disappointing results: the trial randomized 1002 patients with heart failure and an indication for ICD implantation to remote automated pulmonary congestion alert ‘on’ (n = 505) or ‘off’ (n = 497). After 18 months of follow-up, there was no significant difference between groups in primary endpoint, which was a composite of all-cause death and cardiovascular hospitalizations. More promising data are derived from the follow-up report of the CHAMPION Trial that assessed the efficacy of automatic pulmonary pressure measurement in heart failure patients to guide and optimize heart failure therapy. (43) The superiority of the treatment group over the control group previously reported was maintained for an additional 13 months to the end of the Randomized Access Period with a significant reduction of heart failure-related hospitalizations by 33% and of all-cause hospitalizations by 16%. Second, the good results in the treatment group were maintained during an Open Access Period of another 12 months, during which no increase in hospitalizations was observed. Most importantly, heart failure-related hospitalizations and all-cause hospitalizations in the former control group were reduced significantly by 48 and 21%, respectively, after pulmonary artery pressure information became available to guide therapy during the Open Access Period. Thus, implant-based remote telemonitoring seems highly promising to support heart failure therapy and it will be just a matter of time when haemodynamic sensors will be combined with pacemakers, defibrillators, and cardiac resynchronization devices. ## Subcutaneous implantable cardioverter defibrillators Ever since its approval in 2009, the subcutaneous ICD (S-ICD) system has increasingly gained attention and attraction. Indeed, its complete lack of intravascularly placed electrodes is potentially associated with a substantial reduction in morbidity (and mortality) due to lead complications associated with currently used ‘classical’ transvenous ICD systems. In 2015, the new generation EMBLEM S-ICD System was approved, the main feature of which is its 20% thinner size combined with a 40% longer life expectancy when compared with the previous S-ICD system. At the same time, novel algorithms are being developed to overcome the risk of inadequate shock deliveries. (44, 45) Recently published registry results have indicated a decreasing risk of complications, suboptimal programming, and (to a lesser degree) inadequate shock deliveries with increasing experience and volume. (46) In addition, the same registries demonstrated a high efficacy for the termination of VT and VF, with 90.1% of events (100/111) terminated with one shock and 98.5% (109/111) terminated within the available five shocks. (47) As a result of these favourable data, the use of the S-ICD has, for the first time, been incorporated into the guidelines for the prevention of sudden cardiac death as a IIa indication [level of evidence (LoE) C] as an alternative to standard ICD for patients without an indication for bradycardia pacing, cardiac resynchronization, or ATP. (35) Also, the S-ICD may be considered (IIb, LoE C) in patients with difficult venous access, after the transvenous ICD removal for infections or in young patients with a long-term indication for ICD therapy. (35) Indeed, the lack of possibility to deliver ATP or bradycardia pacing remains the most important shortcoming of current S-ICD devices. Combination of the S-ICD with leadless pacers clearly would be one of the most obvious possible solution to this problem. However, with evidence-based programming (high-rate or long-duration detection zones), the overall amount of delivered ATP will likely be decreasing as a result of both spontaneous VT termination and VTs occurring below the detection limit. A prospective, randomized trial (PRAETORIAN) comparing currently available transvenous and subcutaneous ICDs (i.e. without the possibility of ATP) has been initiated and is currently ongoing. ## Wearable cardioverter defibrillator Also for the first time, the new 2015 guidelines for the prevention of sudden cardiac death give recommendations for the use of the wearable cardioverter defibrillator (WCD; **Figure 2**). With a class IIa recommendation (LoE C), WCD be considered for a limited time period for patients with reduced EF who are at risk of sudden arrhythmic death, but who currently cannot receive an ICD, including patients post-lead removal for infection, patients with active myocarditis, and patients with arrhythmias in the early post-myocardial infarction phase. (35) In the absence of a randomized clinical trial, this recommendation was based mainly on large registries such as the recently published prospective registry of patients using the wearable defibrillator (WEARIT-II), which followed 2000 recipients of the WCD with a median wear time for 90 days. (48) In this registry, a total of 120 sustained ventricular tachyarrhythmias (VT/VF) were observed in 41 patients. Of these patients, 54% received appropriate WCD shocks, while only 10 patients (0.5%) received inappropriate WCD therapy. Figure 2. Wearable cardioverter defibrillator. Model of a wearable cardioverter defibrillator (images courtesy of J.S., reprinted with kind permission and patient consent). Importantly, at the end of the individual time frame of WCD use, an ICD was implanted in only 840 patients (42%), with an improvement in EF being the most frequent reason for withholding ICD implantation. Given the potential cost saved for de novo ICD implantation as well as (potentially) associated follow-up cost and cost of complications, this strategy may in addition also turn out cost-effective, but comprehensive analyses in this regard are currently lacking. ## Final thoughts In the year 2015, many interesting studies have surfaced in the field of invasive electrophysiology and cardiac devices, most of which may have (or do already have) important implications for daily clinical practice. Ongoing confirmation and expansion of these data with experience from the real world will be crucial to substantiate their efficacy and safety in the ‘real world’. Coverage of all of the exciting developments in one concise review is impossible; as such, various methods and technologies had to be omitted for the time being, including some preliminary results on the use of multi-site pacing and comparisons of point-by-point vs. single shot ablation. If the rate and quality of innovation persists, undoubtedly the year 2016 will equally be a successful one in the field of arrhythmias. ## Acknowledgments Authors’ contributions: G.H. and J.S. drafted the manuscript, and G.H., J.S., P.J. made critical revision of the manuscript for key intellectual content.

Jasna Čerkez, Habek

Coronary heart disease is the leading cause of mortality in developed countries, and hypercholesterolemia is one of the significant risk factors for the development of atherosclerosis. Attempts to reduce the incidence of cardiovascular events necessitate efficient lowering of LDL cholesterol concentrations, especially since this is a risk factor that we can significantly modify through treatment. Statins are basic drugs for the primary and secondary prevention of cardiovascular diseases, and their activity leads to a reduction in plasma levels of total and LDL cholesterol, but other numerous effects of statins beyond just the reduction of cholesterol levels contribute to atheroma stabilization and slowing down the process of atherosclerosis. It is the metabolic effect of statins that explains the possible etiology of myopathy, which is a relatively common patient complaint leading to reduction in dosage or treatment termination, which once again exposes the patient to increased risk of the development of unwanted cardiovascular events. Thus, the current knowledge on the etiology and treatment of this side effect is also addressed in this article.

Hrvoje Vražić, Sandro Brusich, Šime Manola

It is no exaggeration to say that 2015 has been a year filled with new events in the field of arrhythmology in comparison with previous years. A crucial event was certainly the presentation of the new European Society of Cardiology Guidelines on Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death (1) – a document that had been eagerly expected for a number of years since the last version was published in 2006 (2). Other news and developments are described clearly and in detail in an article published in this issue of Cardiologia Croatica (3), which includes an overview of the main developments in two areas – cardiac arrhythmias and catheter ablation, and electrostimulation devices; herein we will briefly list the news and their relevance in the national context. The previous issue of Cardiologia Croatica included an overview of recent developments in the Republic of Croatia regarding catheter ablation for atrial fibrillation (AF) that included the most recent data from 2015 and certainly provided ample reason for optimism regarding the availability and application of this modality of AF treatment, as well as other arrhythmias treated by ablation (4); these developments will not be readdressed in this overview. In parallel with large advancements in interventional treatment for AF, there has been a significant increase in the total number of arrhythmia ablations in the Republic of Croatia, placing our centers shoulder-to-shoulder alongside centers in neighboring countries such as Hungary, Austria, and Slovakia. However, it is important to stress that significant hopes have been placed in the successful treatment of ventricular arrhythmias using ablation, but so far data from various studies have not provided a clear answer to the question whether such a treatment modality has any effect on spontaneous ventricular tachycardia and ventricular fibrillation – with the aim of reducing risk from sudden cardiac death. Current and future research should give satisfactory answers to this question. (3) The main development in the prevention of stroke in non-valvular AF is that all four peroral anticoagulation drugs not in the vitamin K antagonist group (NOAC) are currently available in Europe: dabigatran, rivaroxaban, apixaban, and edoxaban. Although we still do not have adequate studies directly comparing all four drugs, it is becoming clear that ultimately each drug will likely have a clearly defined group of patients for which it will be the best choice; consequently, none of the drugs will be the absolutely appropriate choice for all patients with non-valvular AF. Furthermore, it is certainly important to note that the newest changes in health insurance provider policies in the Republic of Croatia (bearing in mind that these drugs are still available to patients for significant additional payment) will affect the prescription rates of these drugs, causing even existing patients to choose warfarin over NOAC despite the growing evidence on the superiority of NOAC drugs. In light of the increasing number of studies diverging from the classical concept of examining outcomes (that now include comparative evidence taking into account patient-oriented outcomes using data from the real world), the above is a new challenge for everyday practice. It is certainly a positive trend that an effective antidote is available for at least one drug (dabigatran) and that this is expected to soon be the case for the other drugs as well, given that bleeding is still a significant problem in the application of these drugs due to the inability of conventional methods to neutralize their effect. (3) Percutaneous implantation of an atrial occluder in the left atrial auricle is a new option in the prevention of thromboembolic complications that has become available in our country this year (5). This is an efficient method that has shown itself not to be inferior to anticoagulation therapy in various studies, and is currently indicated and approved in patients with non-valvular AF with contraindications for anticoagulation therapy. Further prospective studies are needed to verify these results and broaden the indications for occluder implantation. As with many other new interventional methods, adequate financing of this procedure has not yet been arranged with the insurance fund. There are now several new options among electric stimulation therapy devices – leadless pacemakers, subcutaneous implantable cardioverter defibrillators (S-ICD), and wearable cardioverter defibrillators. (3) The evidence indicating that these treatments are safe and effective is slowly growing, and while it is to be expected that they will emerge as the ideal choice for very specific patient groups, the main problem, especially given Croatian circumstances, remains the very high price of these devices and, not less important, that the indications for the implantation of these devices will remain very narrow due to their price. Furthermore, the fact that only single chamber leadless pacemakers are currently available, and that S-ICD does not provide electrostimulation in patients who require it, indicate the need for further research and technological improvements that will make these treatment modalities more attractive to a wider patient population. It must be noted that these two treatments have provided an alternative treatment in very narrowly defined patient populations that was surely needed, since there had previously been no treatment alternative. However, since it is not to be expected (based on currently available data) that the number of patients in these very specific populations will be large, these devices will ultimately only be available in a small number of centers in the Republic of Croatia – surely smaller than the number of centers that currently offer classical transvenous devices – pacemakers and implantable cardioverter defibrillators (ICD). Electric stimulation devices that allow telemonitoring are a somewhat distinct group. Although telemonitoring is very interesting, the fact is that while (almost) all modern devices have this option, wider application will be severely limited until adequate payment models are arranged for health institutions that provide that service, since the amount of data that telemonitoring provides presents an additional workload. Furthermore, even if these difficulties are resolved, it seems that a certain number of patients will still prefer follow-up examination and direct contact with medical personnel, as this is also very important for the patients from their own perspective (studies examining this effect are still ongoing; preliminary results were obtained in personal communication). In an additional important development, it has been finally demonstrated that testing is no longer necessary for ICD implantation, except for routine, non-complex implantations; this was corroborated by the results of the Nordic ICD Trial. (6) The trend of a significant increase in the number of electrical stimulation devices being implanted has continued in Croatia. With 635 pacemaker implantations per million inhabitants, Croatia is shoulder-to-shoulder with neighboring countries such as Hungary, Slovenia, and Slovakia (**Figure 1**). Especially noteworthy is the large increase in the number of complex and expensive devices being implanted. In 2015, 388 implantable cardioverter defibrillators were implanted in Croatia, which is 90 devices per million inhabitants and represents an almost 60% increase in comparison with the previous year (**Figure 2**). Additionally, the number of cardiac resynchronization devices being implanted has doubled, for a total of 261 implanted devices, which is 60 implantations per million inhabitants and at the European average (**Figure 3**). Despite this, Croatia is still significantly behind the European average of 120 cardiac resynchronization device implantations per million inhabitants. There are several reasons for this, primarily the complexity of the procedure and the still insufficient number of physicians capable of performing these procedures, as well as inadequate financial support for these implants. Figure 1. The number of pacemaker implantation per milion inhabitants in different europeean countries in 2013 (green bar), 2014 (red bar), and 2015 (blue bar). Figure 2. The number of implantable cardioverter defibrillator implantations per milion inhabitants in different European countries in 2014 (yellow column), 2014 (red column), and 2015 (blue column). Figure 3. The number of cardiac resynchronization therapy implantations per milion inhabitants in different European countries in 2014 (yellow column), 2014 (red column), and 2015 (blue column). In conclusion, we invite our readers to read the article by Steffel et al in its entirety and familiarize themselves with news regarding arrhythmias and electric stimulation therapy devices in 2015. (3) As the authors of the article point out, although some discoveries had to be omitted (preliminary results), it is expected that, if research and innovation continue at this pace, 2016 will be equally if not more successful regarding arrhythmia treatment. Recent developments in the Republic of Croatia certainly bring numerous challenges for the implementation of these discoveries, in which a key role will be played by the Working Group on Arrhythmias and Cardiac Pacing on of the Croatian Cardiac Society that has always worked in the best interests of the field and the patients, and will continue to do so in the future.

