Cardiologia Croatica. 2023;18(1-2)

Rudolf A. de Boer, Johann Bauersachs

The year of 2022 has been an exciting year in heart failure (HF). In this brief report, we will highlight some of the most provocative and impactful papers in the field. Sodium–glucose co-transporter 2 (SGLT2) inhibitors are becoming one of the main treatments for patients with cardiorenal disease. Some uncertainties remained, e.g. if SGLT2 inhibitors were effective in patients with acute HF (AHF), or in HF with a left ventricular ejection fraction (LVEF)>40%, or in patients with improved LVEF. The Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure (EMPULSE; NCT04157751) trial enrolled 530 patients with acute de novo or decompensated HF to receive empagliflozin 10 mg once daily or placebo. (1) The unique aspect of EMPULSE was that patients were randomized in hospital, when clinically stabilized (median time to randomization: 3 days), and were treated for up to 90 days. More patients treated with empagliflozin had clinical benefits compared with placebo (this was assessed by a ‘win’ ratio). Mortality and HF readmissions were also reduced. The Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER, NCT03619213) study was a randomized double-blind clinical trial in 6263 patients with chronic symptomatic HF, LVEF>40%, and elevated natriuretic peptides comparing the effect of dapagliflozin 10 mg once daily vs. placebo, in addition to standard of care. (2) After a median follow-up of 28 months, the primary outcome [death from cardiovascular (CV) causes or HF hospital admissions] occurred in 16.4% in the dapagliflozin group and in 19.5% in the placebo group [hazard ratio (HR) 0.82; 95% confidence interval (95% CI): 0.73–0.92; P5.5 mmol/L) and less reductions in MRA dose. Strikingly, a large proportion of the patients with hyperkalaemia in the past whose RAASi or MRA was downtitrated could tolerate adequate dosages of RAASi and/or MRA during the run-in phase of the DIAMOND trial. In any way, patiromer enables adequate titration of RAASi and MRA in patients with hyperkalaemia, although the number needed to treat to prevent hard clinical outcomes by this strategy appears to be rather high. Diuretic resistance is another clinical dilemma which was addressed by two interesting trials. The Acetazolamide in Acute Decompensated Heart Failure with Volume Overload (ADVOR) trial (6) evaluated if acetazolamide, a carbonic anhydrase inhibitor, reduces proximal tubular sodium reabsorption, on top of loop diuretics in patients with AHF; 519 AHF patients and clinical signs of volume overload and an NT-proBNP level of more than 1000 pg/mL were randomized to either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics. Successful decongestion was more often achieved in the acetazolamide group compared with the placebo group [risk ratio (RR) 1.46, 95% CI: 1.17–1.82; P<0.001; Panel C]. Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. However, neither changes in symptoms, nor weight, nor the EuroQoL outcomes were reported and may complement the published data. The incidence of worsening kidney function, hypokalaemia, hypotension, and adverse events was similar in the two groups. These data likely will shift the standard diuretic regimen in AHF. The Safety and Efficacy of the Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure (CLOROTIC trial; NCT01647932) (7) evaluated if addition of hydrochlorothiazide (HCT) to intravenous furosemide is a safe and effective strategy for improving diuretic response in patients with AHF. In total, 230 patients (48% women, 83 years) were randomized to HCT or placebo; those on HCT lost more weight at 72 h [−2.3 vs.−1.5 kg; −1.14 (95% CI −1.84 to −0.42); P=0.002], but there were no significant differences in patient-reported dyspnoea. Mortality or HF rehospitalization rates were similar between HCT and placebo. Patients with HCT more often had a significant increase in creatinine (46.5% vs. 17.2%; P<0.001). Several other interesting articles were published. First, the long-standing dispute about whether or not patients with ischaemic cardiomyopathy may benefit from revascularization by percutaneous coronary intervention (PCI), when compared with optimal medical therapy (OMT) (i.e. individually adjusted pharmacologic and device therapy for HF), was addressed by the Study of Efficacy and Safety of Percutaneous Coronary Intervention to Improve Survival in Heart Failure (REVIVED-BCIS2; NCT01920048). (8) Patients with an LVEF of 35% or less, extensive coronary artery disease that could be treated by PCI, and demonstrable myocardial viability were randomized to either PCI plus OMT (PCI group) orOMT alone. Totally, 347were assigned to the PCI group and 353 to the OMT group. Over a median of 41 months, a primary outcome (death from any cause or HF hospitalization) occurred in 37.2% in the PCI group and in 38.0% in the OMT group (HR 0.99; 95% CI: 0.78–1.27; P = 0.96; Panel D). The LVEF was similar in the two groups at 6 and 12 months. So, revascularization by PCI has no benefit in these patients on top of medical therapy. Finally, two interesting articles addressed how drug titration in patients with HF may be handled. Until recently, the guidelines recommended initiating therapy in patients with HF in a historical sequence, with slow and controlled up-titration of individual classes of drugs. However, the newest guidelines state that four classes of drugs should be titrated on a faster schedule; however, the order and speed of titration remained unaddressed. A