Oliver Gaemperli, Victoria Delgado, Gilbert Habib, Philipp A. Kaufmann, Jeroen J. Bax

## Preamble Prognostic implications of several non-invasive imaging techniques have been the focus of some landmark studies published in 2015. Non-invasive characterization of atherosclerosis processes and vulnerable plaques have been possible with advances in cardiac magnetic resonance imaging and nuclear imaging techniques. In addition, 3-dimensional echocardiography and multidetector-row computed tomography have improved our understanding of valvular heart disease. Finally, data on the clinical role of integration of non-invasive imaging techniques (fusion imaging) are accumulating and its use is expected to increase in the coming years. The current review provides a summary of selected articles on prognostic impact of current non-invasive imaging techniques and technological innovations. ## Echocardiography In 2015, the new recommendations for cardiac chamber quantification using echocardiography in adults were published providing updated normative values for all four cardiac chambers based on multiple databases compiling data from a large number of normal subjects. (1) In addition, this position document includes reference values for chamber quantification with three-dimensional (3D) echocardiography and myocardial deformation with strain imaging. These normative data permit differentiation between normal and abnormal findings. From a clinical perspective however, definition of the degree of abnormality (mild, moderate, or severe) may be more meaningful. The document acknowledges the difficulties to determine cut-off values that define the degree of abnormality and provides experience-based partition values only for left ventricular (LV) size, function and mass, and for left atrial (LA) volume. Data showing the prognostic value of LV global longitudinal strain (GLS) are accumulating. A recent meta-analysis pooling data from 16 studies (n = 5721), encompassing different cardiac diseases [heart failure, acute myocardial infarction (MI), and valvular heart disease among others], showed that the prognostic value of LV GLS exceeds that of LV ejection fraction (EF). (2) On multivariable analysis, each 1 standard deviation (SD) change in LV GS was independently associated with all-cause mortality (hazard ratio, HR 0.50; 95% CI 0.36–0.69) compared with LVEF (HR 0.81; 95% CI 0.72–0.92), indicating that the HR per each 1 SD change in LV GLS was 1.62 times greater than that of LVEF (95% CI 1.13–2.33; P = 0.009). In patients with MI, regional LV longitudinal strain may clinically be more meaningful than GLS. A subanalysis of the VALIANT (Valsartan in Acute Myocardial Infarction Trial) trial including 248 patients with LV systolic dysfunction, heart failure, or both demonstrated that regional LV longitudinal strain was significantly impaired even in segments with normal wall motion score index compared with healthy controls (−10.4 ± 5.2% vs. −20.0 ± 7.6, P 2 defined severe TR and was observed in 40% of patients. During a mean follow-up of 5.8 years, 82 patients died. An EROA ≥40 mm2 was independently associated with all-cause mortality (HR 2.95; 95% CI 1.67–5.19; P 100 (net reclassification improvement 0.62, P 400 and >1000), the incremental value of CTCA was lost again, probably through less reliable CTCA interpretation. However, conclusions in these subgroups were limited due to low sample sizes and event rates. The Coronary computed tomography angiography (CTA) vascular events in non-cardiac surgery patients cohort evaluation (VISION) study assessed the value of CTCA for predicting the risk of cardiovascular complications of non-cardiac surgery. (13) A total of 955 patients with vascular risk factors were included, of which 74 (8%) suffered a perioperative event (cardiovascular death/MI). Computed tomography coronary angiography findings provided independent prognostic information over revised cardiac risk indices with increasing HRs for non-obstructive (HR 1.51, P = 0.30), obstructive (HR 2.05, P= 0.076), and extensive obstructive (HR 3.76, P CT) continues to raise interest in 2015 through its latest publication, the Prospective LongitudinAl Trial of FFRct: Outcome and Resource IMpacts study. (17) In this trial, 584 symptomatic patients with intermediate CAD pretest probability were prospectively (but not randomly) assigned to receive either usual testing (n = 287, i.e. non-invasive testing or invasive coronary angiography, ICA) or CTCA (n = 297) with additional FFRCT where requested. Among those with intended ICA (n = 380), FFRCT resulted in a significant reduction in the number of invasive catheterizations showing no obstructive CAD (from 73 to 12%) and avoided ICA in 117 (61%) patients, while no differences were noted in the group of patients with intended non-invasive testing (**Figure 2**). Although the PLATFORM study was not randomized, it provides a contemporary snapshot of the current use of diagnostic ‘platforms’ for CAD work-up, and suggests overuse of ICA in intermediate probability patients which could be reduced by wider use of FFRCT. Interestingly, the recently published PLATFORM substudy demonstrated that the use of FFRCT was associated with $3391 costs reduction compared with ICA, whereas differences in downstream costs between FFRCT strategy and usual care (non-invasive testing) were not significant ($7047 vs. $8422, respectively). (18) However, in the non-invasive arm, patients undergoing FFRCT showed better scores on quality-of-life questionnaires compared with patients undergoing usual care, whereas in the invasive arm, there were no differences between FFRCT and ICA. Figure 2. The PLATFORM (Prospective LongitudinAl Trial of FFRct: Outcome and Resource IMpacts) study compared FFRCT as gatekeeper for invasive coronary angiography with direct angiography (right panel), as well as FFRCT vs. routine non-invasive testing as gatekeeper for invasive angiography (left panel). In the patients with planned invasive coronary angiography (right panel), the use of FFRCT as gatekeeper avoided invasive coronary angiography in 61%, and reduced the percentage of non-obstructive coronary artery lesions from 73 to 12%, whereas there were no differences in percentage of non-obstructive lesions on invasive angiography in the patients undergoing planned non-invasive testing (left panel). NI, non-invasive; ICA, invasive coronary angiography; Obs CAD, obstructive coronary artery disease; FFRCT, computation of fractional flow reserve from coronary computed tomographic angiography data. Reprinted from Douglas *et al*. (17) ## Cardiac magnetic resonance Characterization of coronary artery plaques with non-contrast T1-weighted magnetic resonance imaging (MRI) has provided novel insights into the pathophysiology of percutaneous coronary intervention (PCI)-related myocardial injury, a procedural complication which has important prognostic implications. (19) Seventy-seven patients with stable angina and significant coronary artery lesions (>70% stenosis on invasive angiography) underwent 1.5T MRI 48 h prior to PCI and coronary plaque composition was assessed with non-contrast T1-weighted MRI. High-intensity plaques (considered vulnerable plaques) were defined by a ‘coronary plaque to myocardium signal intensity’ ratio of ≥1.4. Percutaneous coronary intervention-related myocardial injury was defined as an increased high-sensitivity cardiac troponin T >5 times the 99th percentile upper reference limit. Patients with high-intensity plaques (n = 31) showed greater plaque burden, larger lipid pool, more frequently positive remodelling, ultrasound attenuation, and intracoronary thrombus on intravascular ultrasound analysis, compared with patients without high-intensity plaques (**Figure 3**). Importantly, the presence of high-intensity plaques was associated with higher frequency of PCI-related myocardial injury (58 vs. 11%, P 1-weighted cardiac magnetic resonance (CMR) imaging. (**A**) A significant stenosis of the mid-right coronary artery (on invasive angiography). On non-contrast T1-weighted CMR (upper left corner), a high-intensity plaque can be observed (plaque to myocardium intensity ratio of 3.09) which shows attenuation and lipid-rich composition on intravascular ultrasound. (**B**) A significant stenosis of the distal right coronary artery and non-high-intensity plaque on CMR. Intravascular ultrasound with virtual histology shows a fibrous plaque. Reproduced with permission from Hoshi *et al*. (19) In survivors of ST-segment elevation acute MI (STEMI), assessment of infarct size and microvascular obstruction with contrast-enhanced CMR has important prognostic value. Interestingly, non-contrast CMR-derived parameters such as native T1 mapping permit characterization of the infarct core tissue. After MI, there is an increase in water content in the ischaemic area that will result in longer native T1 times. Carrick and coworkers investigated in 300 survivors of STEMI, the correlation between native T1 time of the infarct core, infarct size and microvascular obstruction and the prognostic implications of native T1 time in terms of LV adverse remodelling (≥20% increase in end-diastolic volume at 6 months follow-up), all-cause mortality and heart failure hospitalization. (21) Patients underwent cine CMR, native T1 mapping, T2 mapping, T2* mapping and late gadolinium contrast-enhanced (LGE) sequences 2 days after index MI and at 6 months follow-up. Native T1 times were measured in the infarct zone, injured myocardium, and remote myocardium. The infarct zone region was defined as myocardium with pixel values (T1 or T2) >2 SD from the remote zone on T2-weighted CMR sequences. The hypo-intense infarct core was defined as areas within the infarct zone with pixel T1 values 99mTechnetium-labeled peripheral blood mononuclear cells (PBMC). (27) In 10 patients with known cardiovascular disease and 5 healthy controls, a markedly enhanced accumulation of PBMC was found in patients with advanced atherosclerotic lesions. This represents a novel-imaging approach to visualize leukocyte migration and PBMC accumulation to atherosclerosis in humans, potentially lending support to strategies aimed at attenuating leukocyte recruitment as a therapeutic target in patients with cardiovascular disease. Van Wik et al. demonstrated that lipoprotein apheresis leads to a marked reduction of arterial wall inflammation in patients with familial hypercholesterolaemia (FH) characterized by severely elevated plasma low-density lipoprotein cholesterol levels. (28) 18-F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) was used to assess the target-to-background ratio (TBR) of FDG uptake within the arterial wall in 24 patients with known FH and in 14 normolipidemic controls. A second PET scan was acquired after 3 days in 12 patients in whom lipoprotein apheresis was performed and demonstrated a significant reduction of TBR compared with the baseline scan (2.05 ± 0.31 vs. 1.91 ± 0.33; P 5% ischaemic myocardium, while 19.6% of patients with TIMI scores ≥3 had >5%. Furthermore, short-term adverse events were rare at 30 days with only 0.1% mortality and 0.1% of patients undergoing revascularization for acute MI. These findings suggest that SPECT-MPI before discharge after two negative troponins should be helpful in patients with TIMI scores ≥3. In the field of acute MI, it has been shown that FDG-PET may be able to detect inflammation in the acutely infarcted myocardium, if information on late contrast enhancement (scar tissue) from concomitant CMR or CT is integrated. Wollenweber et al. have translated these concepts into 15 patients early after MI by performing PET and CMR within 7 days of first MI. (32) All patients underwent heparin pre-treatment to suppress FDG uptake in remote myocardium. The metabolic rate of glucose was significantly increased in infarcted vs. remote myocardium (2.0 vs. 0.4 mg/min per 100 mL; P = 0.0001). Regionally, FDG score was highest in segments with LGE vs. oedema only and to remote myocardium (2.0 vs. 1.8 vs. 0.4; P 18F-FDG-PET-CT in the diagnosis of cardiac implantable electronic device generator pocket infection. (37) To this end, 46 patients with suspected generator pocket infection and 40 without any infection underwent PET imaging, and FDG activity in the region of the generator pocket (**Figure 4**) was expressed as a semi-quantitative ratio (SQR) defined as the maximum count rate around the generator divided by the count rate between normal right and left lung parenchyma. Patients with suspected generator pocket infection that required generator extraction had significantly higher FDG activity compared with those that did not, and with controls (SQR 4.80 vs. 1.40 vs. 1.10, P 2.0, yielding a very high sensitivity and specificity of 97 and 98%, respectively. These results demonstrate a high diagnostic performance and highlight the potential utility of FDG-PET for the detection of early cardiac implantable electronic device generator pocket infection. Figure 4. **PET-CT in suspected device pocket infection.** Example of a positive 18F-FDG PET/CT scan in a patient with pain at the generator pocket site. (**A**) Increased FDG uptake is seen in the region of the left pre-pectoral pocket on the coronal views (yellow arrows). (**B**) In the sagittal plane, increased FDG uptake can be seen on the muscular aspect of the pre-pectoral generator (yellow arrows) and along the proximal portion of the leads (red arrows). (**C**) Increased FDG uptake visualized on the muscular aspect of the generator pocket (yellow arrows). Reproduced with permission from Ahmed *et al.* (37) Fusion imaging of CT and echocardiography in heart valve disease was reported by Kamperidis et al. (38) The authors addressed the topic of low gradient, but severe aortic stenosis in patients with preserved LVEF; this ‘mismatch’ between the low gradient over the valve (indicating no stenosis) but the small valve area (indicating severe stenosis) may be related to the assumption of a circular shape of the LV outflow tract with 2D echocardiography (which in fact often may have an elliptical shape). Since this parameter contributes significantly to the calculation of the aortic valve area (**Figure 5**), this may contribute to errors in classification of severity of aortic stenosis. The LV outflow tract may be more accurately detected from CT (anatomical) imaging by direct planimetry, and fusion of the CT-derived LV outflow tract area with the echo Doppler data may result in significant reclassification of inconsistently graded severe aortic stenosis. In 191 patients with severe aortic valve stenosis (according to the aortic valve area indexed for body surface area being 2/m2) and preserved LVEF (≥50%), this fusion approach was applied and reclassified 52% of patients with low gradient but severe aortic stenosis and preserved LVEF into moderate aortic stenosis (**Figure 5**). Figure 5. **Quantification of aortic valve area using fusion imaging in aortic stenosis.** Current clinical practice, 2-dimensional and Doppler echocardiography are used to calculate the aortic valve area (**panels A**, **C**, **D** and **E**): the LV outflow tract (LVOT) diameter is measured from the parasternal long-axis view and the flow of the LVOT and gradient of aortic valve are measured with pulsed and continuous wave Doppler. By introducing the true cross-sectional area of the LVOT measured with MDCT (**panel B**) into the Bernoulli equation (**panel E**), the aortic valve area fusion is calculated. In this particular example, an aortic valve area index of 0.58 cm2/m2 calculated with echocardiography (Echo AVAi) indicates severe aortic stenosis whereas by using the MDCT cross-sectional area of the LVOT, the aortic valve area index (Fusion AVAi) increases to 0.79 cm2/m2 indicating moderate aortic stenosis. Reproduced with permission from Kamperidis *et al.* (38) ## Acknowledgments Authors’ contributions: O.G., V.D., G.H., P.A.K., J.J.B. handled funding and supervision. O.G., V.D., G.H., P.A.K., J.J.B. acquired the data. O.G., V.D., G.H., P.A.K., J.J.B. conceived and designed the research. O.G., V.D., G.H., P.A.K., J. J.B. drafted the manuscript. O.G., V.D., G.H., P.A.K., J.J.B.: made critical revision of the manuscript for key intellectual content.

Michel Komajda, Frank Ruschitzka

## Preamble A number of studies conducted both in heart failure with reduced and with preserved ejection fraction were presented and published in 2015. Most of them were neutral and did not demonstrate any benefit on outcomes of the drugs/procedures tested. Nevertheless, they bring important new information on the search for new drugs or procedures in the management of heart failure. Sleep-disordered breathing is common in patients with heart failure and reduced ejection fraction. Two different types of abnormality have been described: obstructive sleep apnoea and central sleep apnoea. The prevalence of central sleep apnoea, which may manifest as Cheynes–Stokes respiration, increases with the severity of heart failure and this condition is associated with poor outcomes. The purpose of SERVE-HF was to assess the effects of adaptive servo-ventilation (ASV) that delivers servo-controlled inspiratory pressure support on top of expiratory positive airway pressure in patients with moderate to severe heart failure and an ejection of <45% who had predominantly central sleep apnoea. ( 1 ) In this trial, 1325 patients were enrolled and randomized to ASV (666) or to control therapy (659). Patients were predominantly in New York Heart Association Class III and were well treated by recommended therapies. The incidence of the primary endpoint made of the composite of death of any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for heart failure did not differ significantly between the two groups (HR = 1.13; 95% CI, 0.97–1.31; P = 0.10). The surprise was the observation of a significant increase of all-cause mortality (HR = 1.28; 95% CI, 1.06–1.55; P = 0.01) and of cardiovascular mortality (HR = 1.34; 95% CI, 1.09–1.65; P = 0.006) in the ASV group. The findings of SERVE-HF contrast with evidence from earlier smaller studies that suggested an improvement in left ventricular function, quality of life, and mortality. One potential explanation for the increase in cardiovascular mortality is that central sleep apnoea may be a compensatory mechanism, and therefore reducing this adaptive respiratory pattern by ASV may be detrimental. The other explanation put forward by Cowie et al. is that the application of positive airway pressure may impair cardiac function, in particular, in patients with low pulmonary capillary wedge pressure. The timing of death and whether the fatal events occurred while patients were under ASV will be therefore important to determine the potential mechanism of harm. One important implication of the negative results of SERVE-HF is that this procedure should not be recommended anymore for patients with heart failure and reduced ejection fraction and central sleep apnoea and stopped in those patients currently treated by this procedure. This, however, does not apply to obstructive sleep apnoea. Whether other techniques diminishing Cheynes–Stokes respiration such as phrenic nerve stimulation are beneficial or harmful remains an open question until the results of the ongoing trial testing phrenic nerve stimulation are available. ## Glucose-lowering agents and risk of heart failure: new and reassuring results Dipeptidyl peptidase 4 inhibitors (DPP4 inhibitors) have been used for several years in the management of type 2 diabetes mellitus. In 2013, the publication of SAVOR-TIMI 53 raised concern on the safety of this class regarding the occurrence of heart failure events. ( 2 ) This large outcome trial including patients with diabetes mellitus and a previous cardiovascular event or at high cardiovascular risk showed that the overall cardiovascular safety of saxagliptin was good, except a 27% increase in the risk of the first event worsening heart failure hospitalization. There was no biological plausible explanation for this observation. Nevertheless, this raised concern on potential harm all the more as another trial EXAMINE conducted in patients with diabetes mellitus and presenting with an acute coronary syndrome suggested a non-significant signal for increased risk of heart failure with another DPP4 inhibitor, alogliptin ( Table 1 ). ( 3 ) The publication of TECOS, another mega trial including 14 671 patients was therefore long awaited. ( 4 ) Patients included had type 2 diabetes mellitus, were 50 years of age or more, and had an established cardiovascular disease and a baseline HbA1C of 6.5–8%. They were randomized to either the DPP4 inhibitor sitagliptin or to control treatment. After 3 years of follow-up, no difference was observed in the occurrence of the composite endpoint of cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina (HR = 0.98; 95% CI, 0.88–1.09; P < 0.001 for non-inferiority). Importantly, the incidence of heart failure was similar in the two arms with a hazard ratio of 1.00 (95% CI, 0.83–1.20; P = 0.98). The explanation for the differential effect of sitagliptin and of saxagliptin on heart failure events remain uncertain: differences in populations enrolled in the two trials are unlikely to play a role since the clinical profile of the patients were rather similar. Differences in affinity of the two inhibitors to the various substrates of DPP4 are a potential explanation. Finally, the play of chance cannot be excluded in this very large trial. Whatever the underlying explanation, the results of this large outcome trial in type 2 diabetes mellitus rule out a class effect of DPP4 inhibitors on heart failure events and are therefore reassuring regarding the safety of sitagliptin in patients with pre-existing heart failure or at high risk of heart failure. Another trial, EMPA-REG OUTCOME, tested two doses of an inhibitor of sodium-glucose co-transporter 2, empagliflozin vs. placebo in 7020 patients with type 2 diabetes at high cardiovascular risk. ( 5 ) After a median observation time of 3.1 years, the primary outcome made of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke was significantly reduced by 14% in the pooled empagliflozin group. Interestingly, hospitalizations for heart failure and the composite of hospitalization for heart failure or death from cardiovascular causes, two secondary endpoints, were also significantly reduced by 35% (P = 0.002) and 34% (P < 0.01), respectively, suggesting that this new anti-diabetic agent added to standard therapy is not only safe but also beneficial for the prevention of heart failure hospitalizations in type 2 diabetes mellitus. ## Management of heart failure with preserved ejection fraction remains a clinical dilemma The medical management of heart failure with preserved ejection fraction (HFpEF) remains challenging, and no drug has demonstrated a clear benefit on morbidity and mortality in this population ( Figure 1 ). Kaplan Meier curve for the primary composite endpoint (all cause death, non fatal myocardial infarction, non fatal stroke and hospitalization for worsening heart failure) in the overall SUPPORT population. ( 6 ) The SUPPORT trial examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure treated with angiotensin-converting enzyme (ACE) inhibitors, beta blockers, or both. In this prospective randomized open-label study, 1147 patients were enrolled. ( 6 ) Mean ejection fraction was 54%. During a median follow-up of 4.4 years, there was no statistical difference in the occurrence of the primary outcome made of all-cause death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure between the two groups (HR = 1.18; 95% CI, 0.96–1.46; P = 0.11), whereas a significant increase in worsening renal function was observed. The addition of olmesartan to patients treated by the combination of ACE inhibitors and beta blockers was, however, associated with a significant increase in the occurrence of the primary endpoint (HR = 1.47; 95% CI, 1.11–1.95; P = 0.006) all-cause death and renal dysfunction. These findings lead to the conclusion that combination therapy of ACE inhibitors, angiotensin receptor antagonists, and beta blockers is not recommended in HFpEF since it is associated with increased cardiovascular risk and increased risk of renal dysfunction. In 2013, the RELAX trial conducted in 216 elderly patients with HFpEF showed the absence of effect of the phosphodiesterase type 5 sildenafil on maximal exercise capacity, 6 min walking distance, clinical status, quality of life, left ventricular remodelling or diastolic function after 24 weeks of follow-up. ( 7 ) These results were in contrast with a previous single centre study that showed benefit on invasively measured haemodynamics, echocardiographic variables, and quality of life in patients with pulmonary hypertension related to HFpEF. ( 8 ) Another just recently published single centre study by Hoendermis et al. published in the European Heart Journal, however, casts further doubt on the use of sildenafil in HFpEF patients with associated pulmonary hypertension. ( 9 ) Fifty-two patients with HFpEF and predominantly isolated post-capillary pulmonary hypertension were randomized to sildenafil or placebo. After 24 weeks, sildenafil did not reduce pulmonary artery pressures and did not improve other invasive haemodynamic or clinical parameters, thus confirming the findings of the aforementioned RELAX study that HFpEF patients with associated pulmonary hypertension do not benefit from treatment with this drug. The current paradigm of HFpEF is that an abnormal nitric oxide bioavailability results in decreased cyclic guanylate monophosphate (cGMP) in the myocytes. One potential explanation of the lack of benefit from sildenafil is therefore that the defect is more a decrease in the production of cGMP than a problem of increased degradation that is inhibited by PDE5 inhibitors such as sildenafil. It will therefore be interesting to see the results of studies using a soluble guanylate cyclase (sGC) stimulator, such as riociguat, which is currently under evaluation. The results of the SOCRATES-REDUCED study, however, highlight the challenges in moving the concept of modulating sGC and thereby addressing the relative cGMP deficit forward. ( 10 ) In SOCRATES-REDUCED, a phase 2 dose-finding study in patients with heart failure with reduced ejection fraction and worsening chronic HF, the oral sGC stimulator vericiguat did not meet its primary endpoint of reducing N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 12 weeks when all doses were combined, but was well tolerated. While subgroup analysis did suggest efficacy and safety in its 10 mg subgroup, further studies are needed to determine the potential role of this class of drugs for patients with worsening chronic HF. The current paradigm that increasing nitric oxide bioavailability may provide meaningful net clinical benefit was further questioned by the just recently published results of the multicentre, double-blind, placebo-controlled Nitrate’s Effect on Activity, Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF) trial. ( 11 ) In this National Heart, Lung, and Blood Institute-sponsored trial, 110 patients with heart failure and preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. Intriguingly, at every tested nitrate dose patients with HFpEF had lower levels of activity and did not have better quality of life or submaximal exercise capacity than patients taking placebo. Of note, no interaction between the subgroups, including by age, sex, heart failure aetiology, natriuretic peptide levels, or blood pressure, was observed. It is intriguing to speculate whether other Nitric Oxyde donors than isosorbide mononitrate, such as inorganic nitrite or nitrate (which have been shown to increase nitric oxide bioavailability during exercise), might have yielded more beneficial results under the conditions of the study. This notwithstanding, the somewhat counterintuitive findings of NEAT-HFpEF once again highlight the distinct pathophysiologic differences between HFpEF vs. heart failure with reduced ejection fraction (HFrEF). Indeed, since long-acting nitrates improve symptoms in HFrEF, the results of NEAT-HFpEF therefore suggest that the potential haemodynamic benefits of nitrates are less likely to come into play under the conditions of increased ventricular systolic and vascular stiffness, autonomic dysfunction, chronotropic incompetence, and altered baroreflex sensitivity as they are common in in patients with HFpEF. ## Angioedema and angiotensin-converting enzyme inhibitors Angioedema is a rare but potentially life-threatening side effects of ACE inhibitors and there is no approved treatment. It is generally related to the inhibition of the degradation of bradykinin, therefore increasing the activity of this peptide. A phase 2 study compared the effects of subcutaneous icatiband, a selective bradykinin B2 receptor antagonist to intravenous prednisolone plus an antihistaminic agent, clemastine, in 27 patients who had ACE-induced angioedema of the upper aerodigestive tract. ( 12 ) Icatiband induced a complete resolution of symptoms in 8 h on average compared with 27 h with standard therapy. These results suggest that the use of a bradykinin receptor antagonist allows complete resolution of ACE inhibitors induced angioedema faster than with the standard therapy. ## Alcohol consumption and risk of heart failure Heavy alcohol consumption is associated with cardiac dysfunction and eventual alcoholic cardiomyopathy ( Figure 2 ). However, the relationship between moderate alcohol intake and risk of heart failure is controversial. Self-reported alcohol consumption was assessed in 14 629 participants of the Atherosclerosis Risk in Communities (ARIC) study without prevalent heart failure at baseline. ( 13 ) During an average follow-up of 24 years, incident heart failure occurred in 1271 men and 1237 women. Men consuming up to 7 drinks a week (one drink = 14 g of alcohol) had a reduced risk of heart failure relative to abstainers (HR = 0.80; 95% CI, 0.68–0.94; P = 0.006). This ‘protective’ effect was less robust in women (HR = 0.84; 95% CI, 0.71–1.00; P = 0.05). In the heavy drinking categories, the risk of heart failure was not different from abstainers either in women or in men. These results suggest therefore that modest alcohol consumption may be associated with a lower risk of heart failure. Relative risk of incident heart failure as a function of alcohol intake at baseline by sex. The 95% confidence intervals are indicated by the dash lines. Models are adjusted for age, diabetes, hypertension, coronary artery disease, body mass index, total cholesterol physical activity, education level, smoking status and incident myocardial infarction as time-varying covariate. ( 13 ) ## Gene therapy in chronic heart failure: disappointment Cardiac regeneration using gene transfer in the myocardium is a novel approach to the treatment of heart failure. Abnormal calcium cycling in the cardiomyocyctes is a hall mark of moderate to severe heart failure, and one key element is deficient expression and activity of sarcoplasmic reticulum Ca 2+ ATPase type 2a (SERCA2a), the molecule that pumps calcium from the cytosol to the intracellular stores, i.e. the sarcoplasmic reticulum. Preclinical studies have shown that the increased expression of SERCA2a in cardiomyocytes normalizes calcium cycling and that SERCA2a gene transfer in large animal models can reverse cardiac dysfunction. CUPID 2 enrolled 250 patients with severe heart failure who received intracoronary either the transgene (123) or placebo (127). ( 14 ) The primary endpoint was time to recurrent heart failure-related hospitalizations and ambulatory worsening heart failure in presence of terminal events, including all-cause death or transplant. There was no difference between the active and the conventional arms for the primary endpoint (HR = 0.93; 95% CI, 0.53–1.65; P = 0.81) or for any of the secondary endpoints. No safety issue was raised during the trial. These disappointing results have no clear explanation and are in particular in contradiction with a previous smaller trial (CUPID), which suggested that intracoronary injection of SERCA2a transgene was associated with a dose-dependent beneficial effect on ventricular function, patient well-being, and biomarkers at 6 and 12 months and that outcomes were improved at 3 years in the patients treated with the high dose. Potential explanations for failure include dose of the transgene, mode of injection, durability of the effect, type of vector (here an adenovirus) and promoter (cytomegalovirus), or the target. It is hoped that these negative results will not freeze research in this area and that different approaches including more cardio specific promoters, mode of injection, or vectors will be tested to better assess the potential role of gene transfer for cardiac regeneration. ## Treatment of Chagas’ cardiomyopathy by benznidazole Chagas’disease is a common parasitic disease in Latin America and is responsible for the most common form of non-ischaemic cardiomyopathy in this area. Chagas’cardiomyopathy develops in 25% of patients infected by Trypanosoma cruzi 20–30 years after the acute infection. The role of trypanocidal therapy at the stage of Chagas’cardiomyopathy is unproven .The Benznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial evaluated the effects on outcomes of oral benznidazole, a trypanocidal agent vs. placebo in 2854 patients who had evidence of Chagas’cardiomyopathy. ( 15 ) The drug was administered for 40–80 days and patients were followed for a mean of 5.4 years. The primary outcome was time to death, resuscitated ventricular tachycardia, insertion of a pacemaker or implantable cardioverter-defibrillator, cardiac transplantation, new heart failure, stroke, or other thromboembolic event. Although trypanocidal therapy with benznidazole significantly reduced serum parasite detection by polymerase chain reaction, there was no significant effect on the primary outcome (HR = 0.93; 95% CI, 0.81–1.07; P = 0.31). Potential explanations for these negative results include genetic variations of T. cruzi, insufficient period of observation, and late treatment at a stage of advanced cardiac disease.