first study (9) to address this was a retrospective study analysing data from six major mortality trials in HF: the SOLVD-Treatment trial (angiotensin-converting enzyme inhibition, enalapril), the MERIT-HF trial (beta-blockade, metoprolol), EMPHASIS-HF (MRA, eplerenone), the PARADIGM-HF trial (angiotensin receptor–neprilysin inhibition), DAPA-HF (SGLT2 inhibition, dapagliflozin), and CHARM (angiotensin receptor blocker, candesartan). The authors modelled the potential reductions in CV events that might be expected from more rapid uptitration in the conventional order (based on a chronology of trials), and compared this to accelerated up-titration, using treatments in different orders than currently is conventional. Indeed, a rapid up-titration schedule was associated with fewer HF hospitalization or CV death. Furthermore, an optimal ‘alternative’ sequence of drugs was identified, which proposed SGLT2i and an MRA as the first two therapies. A second study addressing this pressing issue was the Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP testinG, of Heart Failure Therapies (STRONG-HF; NCT03412201). (10) STRONG-HF randomized patients who were admitted to the hospital with AHF, who were not treated with full doses of guideline-directed drug treatment, to usual care or high-intensity care (HIC). HIC was defined by the up-titration of treatments to 100% of recommended doses within 2 weeks of discharge, with four scheduled outpatient visits over the 2 months after discharge, to closely monitor clinical status, laboratory values, and biomarkers. The primary endpoint was 180-day readmission for HF or all-cause death. In total, 1078 patients were randomized to HIC (n=542) or usual care (n=536). The study was stopped prematurely by the DSMB because of greater than expected between-group differences. A higher proportion of HIC patients had been up-titrated to full doses of prescribed drugs. HF readmission or all-cause death up to day 180 occurred in 74 (15.2%) of 506 patients in the HIC group and 109 (23.3%) of 502 patients in the usual care group (difference: 8.1%; RR 0.66, 95% CI: 0.50–0.86). Patients receiving HIC thus ended up having both more medical attention and visits as well as higher dosages of drugs—it remains uncertain what part of the benefit is explained by what element. More adverse events by 90 days occurred in the HIC group (41%) than in the usual care group (29%), but similar incidences of serious adverse events were reported in each group. Overall, these two trials provide strong support for accelerated titration of guideline-directed drug treatment, while the order of drugs installed does not need to be based on historical grounds.

Pier D Lambiase, Prashantan Sanders, Harry JGM Crijns

## Top arrhythmia papers — the 2022 ventricular arrhythmia guidelines Among the top 10 arrhythmia papers is the 2022 ESC guidelines for the management of patients with ventricular arrhythmias (VAs) and the prevention of sudden cardiac death (SCD). (1) The Guidelines summarizing figure provides a comprehensive clinical, electrocardiographic, and genetic overview of the various diseases associated with VA or SCD (**Graphical Abstract, A in the original article**). They promote public access to defibrillation supported by mobile health and a much larger role in catheter ablation (**Graphical Abstract, B in the original article**). Also, multiple recommendations are provided on the use of CMR and genetic testing to improve diagnosis and steer therapy for several cardiomyopathies in particular if specific risk features are present. To enhance efficient ICD therapy in cardiomyopathies, novel risk factor-based recommendations are provided. (1) ## Crossing borders—imaging and arrhythmias The increasing role of CMR in VAs contrasts with the negative randomized DECAAF trial in persistent atrial fibrillation (AF) indicating that CMR-steered ablation targeting gadolinium late-enhanced potentially arrhythmogenic atrial areas does not impact recurrences compared with standard pulmonary vein isolation, and the extended approach may even be associated with stroke. (2) At present, atrial CMR is not robust enough in identifying relevant ablation targets. Studies linking CMR findings with electro-anatomic and functional arrhythmogenesis are clearly needed including studies into electrophysiologic and pathological effects of ablation in so-called fibrotic tissue. ## Translational papers — arrhythmogenic right ventricular cardiomyopathy How exercise aggravates arrhythmogenic right ventricular cardiomyopathy (ARVC) is not well known. In their translational study, Cerrone et al. (3) speculate that exercise challenges a cardiomyocyte’s desmosomal reserve which, if impaired genetically [e.g. plakophilin (PKP2) loss], accelerates the progression of cardiomyopathy (**Graphical Abstract, C in the original article**). Desmosomes not only regulate cell–cell mechanical coupling but also play a significant role in cell signalling regulating cell proliferation, apoptosis, electrolyte signalling, and mitochondrial and metabolic functioning. When desmosomal reserve is reduced, myocytes are not well protected by their desmosomes against the effects of exercise leading to cell death and arrhythmias. (3) One clinical study in ARVC highlighted for the first time that desmosomal mutation status plays a key role in the risk of VA events, whilst previous risk models have focused on ventricular function, PVC burden, and ECG biomarkers. (4) Patients with a definite diagnosis of