Duška Glavaš

## Introduction A number of studies on heart failure (HF) have been published in recent years, most of these revealing no significant discoveries in terms of diagnosis or therapy. However, some interesting conclusions have been reached. In addition, new Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC) were launched at the European Heart Failure Congress, held on May 21, 2016 in Florence, Italy (1, 2). ## ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure The new Guidelines bring the following major changes relative to the previous 2012 version: 1. A new term has been introduced for patients with HF and left ventricular ejection fraction (LVEF) of 40%-49%: “HF with medium (mildly reduced) EF (HFmrEF)”. Identification of this specific subgroup is believed to stimulate research focused on determining the characteristics, pathophysiology and management of these patients. 2. Distinct recommendations have been issued for diagnosing HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF) and preserved EF (HFpEF). 3. A new algorithm for diagnosing HF in non-acute states has been recommended; it is based on evaluating the likelihood of HF. 4. There are recommendations with the aim to prevent or delay development of symptomatic HF, or to prevent mortality before the onset of symptoms. 5. Indications have been established for administration of a novel combined drug, sacubitril/valsartan, the first one in the class of angiotensin receptor/neprilysin inhibitors (ARNIs). 6. Indications for cardiac resynchronization therapy (CRT) have been changed. 7. The concept of early initiation of appropriate therapy is recommended, i.e. the diagnosis and therapy of acute HF should be performed in parallel – the ‘time to therapy’ approach (adopted in the management of acute coronary syndrome for years now). 8. A new algorithm for the diagnosis and treatment of acute HF, based on the presence or absence of congestion or hypoperfusion, has been issued. ## Criteria for heart failure subtypes The criteria for heart failure subtypes are as follows: - **HFrEF**: LVEF <40%, with symptoms and signs of HF; - **HFmEF**: LVEF 40%-49%, with symptoms and signs of HF, elevated natriuretic peptide levels, and at least one of the additional criteria: relevant structural heart disease or diastolic dysfunction; and - **HFpEF**: LVEF ≥50%, with symptoms and signs of HF, elevated natriuretic peptide levels, and at least one of the additional criteria: relevant structural heart disease or diastolic dysfunction. ## The new algorithm for diagnosing heart failure in non-acute states In patients presenting with symptoms or signs of HF for the first time and in non-acute form, it should first be established at the family physician office or hospital polyclinic whether it is a case of HF. The diagnosis is based on patient history (coronary heart disease, arterial hypertension, cardiotoxic drugs, irradiation, use of diuretics, etc.), symptoms (moist rales, orthopnea, paroxysmal nocturnal dyspnea, heart murmur), physical finding (bilateral edema, elevated jugular venous pressure, etc.) and 12-lead electrocardiogram (the possible presence of abnormalities). If all these elements prove normal, the diagnosis of HF is not likely and other causes should be looked for. Finding at least one abnormality requires natriuretic peptide analysis. In case of elevated natriuretic peptide levels (or if natriuretic peptide analysis is not available), echocardiography should be performed. Positive values of the brain natriuretic peptides (BNP) are as follows: BNP ≥35/pg/mL and NT-proBNP ≥125/pg/mL. Upon making the diagnosis, the etiology should be determined and appropriate treatment introduced. ## Recommendations aiming to prevent or delay development of symptomatic heart failure or to prevent mortality before the onset of symptoms There are data indicating that the onset of HF can be delayed or prevented by interventions for correction of risk factors or therapy for asymptomatic systolic left ventricular dysfunction. For example, in individuals older than 40 with known cardiovascular risks, analysis of natriuretic peptides can prove helpful. It is of paramount importance to treat arterial hypertension as one of the best known risk factors for HF (SPRINT study). Recent data show that empagliflozin, a sodium-glucose cotransporter 2 inhibitor, improves prognosis of patients with diabetes mellitus type 2 (including reduced mortality and hospitalization for heart failure). Smoking cessation can also have favorable effects. The individuals using moderate amounts of alcoholic drinks are at a lower risk of de novo HF occurrence. Moderate physical activity is also useful. Glycemic impairment and overweight should also be treated properly. Statins reduce the risk of some cardiovascular events and mortality, thus potentially preventing or delaying the occurrence of HF indirectly. In patients with coronary heart disease (CHD), the use of angiotensin-converting enzyme (ACE) inhibitors can prevent or delay the occurrence of HF, thus reducing cardiovascular as well as total mortality. In acute myocardial infarction with ST-segment elevation (STEMI), primary coronary intervention (PCI) can prevent or delay the occurrence of HF by reducing the infarct zone. The administration of ACE inhibitors, beta-blockers and mineralocorticoid receptor antagonists (MRA) immediately after myocardial infarction, along with statins, can also prove useful. In asymptomatic patients with chronic reduction of the left ventricular systolic function (irrespective of etiology), using ACE inhibitors can reduce the risk of hospital treatment for HF. The use of implantable cardioverter defibrillators (ICD) is recommended in patients with: - asymptomatic left ventricular systolic dysfunction (LVEF ≤30%) of ischemic etiology, if at least 40 days have elapsed since acute myocardial infarction; and - asymptomatic non-ischemic dilatative cardiomyopathy (LVEF ≤30%) receiving optimal medicamentous therapy. ## A new drug for heart failure treatment with good results Neurohormonal antagonists (ACE inhibitors, MRA and beta-blockers) have been demonstrated to improve survival in patients with HFrEF and are recommended for treatment of all patients with HFrEF unless there is a contraindication for their use or patient intolerance. A new combined drug (LCZ696) consists of the angiotensin receptor blocker (ARB) valsartan and the neprilysin (NEP) inhibitor sacubitril. Results of a recent study with strict inclusion/exclusion criteria showed it to be superior to ACE inhibitors (enalapril) in reducing the risk of death and hospitalization due to HF. Therefore, sacubitril/valsartan has been recommended as a substitute for ACE inhibitor in outpatients with HFrEF having remained symptomatic despite optimal therapy and meeting the study criteria. Drugs from the group of angiotensin receptor blockers failed to demonstrate significant reduction of mortality in patients with HFrEF, therefore their use should be limited to patients not tolerating ACE inhibitors or those taking ACE inhibitors but not tolerating MRA. Ivabradine decreases elevated heart rate, which is frequently recorded in HFrEF patients, and has been associated with improved survival in HF patients; it is therefore recommended to include it in patient therapy, in line with the respective criteria. The above mentioned drugs are administered together with diuretics in patients with symptoms and/or signs of HF. ## Modified indications for cardiac resynchronization therapy Cardiac resynchronization therapy (CRT) improves cardiac parameters in selected patients diagnosed with HF, thus reducing the symptoms, overall morbidity and mortality, while upgrading the patient general condition. The following are recommendations for CRT in HF patients: - CRT is recommended in symptomatic patients with HF in sinus rhythm, with QRS complex width ≥150 msec, QRS showing left bundle branch block (LBBB) morphology, and LVEF ≤35% while on optimal therapy, in order to reduce the symptoms, morbidity and mortality (I A according to Guidelines); - CRT should be considered in symptomatic patients in sinus rhythm, with QRS width ≥150 msec, QRS not showing LBBB morphology, and LVEF ≤35% while on optimal therapy, in order to reduce the symptoms, morbidity and mortality (IIa B); - CRT is recommended in symptomatic patients in sinus rhythm, with QRS width 130-149 msec, QRS showing LBBB morphology, and LVEF ≤35% despite therapy, in order to reduce the symptoms, morbidity and mortality (I B); - CRT should be considered in symptomatic patients in sinus rhythm, with QRS width 130-149 msec, QRS not showing LBBB morphology, and LVEF ≤35% despite optimal medicamentous therapy, in order to reduce the symptoms, morbidity and mortality (IIb B); - CRT rather than right ventricular stimulation is recommended in patients with HFrEF (irrespective of NYHA class) that have an indication for ventricular stimulation and high grade AV block, in order to reduce morbidity. This also includes patients with atrial fibrillation (I A); - CRT should be considered in patients with LVEF ≤35% in NYHA class III-IV despite optimal medicamentous therapy, in order to reduce the symptoms, morbidity and mortality, if there is atrial fibrillation and QRS width ≥130 msec (IIa B); - CRT can be considered in patients diagnosed with HFrEF having already received conventional pacemaker or ICD but have experienced HF exacerbation despite optimal therapy, along with high right ventricular stimulation. This does not apply to patients in stable stage HF (IIb B); - CRT is contraindicated in patients with QRS duration <130 msec (III A); and - implantation of defibrillator with CRT (CRT-D) should be considered in patients with QRS width <130 msec. ## The concept of early initiation of appropriate therapy is recommended The diagnosis and therapy of acute HF should proceed in parallel, implying the ‘time to therapy is crucial’ principle. Such an approach to treatment has been successfully employed in the management of acute coronary syndrome (ACS) for quite a long time now. It is of utmost importance to timely diagnose and treat particular comorbidities such as CHD, arterial hypertension, valvular disease, arrhythmias (atrial fibrillation and ventricular rhythm abnormalities in particular), diabetes, pulmonary diseases (COPD, asthma), central nervous system diseases (depression, stroke, autonomic dysfunction, etc.), sleep disorders, anemia, renal insufficiency, electrolyte imbalance (hypokalemia and hyperkalemia in particular), dyslipidemia, cachexia/obesity, uric diathesis, arthritis, and erectile dysfunction. ## The New Algorithm for Diagnosis and Treatment of Acute Heart Failure The new algorithm for diagnosis and treatment of acute heart failure (AHF), based on the presence or absence of the signs of congestion or hypoperfusion, has been issued. The diagnosis of AHF implies abrupt occurrence or exacerbation of the symptoms and/or signs of HF. It is a life threatening state that requires urgent diagnosis, treatment and hospitalization. AHF occurs de novo or as chronic HF exacerbation, and can be caused by primary cardiac dysfunction or precipitating factors. The most common causes include myocardial dysfunction (ischemia, inflammation, toxic agents), acute valve insufficiency, and pericardial tamponade. Chronic HF exacerbation can occur independently, but it is most frequently associated with precipitating factors such as infection, uncontrolled hypertension, rhythm abnormalities, and inappropriate medication and food intake. The classification of AHF relies on the patient clinical examination, which should reveal the symptoms and signs of congestion (‘moist’/’dry’ state; yes/no) and hypoperfusion (‘cold’/’warm’ state; yes/no). Using this combination, four groups are distinguished: - warm and moist (good perfusion and congestion); - cold and moist (hypoperfusion and congestion); - cold and dry (hypoperfusion without congestion); and - warm and dry (good perfusion, no congestion). This classification helps determine therapy in the initial stage and may provide useful prognostic information. Urgent diagnosis and early treatment initiation are of utmost importance in AHF patients. ## Selected Reading from Recent Studies on Heart Failure ## Adaptive servo-ventilation (ASV) in heart failure and central sleep apnea Sleep apnea is a frequent comorbidity in HF patients with decreased systolic left ventricular function. Two types of the disorder have been described, i.e. obstructive sleep apnea and central sleep apnea. The prevalence of central sleep apnea that usually manifests as Cheyne-Stokes respiration increases with the severity of heart failure. This form of the disease is associated with poorer prognosis. The aim of the SERVE-HF study was to assess the effect of adaptive servo-ventilation (ASV), which provides the servo-controlled inspiratory pressure support based on expiratory positive airway pressure in patients with moderate to severe form of HF and LVEF ≤45% that predominantly suffer from central sleep apnea. The study included 1325 patients in NYHA class III HF on appropriate standard therapy, randomized to ASV or control therapy. Surprisingly, a significant increase in total and cardiovascular mortality was recorded in the ASV group. Results of the SERVE-HF study were opposite to the results of some earlier small studies. One of the potential explanations of this increase in cardiovascular mortality in central sleep apnea may imply the compensatory mechanism, as reduction of this adaptive respiratory mechanism may be detrimental in combination with ASV. Another explanation is that the use of positive pressure upon the respiratory system may modify cardiac function, in particular in patients with decreased pulmonary capillary pressure. An important implication of the negative result of the SERVE-HF study is that this procedure should not be advised in patients with HF, reduced systolic left ventricular function and central sleep apnea, and that it should be discontinued in such patients currently using it. However, the procedure can be used in patients with obstructive sleep apnea. ## Hypoglycemic agents and heart failure The EMPA-REG OUTCOME study tested two doses of empagliflozin, a sodium-glucose cotransporter 2 inhibitor, in comparison with placebo in 7020 patients with diabetes mellitus type 2 and high cardiovascular risk. Following 3.1-year observation, the primary endpoint (death from cardiovascular events, nonfatal myocardial infarction or nonfatal stroke) was significantly reduced by 14% in the empagliflozin group. Interestingly, hospitalization for HF and composite outcome consisting of hospitalization for HF or death from cardiovascular events were also significantly reduced. It is concluded that this novel antidiabetic agent administered along with standard therapy is not only safe for use in HF patients but is also beneficial for prevention of hospitalization for HF in patients with diabetes mellitus type 2. ## Alcohol and risk of heart failure Excessive alcohol consumption leads to cardiac dysfunction and occasionally to alcoholic cardiomyopathy. However, the association of moderate alcohol consumption and the risk of HF is a controversial issue. The ARIC study analyzed data obtained in 14,629 subjects (without HF diagnosis at study entry) having made records of their use of alcoholic drinks. During a mean 24-year follow up, HF developed in 1271 male and 1237 female subjects. The men that reported taking up to 7 drinks *per* week (1 drink = 14 g alcohol) had a lower risk of HF development as compared with alcohol abstainers (HR=0.80; 95% CI 0.68-0.94; p=0.006). This ‘protective’ effect was less pronounced in women (HR=0.84; 95% CI 0.71-1.00; p=0.05). In subjects taking alcoholic drinks in excess, the risk of HF did not differ from that recorded in abstainers, irrespective of sex. These results suggest that moderate intake of alcoholic drinks may be associated with a lower risk of HF development.

Luka Zaputović, Željka Rubeša Miculinić, Sanja Matijević Rončević, David Gobić, Teodora Zaninović Jurjević

Croatia belongs to a group of European countries with a high cardiovascular risk and growing prevalence of diabetes mellitus type 2 (DMT2). According to data of the National Diabetes Registry (CroDiab registry), a total of 254,296 individuals aged >18 suffering from diabetes were registered in 2014 (7.9%). Along with hypertension and hyperlipidemia, DMT2 is one of the leading cardiovascular risk factors. Prompted by adverse cardiovascular effects of rosiglitazone, demonstrated in the RECORD study and subsequent meta-analyses, the main drug regulatory agencies require clinical trials of the effect on cardiovascular outcomes and safety evidence for all antidiabetic drugs. On assessing the effects of antidiabetic drugs on cardiovascular risk, the two-sided confidence interval upper borderline value of 95% (95% CI) is highly relevant for the estimated risk ratio. Additional safety testing is required for all antidiabetic drugs with the risk ratio upper limit ≥1.3. Cardiovascular safety of oral antidiabetic drugs is of special importance in patients with heart failure. Considering the great number of antidiabetic drugs on the market, decision on optimal DMT2 therapy should be made in dependence of specific characteristics of each individual patient and cardiovascular risk assessment.

M. John Chapman, Stefan Blankenberg, Ulf Landmesser

## Preamble Improved prevention of cardiovascular disease (CVD) is of critical importance, as coronary heart disease (CHD) still represents the most common cause of death worldwide, engendering inestimable socioeconomic cost. The year 2015 has witnessed dramatic progress in CVD prevention on several fronts. Notably, this includes (**i**) event reduction in high-risk patients in general practice following introduction of a comprehensive strategy to attenuate modifiable risk factors, including lifestyle and dietary habits; (**ii**) the study of hybrid imaging to detect subclinical atherosclerosis, with potential improvement in risk prediction/ management; (**iii**) the clinical demonstration, that culprit plaque rupture was observed in only 50 – 77% of patients with acute coronary syndromes; (**iv**) the emergence of ‘omics’ technologies to identify new causal biofactors; (**v**) the validation in clinical trials of the efficacy of monoclonal antibodies targeted to proprotein convertase subtilisin/kexin type 9 (PCSK9) in markedly reducing levels of low-density lipoprotein cholesterol (LDL-C) across a spectrum of patients at high risk of premature CVD, with preliminary findings strongly suggestive of reduction in cardiovascular events; (**vi**) significant reduction of cardiovascular and all-cause mortality in diabetic patients in the EMPA-REG OUTCOME trial with the anti-hyperglycaemic agent, empagliflozin, a selective sodium-glucose co-transporter-2 (SGLAT-2) inhibitor; (**vii**) new pharmacotherapeutic strategies for superior control of hypertension emanating from the PATHWAY-2 and PATHWAY-3 clinical trials involving spironoloactone add-on therapy in resistant hypertension, and amiloride plus hydrochlorothiazide in hypertensive patients requiring a diuretic, respectively; and finally (**viii**) a reduced mortality associated with a lower blood pressure target of 120 mmHg in patients at high cardiovascular risk in the SPRINT trial. Considered together, such progress augurs well for the future control of dyslipidaemia, hyperglycaemia, and hypertension, and with it, progressive reduction in atherosclerotic vascular disease and associated cardiovascular events in high-risk patients. ## Introduction The prevention of CVDs represents an enormous challenge to health professionals on a global scale. Indeed, on the basis of the 2015 World Health Organization database for the European region, and calculating age-standardized mortality rates with the new European Standard population, CVD remains the most common cause of death among Europeans, accounting for 40% in males and 49% in females, and equating to >4 million deaths per year. (1) While mortality from CHD and stroke have decreased overall across Europe over the past decade, CHD continues to represent the single most common cause of death. (1) Importantly, morbidity data reveal that population-based rates of hospitalization for both CVD and stroke have increased; considered together with ever increasing rates of cardiovascular interventions, greater use of medications, and expanding needs for rehabilitation for disabilities, these overwhelming socioeconomic costs present a major burden to healthcare systems across Europe. (1) How can we address this insurmountable challenge? Clearly lifestyle and diet represent our first line of action as currently recommended in recent guidelines, (2, 3) and early identification and management of modifiable risk factors is paramount. Indeed, Avanzini et al (4) have recently demonstrated that application of a comprehensive personalized preventive strategy in >12 000 high-risk subjects in general practice, but with suboptimal baseline risk factor control, led to gradual and significant improvement in global cardiovascular risk profile over a 5-year period. Thus, improvement in risk factor profile in the first year (including physical inactivity, hypertension, hypercholesterolaemia, diabetes, and an unhealthy diet) was independently and significantly associated with lower rates of cardiovascular events in subsequent years. These findings are entirely consistent with new observations from the EPIC-Norfolk prospective population study, in which even small improvement in modifiable risk factors led to substantial reduction in cardiovascular events. (5) These important findings indicate not only that an integrated approach to modifiable risk factor control is feasible, but equally that it is achievable in general practice. Finally, imaging technologies for detection of subclinical atherosclerosis may be invaluable in adding incremental value to strategies for diagnosis, risk stratification, and early initiation of prevention (see below). The year 2015 is—and continues to be—a vintage one for seminal progress in our knowledge of the pathophysiology underlying acute coronary syndromes (ACSs), and of the epidemiology, diagnosis, and prognosis of CVD, thereby reflecting concerted efforts in our quest to prevent the global scourge of atherosclerotic vascular disease and its thrombotic complications. Such advances have been paralleled by the successful and rapid development of highly efficacious, innovative therapeutics to markedly lower circulating levels of LDL-C. Indeed, in the landmark INTERHEART study of risk factors for the first myocardial infarction across 52 countries worldwide, atherogenic cholesterol transported as LDL predominated, accounting for the majority of population-attributable risk. (6) In this context, it is especially relevant that recent genetic findings, involving Mendelian randomization strategies which integrate lifelong and therefore cumulative risk exposure, have consolidated the evidence base for a causal role of LDL in the pathophysiology of atherosclerosis and CVD (7-9) (**Table 1**). Moreover, the IMPROVE-IT trial (10) has now demonstrated that a mechanism of LDL lowering distinct from that of statins translates into clinical benefit. Ezetimibe-mediated inhibition of intestinal cholesterol absorption yielded incremental lowering of LDL-C on a background of statin treatment in this trial (involving 18 144 patients hospitalized for an ACS over 7 years) and translated into moderate improvement in cardiovascular outcomes, i.e. a 7.2% lower rate of major vascular events. Baseline levels of LDL-C were low (1.8 mmol/L or 70 mg/dL), with a 24% further reduction when ezetimibe was added to simvastatin; that cardiovascular benefit is proportional to the degree of LDL-C reduction is of critical relevance in this context. (11) Cardiovascular mortality was not modified, a finding which may result from several factors, and particularly the need for post-trial, long-term follow-up data on clinical benefit. Indeed, it is increasingly evident that such follow-up reveals legacy benefits of LDL lowering beyond the active intervention period in randomized, placebo-controlled statin trials typically featuring decrease in cardiovascular death rates. (12) Clearly then, a new paradigm is appearing in which LDL lowering therapies may alter the pathophysiological course of atherosclerotic vascular disease and its thrombotic complications, potentially by inducing lesion stabilization, or lesion regression, or both. ### TABLE 1: Evidence that LDL is causal in the pathophysiology of atherosclerotic vascular disease and cardiovascular events. | Epidemiology of risk factors for myocardial infarction, INTERHEART | | --- | | Familial hypercholesterolaemia | | RCTs with statins and ezetimibe (intestinal cholesterol absorption inhibition) | | Molecular genetics - Mendelian randomization studies - PCSK9 loss-of-function mutations and variants - PCSK9 gain-of-function mutations | | Arterial lipoprotein retention and direct implication of LDL in plaque lipid accumulation | | Statin-mediated reduction in circulating LDL-C levels with concomitant decrease in plaque lipid and increase in extracellular matrix content, favouring plaque stabilization | | Plaque regression (reduction in atheroma volume) by statins | | RCTs = randomized controlled trials. | In this condensed distillate of advances in prevention of CVD over the past year, three key areas stand out. First, the evolution from emphasis on the ruptured, vulnerable coronary plaque to coronary plaque erosion in the context of ACS, with immediate relevance to approaches searching for ‘vulnerable’ plaques. (13) Second, the appearance of advanced molecular methodologies for identification of biomarkers with potential for high predictive value. (14) Third, the advanced development, based on the molecular genetics of familial traits for cholesterol dysmetabolism associated with premature atherosclerosis, of monoclonal antibodies targeted to PCSK9 for marked reduction in LDL-C levels. (15) Importantly, progress in all three areas holds great promise to positively impact the care pathway for patients at high risk of CVD. ## Plaque imaging and cardiovascular risk prediction A recent hybrid imaging study to evaluate the systemic extent of atherosclerotic disease in the carotid, abdominal aortic, iliofemoral, and coronary arteries in a middle-aged population (the PESA Study, Progression of Early Subclinical Atherosclerosis) revealed subclinical atherosclerosis in 63% of participants (71% men, 48% women), who ranged from low to high risk. (16) With a similar approach, BioImage Study (A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population) evaluated the predictive value of carotid plaque burden (as examined by 3D ultrasound) and coronary artery calcification for cardiovascular risk assessment in a population of ≈6000 asymptomatic adults who underwent multimodality vascular imaging of both coronary and carotid arteries. Both imaging methods suggested that higher detected plaque burden was associated with adverse cardiovascular events; furthermore, both imaging methods improved cardiovascular risk prediction to a similar degree. (17) ## Novel insights into coronary plaque pathobiology and mechanisms leading to progression towards acute coronary syndromes Over recent years, coronary atherosclerotic plaque rupture and subsequent thrombus formation have been widely considered as the mechanism causing ACS. Subsequently, imaging studies have aimed to reveal the ‘vulnerable plaque’. High-resolution intracoronary imaging studies using optical coherence tomography (OCT) have now revealed that a significant proportion of ACS events are caused by coronary plaque erosion (on an intact fibrous cap) and subsequent intracoronary thrombus formation, in addition to those ‘classically’ resulting from coronary plaque rupture of vulnerable thin-cap fibro-atheroma rich in lipid. (14) Indeed, Libby and Pasterkamp (13) have highlighted this consideration in an editorial entitled ‘The requiem of the vulnerable plaque’, in which they discuss different plaque pathobiologies leading to ACS. Moreover, Niccoli et al (18) reported that ACS caused by coronary plaque erosion may have a better prognosis as compared with those due to coronary plaque rupture, as such events appear to result from late thrombi suggestive of less intense thrombotic stimuli, thereby allowing time for thrombus dissolution caused by spontaneous fibrinolysis. Finally, a recent meta-analysis of OCT studies suggested that the mean prevalence of culprit plaque rupture and thin-cap fibro-atheroma was almost 50% across different clinical subsets of patients; importantly, such events were most prominent in ST-elevation myocardial infarction (70 – 77%). (19) ## Innovative methodologies for novel biomarker identification to assess cardiovascular risk Although current risk models allow for increasingly precise risk equations in the general population, predicting life-threatening cardiovascular events at the level of the individual remains a challenge. More precise risk stratification, ideally based on causal factors, and personalization both of risk factor assessment and management are increasingly needed. A number of strategies have been employed to search for novel biomarkers of CVD. Unbiased technologies, including genomics, proteomics, and metabolomics, all utilize a ‘big data’ approach for novel biomarker discovery, but to date these technologies have failed to deliver on their initial promise, yielding no new clinically useful biomarkers in cardiac care. A genetic risk score has been analysed recently in clinical cohorts and data from randomized clinical statin trials and may identify individuals at increased risk for both incident and recurrent CHD events. People with the highest burden of this genetic risk derived the largest relative and absolute clinical benefit from statin therapy. (20) An alternative strategy is to focus on known proteins reflecting mediating pathways to ensure a higher probability of association with CVD, an approach that can now be implemented on a massive scale using new multiplex immunoassay techniques that allow conservation of sample volume. This approach yielded promising results as recently tested in individuals with dysglycaemia. (21) Further, noncoding RNAs including microRNAs are considered a potential biomarker, which might support diagnosis and prognosis in different cardiovascular conditions. (22) Irrespective of big data approaches, single plasma biomarker assessment might be attractive to improve risk prediction models. Sensitive techniques to assess low concentrations of troponin I might open avenues to improve risk prediction in the general population by use of a cardiac-specific biomarker. (22, 23) Indeed, in the Bypass Angioplasty Revascularisation Investigation in Type 2 Diabetes trial, cardiac troponin T concentration measured with a high sensitivity assay was an independent predictor of death from cardiovascular causes, myocardial infarction, or stroke in patients who had both type 2 diabetes and stable ischaemic heart disease. (24) Nevertheless, development of new strategies to identify causal biofactors is warranted in biological fluids, circulating cells, and tissues, and it is in this framework that emerging ‘omics’ technologies—metabolomics, lipidomics, proteomics, transcriptomics, and miRNAomics—augur well. (14) ## Prevention of atherosclerotic vascular disease and cardiovascular events in dyslipidaemia ## Statin intolerance As recommended in current European guidelines, statins constitute first-line therapy in standard care for dyslipidaemic patients at high and very high cardiovascular risk in primary and secondary prevention. (2, 3) While the Cholesterol Treatment Trialists’ meta-analyses of randomized controlled trials involving statins strongly substantiate their clinical efficacy, (11) nonetheless, the profile of statin-associated adverse effects has been progressively clarified to reveal not only that statin-associated muscle symptoms (SAMSs) predominate in observational studies, registries, and clinical practice (range of prevalence 7 – 29%), but also that they are the primary cause of statin discontinuation. (25) To this end, the European Atherosclerosis Society (EAS) Consensus Panel recently issued a statement providing clinical guidance in the form of a flow-chart for management of patients with SAMS, and recognized the central role of attenuated mitochondrial energy production in skeletal muscle in its pathophysiology; it is noteworthy that inefficient first-pass statin uptake into the liver may critically underlie SAMS (**Figure 1**). (25) It is equally relevant that SAMSs are a central feature of ‘statin intolerance’, which also includes adverse events at the level of the liver, kidney, peripheral tissues, and potentially the central nervous system, but whose frequency is markedly less than that of SAMS. (25) FIGURE 1. Statin-associated muscle symptoms predominate as adverse effects among dyslipidaemic subjects who discontinue statin treatment. Available evidence suggests that the pathophysiological basis for statin-associated muscle symptoms arises from inefficient uptake of statins by the liver, i.e. ‘statin escape’, frequently as a result of genetically determined variation in the structure of organic anion transporter proteins, such as organic anion transporting polypeptide 1 encoded by the *SLCO1B1* gene. Thus, variant forms of the protein may exhibit low binding affinity for the statin. Under these conditions, first-pass hepatic uptake of the statin is incomplete, leading to elevated levels of statin in the circulation with prolonged residence time. At high statin doses, accumulation of statins in plasma correlates with a poor low-density lipoprotein cholesterol lowering response and a distinct trend to increased frequency of statin-associated muscle symptoms and myopathy. (25) As a consequence, peripheral tissues such as skeletal muscle are exposed to high statin concentrations with the potential for enhanced uptake; several mechanisms appear to contribute to statin-induced reduction in ATP production and mitochondrial function in muscle cells. (25) High demand for energy production in muscle, as occurs in intense exercise, may potentiate statin-associated muscle symptoms. ## Inter-individual variability in response to statin therapy Inter-individual variability in response to statin treatment has received little attention until late, when a pharmacogenetic meta-analysis of genome-wide association studies from randomized controlled trials and observational studies was reported, identifying the implication of two new genetic loci, SORT1/CELSR2/PSRC1 and SLCO1B1, in addition to those of APOE and LPA, in variation in LDL-C response. (26) These findings take on added significance when it is considered that a substantial proportion of patients with incident CHD are hypo-responders to statin therapy, show minimal LDL-C reductions, and most importantly, greater atheroma progression as compared with responders. (27) Under such circumstances, follow-up monitoring of LDL-C levels after initiation of statin becomes primordial to ensure goal attainment. ## Familial hypercholesterolaemia Alarmingly, the proportion of patients with familial hypercholesterolaemia (FH) at LDL-C goal on statin treatment has been reported to be as low as 20% in the seminal Dutch experience; such patients are characterized by accelerated and premature atherosclerotic vascular disease and CHD. (28, 29) Several reasons may underlie this situation, some of which arise from the markedly elevated LDL-C levels frequently encountered at baseline in such patients. A maximally tolerated dose of an intensive statin is therefore the order of the day in FH, potentially in combination with ezetimibe, a synergistic association. (7, 28-30) Despite currently available therapies, however, FH in both its homozygous and heterozygous forms is widely underdiagnosed and undertreated, as emphasized by the EAS FH Consensus Panel. (28, 29) Indeed, the recent revelation from population genetic studies that FH is the most commonly inherited metabolic condition, with a population frequency approaching 1:200 persons, has warranted a call to action, with widespread creation of patient registries and FH patient advocacy groups. (28, 31) The under-diagnosis of FH is especially critical in children and adolescents, as emphasized recently by Wiegman et al. (31) The evidence base in FH children treated with statins indicates not only that intervention with lipid lowering therapy may be safely initiated as early as 8 years of age, but also that when treated early in childhood, children born to FH families can anticipate normal life expectancy. (31) ## The need for therapeutic innovation: PCSK9 inhibition From the above, it is evident that innovative lipid lowering therapies have been—and remain—urgently needed, always on a background of statin treatment whenever possible, to fully translate the exceptional evidence base for reduction in cardiovascular events concomitant with LDL-C lowering into reality for many dyslipidaemic patients at high risk. Such patients include those with FH, those in secondary prevention, and those who are statin intolerant; additional patient populations may include individuals with diabetes, chronic kidney disease (CKD), and non-FH hypercholesterolaemia. (15) It is in this context that the recent approval in the USA and Europe of two humanized monoclonal antibodies to PCSK9, alirocumab and evolocumab, is especially pertinent; the development of a third, bococizumab, which is partially humanized, is ongoing (32); all are well tolerated with a satisfactory safety pro- file. (15, 33-35) As exemplified by alirocumab, these antibodies act in vivo primarily by accelerating the fractional catabolic rate of LDL. (36) An alternative approach to reduction of plasma PCSK9 concentrations involves direct inhibition of its hepatic production. A novel RNA interference drug, ALN-PCSsc (given as a subcutaneous formulation), has demonstrated the feasibility of this modality in phase 1 studies, resulting in a dose-dependent reduction in circulating PCSK9 levels of up to ≈80%, and a mean reduction in LDL-C of 40% for periods of 1 month or more, with favourable safety and tolerability. (37) ## Monoclonal antibodies to PCSK9 The decade required for the development of monoclonal antibodies to inhibit PCSK9 has been driven by novel genetic and mechanistic insights into the role of this protein in the regulation of the availability of surface LDL receptors primarily in the liver, its relation to the regulation of circulating LDL-C levels, and ultimately to cardiovascular morbi-mortality. (38) Quasi-complete removal of plasma PCSK9 by antibody binding results in highly efficacious lowering of LDL-C in the range of 40 – 70% as a function of dose across dyslipidaemic patient phenotypes in monotherapy or on a statin background, with uptake of LDL – antibody complexes by cells of the reticuloendothelial system; the duration of antibody action is dose-dependent for both alirocumab and evolocumab, whose (single dose) pharmacokinetics and pharmacodynamics resemble each other. (15, 33, 38) Moreover, anti-PCSK9-mediated LDL lowering is additive to that of statins and ezetimibe. (15, 33, 38) Importantly, the efficacy of these antibodies is independent of the specific class of the mutation of the LDL receptor (receptor negative, defective, unclassified, or no mutation detected) in heterozygous FH (39); this effect attests to the fact that PCSK9 action in vivo typically leads to the premature degradation of a major proportion of LDL receptors, a pathway largely neutralized by PCSK9 antibody treatment. (15) In the ‘Year in Cardiology 2014’, De Backer et al comprehensively reviewed extensive data from the phase III randomized controlled trials with alirocumab and evolocumab (40); clinical trial updates for 2015 are currently available in recent reviews. (15, 38) Of late, the ODYSSEY FH I and FH II (heterozygous FH) trials included the option to increase the antibody dose to 150 mg every 2 weeks when LDL-C goal was not attained on the starting dose (75 mg every 2 weeks). In this way, some 59 – 68% of patients achieved an LDL-C goal of 10 000 patients, highlighted a 55% reduction in all-cause mortality (P 70 000 high-risk dyslipidaemic patients **(****Figure 2**). While the findings are fully anticipated to confirm the preliminary observations discussed above, they will be essential elements in the evaluation of the long-term efficacy, tolerability, and cost-effectiveness of PCSK9 inhibition. We should not forget, however, that the trajectory of CVD over time is not limited to a single cardiovascular event, and that lowering LDL-C exerts cumulative, long-term arterial benefit, modifying the pathophysiological trajectory of atherosclerotic vascular disease. (12) Therefore, critical appraisal of these agents should integrate their cumulative, long-term health benefits both for the individual and potentially for healthcare systems. In this light, we summarize future perspectives for PCSK9 inhibition in **Table 2**. FIGURE 2. A schematic summary of the ongoing cardiovascular outcome trials for the three monoclonal antibodies to proprotein convertase subtilisin/kexin type 9, on a background of human LDL particles visualized by negative stain electron microscopy (copyright M.J.C.). The upper section of the figure shows a 2D image of the PCSK9 protein,while the lower section shows an image of an LDL particle bound to the biding domain of the LDL receptor. Overall, some 70 000 dyslipidaemic patients at high risk will be included in these multicentre, international trials. The primary endpoints in these trials, which are expected to report over the period of 2016 – 17 are as follows: FOURIER: cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization, whichever occurs first; (56) ODYSSEY OUTCOMES: coronary heart disease death, any non-fatal myocardial infarction, fatal and non-fatal ischaemic stroke, unstable angina requiring hospitalization; (57) SPIRE 1 and SPIRE-2: major cardiovascular event, a composite endpoint that includes cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina needing urgent revascularization. (54, 55) ACS = acute coronary syndrome; CV = cardiovascular; CVD = cardiovascular disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol. ### TABLE 2: PCSK9 inhibition: future perspectives. | Cardiovascular outcomes from phase III trials | | --- | | Impact on atherosclerotic vascular disease (Glagov imaging trial) | | Impact of triglyceride-rich lipoproteins, remnant and lipoprotein(a) lowering, and HDL/apolipoprotein AI raising, on progression of disease and reduction in cardiovascular events | | Long-term, real-life, safety data from post-marketing surveillance, including the safety of very low levels of LDL-C, and potential frequency of anti-drug binding or neutralizing antibodies | | Evaluation of efficacy and safety in children and adolescents with heterozygous familial hypercholesterolaemia at high risk (the HAUSER-RCT trial) | | Evaluation of efficacy in other patient populations at high risk, to include post-menopausal females, chronic kidney disease, type 1 and type 2 diabetics, peripheral arterial disease and autoimmune diseases | | Use of PCSK9 antibody therapy to amplify and prolong LDL apheresis-mediated LDL-C lowering in severely affected familial hypercholesterolaemia patients, with potential to reduce frequency of apheresis treatment sessions | | Evaluation of long-term cost-effectiveness as a function of long-term patient follow-up in individual healthcare systems | | HDL = high-density lipoprotein; LDL = low-density lipoprotein; LDL-C = LDL cholesterol. | ## Beyond the LDL-C target: triglyceride-rich lipoproteins and lipoprotein(a) In addition to LDL-C, PCSK9 inhibition, by virtue of its marked enhancement of LDL receptor number, may impact components of the atherogenic lipid profile beyond LDL-C, including triglyceride-rich lipoproteins and remnants (TGRL); such action may equally modulate levels of both high-density lipoprotein (HDL) and apolipoprotein (apo)AI via intravascular remodelling mechanisms. As exemplified by early results from OSLER, atherogenic TGRL levels are significantly reduced when PCSK9 is inhibited, while those of HDL/apoAI may increase (44); similar findings have been made across the ODYSSEY phase III studies. (34) Further information on these actions as a function of baseline lipid profile will be of special interest, as we cannot exclude the possibility that they may enhance clinical benefit gained from LDL-C reduction alone. The lack of therapeutic effect of statins on a potent atherothrombogenic lipid risk factor, Lp(a) has been perplexing, especially as abundant evidence now supports the contention that it is a causal, genetically determined and independent risk factor for premature CVD. (58, 59) Moreover, Mendelian randomization studies have documented a key role for Lp(a) in calcific aortic valve disease, an observation supported by new mechanistic insights intimately linked to its content of oxidized phospholipids. (60, 61) The finding then that PCSK9 inhibition reduces circulating Lp(a) levels by up to 35%, (62, 63) and that this effect may reside at least partially in the supra-physiological availability of LDL receptors for its catabolism, represents a major mechanistic advance. (64) The ongoing cardiovascular outcomes studies for PCSK9 inhibitors may reveal whether Lp(a) reduction contributes to overall reduction in events. Ultimately, however, the answer to this question may require an outcomes trial involving anti-sense inhibition of hepatic apo(a) production in patients at high cardiovascular risk displaying elevated Lp(a) levels; such a scenario has entered the realm of possibility with the ongoing development of ISIS-APO(a) Rx, which can reduce Lp(a) concentrations by up to 80% dose-dependently. (65) ## Unmet clinical needs in dyslipidaemia: the therapeutic horizon Clinical needs in moderate hypertriglyceridaemia are largely unmet to date, and are a central target on our therapeutic radar screen, especially the highly atherogenic mixed dyslipidaemia involving elevated levels of TGRL and subnormal HDL-C, a profile typical of insulin resistance. (66, 67) Molecular genetics has clearly identified the majority of such dyslipidaemic states as polygenic, upon which environmental influences are superimposed. (66, 68) Nonetheless, in the light of new genetic insights indicating that a loss-of-function mutation in apoCIII leads to concomitant fall in levels of TGRL and in cardiovascular risk, novel targeting of the apoCIII gene by antisense inhibition brings considerable optimism to this arena. (69) Indeed, dose-dependent reductions attaining ≈80% in hypertriglyceridaemic patients (baseline triglycerides ≈4.0 – 22.6 mmol/L or 350 – 2000 mg/dL) were found using a weekly injection protocol in phase II studies. (69) No safety concerns were identified. Patients with CKD are at high cardiovascular risk (3); preliminary findings suggest that PCSK9 inhibition is as efficacious in LDL-C lowering in those with moderate CKD as in those with mild or without CKD, with no evidence of safety issues. (70) ## Cardiovascular prevention in diabetes After numerous cardiovascular outcome studies over the past years in patients with diabetes, suggesting no short- and medium-term risk reduction with anti-hyperglycaemic agents, the EMPA-REG OUTCOME trial reported a significant reduction of cardiovascular and all-cause mortality using a selective SGLAT-2 inhibitor, empagliflozin in patients with type 2 diabetes at high cardiovascular risk. (71) These observations will have a significant impact on the future management of cardiovascular prevention in patients with type 2 diabetes. ## Novel insights into better control of hypertension The PATHWAY-2 study has suggested that spironolactone is a particularly effective add-on drug for the treatment of resistant hypertension. (72) The results of the PATHWAY-3 study support the first-line use of amiloride plus hydrochlorothiazide in hypertensive patients who need treatment with a diuretic. (73) The DENERHTN study examined 106 patients with well-defined resistant hypertension and suggested that renal denervation plus an standardized stepped-care antihypertensive treatment (SSAHT) decreased ambulatory blood pressure more than the same SSAHT alone at 6 months, (74) raising hope that renal denervation may lower blood pressure in well-selected patients. Importantly, the SPRINT study (75) demonstrated that among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of <120 mmHg, as compared with <140 mmHg, resulted in lower rates of fatal and non-fatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. This trial was larger than the previous ACCORD study, where a trend for a lower rate of cardiovascular events was observed with more intensive blood pressure lowering. ## Summary and conclusion The year 2015 has seen dramatic progress in the control of dyslipidaemia, hyperglycaemia, and hypertension. These risk factors exert their nocivity throughout the course of the atherogenic process. Dyslipidaemia may, however, be unique as a target to attenuate progression of advanced plaques, and it is in this context that the marked efficacy of PCSK9 inhibition in lowering LDL-C to levels below the critical value of 1.8 – 2.1 mmol/L (70 – 80 mg/dL) required to stop progression in the majority of patients may present major therapeutic interest. (76, 77) Indeed, could rapid reduction of LDL-C to very low levels post cardiovascular event result in rapid lipid depletion and enhanced fibrous matrix content across diffuse plaques in the arterial tree, and with it, irreversible—or long-term—plaque stabilization with subsequent reduction in cardiovascular events? Could rapid attenuation of dyslipidaemia by PCSK9 inhibitors attenuate endothelial erosion on complex plaques, indirectly diminishing thrombotic complications? Such questions challenge cardiology, obliging us to determine the most efficacious pharmacotherapeutic strategies for CVD prevention. Finally, the first large cardiovascular outcome data of SGLAT-2 inhibition will have a major impact on the future treatment of diabetes, and in hypertension, the PATHWAY and SPRINT studies have provided valuable insights into optimization of treatment. ## Acknowledgments Authors’ contributions: M.J.C., S.B., and U.L. acquired the data, drafted the manuscript, and made critical revision of the manuscript for key intellectual content. Acknowledgement: The authors are indebted to Jane Stock for assistance with literature documentation.

Aleksandar Knežević

Cardiovascular diseases (CVD) are still the leading cause of mortality in Croatia. According to the latest data for 2014, they were the cause of 47% of total deaths (coronary heart disease 21%, cerebrovascular disease 14%, and heart failure 3%). The mortality rate for these diseases is much higher in Croatian when compared with more developed European countries (from the EU15 group), but it is better than the average for other countries in the European region of the World Health Organization composed of the so-called transitional countries (340/100,000 inhabitants in Croatia; 160 for EU15 countries; 630 for transitional countries) (1). Although there have been advancements in CVD treatment in comparison with earlier times, they are still the leading public health problem, and it is crucial to ensure the availability of all existing treatment approaches that we can provide, given our conditions. Of course, CVD prevention is even more important than treatment because it allows us to achieve greater results with fewer resources. According to studies performed in various populations, as much as 44-76% of coronary heart disease mortality reduction is ascribed to prevention and changes in health-risk behavior, while 23-47% of mortality reduction is a result of treatment interventions. Prevention results in Croatia have so far been unsatisfactory (2). Significant advances in CVD prevention have been achieved over the last year. This is a result of: - Reducing cardiovascular events in high-risk patients though diet and modification of unhealthy lifestyles. - Introducing new imaging methods that allow earlier detection of subclinical atherosclerosis, which leads to better CVD prevention. - New clinical evidence that plaque rupture at the culprit lesion happens in only 50-77% of patients with acute coronary syndrome. - Evidence from clinical trials on the effectiveness of treatment based on monoclonal antibodies targeting PCSK9, which leads to significant reduction in LDL cholesterol and consequently a reduction in CV events. - Significant reduction of cardiovascular and total mortality in patients with diabetes treated with empagliflozin (a SGLAT-2 inhibitor), demonstrated in the EMPA-REG OUTCOME clinical trial. - Improved management of arterial hypertension, especially resistant hypertension, through the application of spironolactone in the PATHWAY-2 and PATHWAY-3 clinical trials, and the application of the combination of amiloride and hydrochlorothiazide treatment in patients using diuretics to treat hypertension. - Reduced mortality in patients with arterial hypertension with target systolic blood pressure values of 120 mmHg in the SPRINT clinical trial. All of the above has led to better control of: dyslipidemia, hyperglycemia, and hypertension, resulting in progressive reduction of atherosclerotic vascular disease and cardiovascular events in high-risk patients. In a review article on the state of CVD prevention in 2015, Chapman et al. (3) attributed the greatest significance for cardiovascular prevention to good regulation of LDL cholesterol, citing the registration of two drugs that act on the inhibition of PCSK9 in the plasma, and consequently on the reduction of LDL cholesterol values, as an important advancement in cardiovascular prevention (especially in patients with a family hypercholesterolemia). These two drugs (monoclonal antibodies) under the trade names Praluent® (alirocumab) and Repatha® (evolocumab) have been registered in the European Union in 2015 and thus automatically in Croatia as well. It is not yet know when they will be placed on the medication List of the Croatian Health Insurance Fund, given the current price of monthly treatment of approx. 5,000 HRK. The importance assigned to hypolipidemic therapy in our country is demonstrated by the expenditure of medication for the regulation of dyslipidemia (mostly statins), which has grown sharply over the last decade (2004-2014) in DDD/100 inhabitants from 28.13 to 61.79, which is more than double. (4) However, since CVD are the leading cause of mortality and morbidity in Croatia, this increase in the use of hypolipidemic agents should definitely be larger, especially since elevated cholesterol values are also, along with smoking, the most important risk factor in our country. Thus, one trial on "healthy" participants found a prevalence of cholesterol levels above 5.5 mmol/L in 67% of the participants5 (5) In addition to dyslipidemia regulation, adequate regulation of blood pressure (BP) is still very significant and still not satisfactory in Croatia. A recent study found that only a quarter of patients have well-regulated BP values (6). Chapman et al. (2) cite two studies regarding arterial hypertension regulation: PATHWAY 2 and PATHWAY 3. (7, 8) The PATHWAY 2 study examined the role of spironolactone in the treatment of resistant arterial hypertension (AH), where it showed good results. (7) The results of the PATHWAY 3 study showed that the combination of amiloride and hydrochlorothiazide treatment was the preferred diuretic in the treatment of hypertensive patients due to its neutral metabolic effects. (8) This drug, which had been available under the name Moduretic® in Croatia for many years, has unfortunately been withdrawn from the market last year, most likely due to commercial reasons. It remains to be seen how the guideline authors for AH treatment will receive the results of this study, but it will likely result in this drug once again becoming available in Croatia. According to the latest European and American guidelines, AH management was less strict than before. However, this relaxation in the recommended target AP values has been brought into question by the recently published results of the SPRINT study in which patients that achieved AT values from 120/80 mmHg had 25% better cardiovascular outcomes (myocardial infarction, stroke, heart failure, acute coronary syndrome, cardiovascular death) than those with AP values at 140/90 mmHg. This was accompanied with an increase in the number of side-effects (hypotension, syncope, electrolyte imbalance, renal failure) in patients from the group with intensive pressure control (4.7 vs. 2.5%) (9). The authors also cite this study as significant for cardiovascular prevention. A significant achievement from the field of cardiovascular prevention in the last year was the EMP-REG OUTCOME clinical study which demonstrated a significant reduction of cardiovascular and total mortality in patients with type 2 diabetes and high cardiovascular risk that used empagliflozin, a selective SGLAT-2 inhibitor. Since all new antidiabetics must pass cardiovascular safety studies after the "rosiglitazone affair", i.e. must be proven not to increase cardiovascular morbidity and mortality, the results of this study show that one of them in fact reduces them (10). In conclusion, the Chapman et al. article on the news in cardiovascular prevention in 2015 once again stressed good risk factor management (dyslipidemia, hyperglycemia, and arterial hypertension), which saw dramatic advancements in the past year, according to the authors. It is significant that most medications that have achieved this are available in Croatia, so there should be no obstacles to significantly improving the prevention of cardiovascular diseases.

Assist. Prof. Mario Ivanuša

This well-polished echocardiography field guide is immediately attractive due to its practical pocket-size. It is edited by Prof. Lancellotti (Head of the European Association of Cardiovascular Imaging in the 2012-2014 term) and Prof. Cosyns (Nucleus Head of the Echocardiographic section of the European Association of Cardiovascular Imaging). The modern presentation that will help train the skills used in echocardiographic examinations is the result of the efforts of 30 leading experts and five section editors (Prof Donal, Dr Garbi, Dr Jurcut, Dr Monney, and Prof Šeparović Hanževački). The book is structured into 17 chapters that follow the logic of everyday practice in an echocardiographic laboratory. The elaboration of individual thematic areas is excellent, integrating extensive insights from the expert literature into a logical and easily-intelligible way, and represents a step forward that is important to the education of every internist and cardiologist in the field of cardiovascular imaging.

Vlatka Rešković, Lukšić, Jadranka Šeparović, Hanževački

For several years, Croatia has been recognized as an equal member of the European Association of Cardiovascular Imaging (EACVI). This was confirmed by numerous activities of our Working Group at the national and European level over the past year. As in Europe, we have also recognized the importance of comprehensive, complex, and multi-modality imaging due to the increasingly demanding needs of complex heart pathology we are faced with today. In parallel with the development of technology, a more and more complex approach to the analysis of heart morphology and hemodynamics is being developed, providing unprecedented possibilities for imaging and hemodynamic calculations. However, these procedures require the engagement of highly educated specialist/subspecialists for the analysis of archived images and data, which can last from a minimum of 30 minutes to as much as several hours. Advancements in echocardiography over the last few years have been accompanied with the development of several new methods that are already being implemented in our daily clinical practice. This includes deformation analysis using the 2D speckle tracking method or tissue Doppler imaging, which can provide valuable information on myocardial function in, for instance, coronary heart disease (CHD), following the effects of cardiotoxic therapy, cardiomyopathies, myocarditis, etc. Tissue Doppler imaging is also used for dyssynchrony study, which allows very successful selection of appropriate candidates for the implantation of resynchronization devices and monitoring of myocardial function recovery due to resynchronization therapy. Furthermore, stress echocardiography is a method that has seen increasingly common use in recent years and is used not only in CHD for the assessment of inducible ischemia and viability, but increasingly also in valvular heart disease, as well as in some cardiomyopathies. When dealing with valvular heart disease, especially complex or multiple valve disease, the conventional methods include color Doppler imaging, hemodynamic measurements, and 2D imaging, but over the last few years these examinations have become inconceivable without the use of 3D transthoracic (TTE) and transesophageal echocardiography (TEE). For instance, the assessment of mitral regurgitation begins with a TTE with hemodynamic measurements, determination of etiology and severity quantification using volumetric quantitative and semi-quantitative methods. This is followed by transesophageal echocardiography (TEE) with 3D or 4D TEE. The data is analyzed later, not only by 3D image reconstruction for visualization of valve morphology, but also by preforming very specific measurements of annulus size, coaptation height and coaptation areas, tenting angle, etc., in order to decide on further optimal treatment options. This is because different etiologies of valvular diseases indicate different decisions on when and how the intervention should be performed. Exercise stress can also help in this process by, for instance, recognizing progression of valve regurgitation or development of pulmonary hypertension in exertion, or, in case of valvular stenosis, for measurement of gradient increase, valvular area change and assessment of contractile reserve during exercise. When cardiac surgery is expected, a good echosonographer should be able to provide the surgeon with exact measurements of regurgitant volumes, stenotic areas, annulus sizes and areas; to precisely analyze valve morphology and define concomitant valve diseases, as well as to follow up, by the means of echocardiography, the patient’s whole intraoperative and postoperative period. With the development of new percutaneous methods of valve reparation and replacement that are already used worldwide, more and more is to be expected from us. Thus, to achieve quality standards of practicing this new methods and their implementation in daily clinical practice, continuous education and the acquisition of new knowledge and skills is required; it is also necessary to ensure there is enough time to perform these complex examinations. Consequently, new diagnostic-therapeutic procedures (DPT) have been introduced. However, for a laboratory to be capable of performing complex examinations, the personnel employed must be accredited and the procedures standardized. This ensures a coherent, consistent, and high-quality approach to echocardiography throughout our country. In line with the recommendations of the European Association of Cardiovascular Imaging (EAVCI) (1), the Working Group on Echocardiography and Cardiac Imaging Modalities of the Croatian Cardiac Society advocates the standardization of echocardiographic examinations as the first step towards consistent and comparable quality in echocardiographic data and their applicability, which is ultimately for the benefit and safety of the patients (2, 3). The second step is accreditation. The National Accreditation exam was held last year, with several candidates completing the written part of the examination and one completing the whole accreditation procedure. The accreditation of Working Group members is important in order to apply for national and European accreditation of echocardiographic laboratories, which will in turn allow us to participate in many European projects and registries. One of these is EuroEndo, the European registry for endocarditis, which is just starting to include the first patients with the participation of six Croatian centers. The results of the EACVI study “Cardiovascular imaging practice in Europe” (4) were published in May 2015; 41 European countries participated in the study, including Croatia. The goal was to establish the current state of particular imaging methods in Europe. The results showed that we are among the leading European countries in this area: our National Accreditation program has been regularly held already since 2011, and such programs exist in only a fifth of the examined countries. However, examination costs in Croatia are still lower than in Europe (e.g. transesophageal ultrasound and stress echocardiography are priced at over 200 EUR in a fifth of the examined countries). Waiting lists are long in other countries as well, and in Croatia the list is based on medical indications. Regarding the activity of the Working Group in Croatia, the most significant event was certainly the CroEcho 2015 congress that was held in Opatija from the 28th to the 30th of May, 2015. More than 360 Croatian and foreign participants, lecturers, and presenters attended the congress, which confirms its status as the larges echocardiographic gathering in the region. A large part of the congress program was dedicated to educational content from echocardiography as part of the Teaching Course that included interactive imagining workshops with examples from clinical practice. Participants could also attend workshops in advanced echocardiography on the topics of 2D myocardial deformation analysis, 3D echocardiography, and mechanical dyssynchrony assessment. The quality of the congress was recognized by the European Board of Accreditation in Cardiology (EBAC), and the quality of the Teaching Course by the Education Board of EAVCI. In addition to CroEcho, the ESC pocket guidelines for the treatment of valvular heart disease were translated with the cooperation of the Working Group for Valvular Heart Disease. The translations of EACVI recommendations are also in progress. Education is still the focus of the activities of the Working Group, and field workshops have regularly been held across the country for the past several years as part of the “Echo on wheels” project. We can announce that 4 workshops will be held this year (information on the topics, locations, and schedules of the workshops can be found on the webpage http://croecho.kardio.hr/), and the next CroEcho 2017 will be held from May 4 to May 6, 2017.