ARVC and no history of sustained VAs were followed for a mean of 6 years. Classical risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but overestimated VA risk. Four gene groups were studied: plakophilin-2 (PKP2), desmoplakin (DSP), other desmosomal, and gene-elusive patients. PKP2 had the highest discrimination and calibration of risk while these were lowest in gene-elusive patients. Interestingly, clinical markers performed differently in the specific gene groups e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite was true for left ventricular systolic function. Overall, the 2019 ARVC risk model performed reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. This study highlights that gene status should be included in future risk models for ARVC. Furthermore, there still needs to be independent cohort comparisons of risk models in ARVC, a major challenge for all rare diseases. ## Novel, read all about it! — randomized VT ablation studies In the field of VT ablation, three randomized controlled trials were published this year focusing on the timing of VT ablation, either first-line pre-emptive ablation at the time of ICD implantation (5) or after the first ICD therapy (6, 7) (**Graphical Abstract, B in the original article**). PARTITA randomized 56 patients with ischaemic and non-ischaemic cardiomyopathy to ablation vs. medical therapy after their first appropriate ICD shock. Interestingly, amiodarone was not allowed. (6) No deaths occurred in the ablation group vs. eight deaths (33%) in the control group (P=0.004); there were one (4%) and four (17%) worsening heart failure hospitalizations, respectively; P=0.159. ICD shocks were less frequent in the ablation group (9%) than in the control group (42%; P=0.039). The ablation strategy employed an extensive substrate-modification approach with multiple inductions of VT to ensure non-inducibility which almost certainly contributed to the positive outcome in highly experienced centres of excellence for VT ablation. The fact that mortality was reduced by early VT ablation is a key observation but not proven in previous randomized trials. In SURVIVE-VT, 144 patients with ischaemic cardiomyopathy who suffered ICD shock, had syncopal VT or monomorphic VT needing ICD, were randomized to complete endocardial substrate-based catheter ablation or antiarrhythmic therapy (amiodarone, sotalol, beta-blockers). The primary outcome was a composite of cardiovascular death, appropriate ICD shock, unplanned hospitalization for worsening heart failure, or severe treatment-related complications. After 24 months, the primary outcome occurred in 28.2% of patients in the ablation group and 46.6% of those in the AAD group. (7) This difference was driven by a significant reduction in severe antiarrhythmic treatment-related complications, in particular slow or incessant VT. In the PAUSE-SCD trial, 121 patients comprising 35% ischaemic, 30% non-ischaemic, and 35% ARVC, were randomly assigned (1:1) to ablation vs. conventional medical therapy at the time of ICD implantation.5 The primary outcome was a composite endpoint of VT recurrence, cardiovascular hospitalization, or death. At 31 months, the primary outcome occurred in 49.3% of the ablation group and 65.5% in the control group (P=0.04). The observed difference was driven by a reduction in VT recurrence in the ablation arm (P= 0.02). Similar results were seen in a non-ICD registry arm receiving ablation. No differences in cardiovascular hospitalization or mortality occurred and 8.3% of patients had ablation-related complications. (5) Although all these studies were relatively small (5–7) and had very long inclusion periods (6, 7) their findings promote early ablation of VT in ICD carriers at risk of recurrences, with PARTITA and PAUSE-SCD helping to expand early VT ablation to structural heart disease other than ischaemic cardiomyopathy. (5, 6) The fact there was a significant complication burden needs to be minimized especially if first-line ablation is to develop traction more widely. Since AAD complications drove the outcomes in SURVIVE-VT, this indicates that these drugs especially amiodarone are not an optimal alternative in a high proportion of patients. The challenge is to achieve successful ablation with minimal complications in these often fragile patients as it is clear that ablation is certainly effective in reducing VA events. However, newer heart failure medications including SGLT2 inhibitors and sacubitril-valsartan mean the background risk is changing. ## And more news — stroke prevention in atrial fibrillation In 2022, three innovative and guideline-relevant arrhythmia papers dealt with stroke prevention in AF. Patients with inherited factor XI deficiency do not suffer from spontaneous bleeding and may have lower rates of cardiovascular events, including cardioembolic stroke. This seeming paradox may relate to FXIa contributing to clot progression but not to clot consolidation. In the dose-finding PACIFIC-AF trial, 20 and 50 mg of asundexian reliably suppressed activated coagulation factor XI (FXIa) with once-daily dosing and resulted in significantly lower rates of bleeding compared with apixaban. (8) Therefore, FXIa may represent a novel therapeutic target for clot prevention across a variety of thromboembolic diseases significantly avoiding the bleeding side effect which remains to be seen in larger clinical outcome studies. The randomized non-inferiority INVICTUS trial fills an evidence gap in the application of non-vitamin K oral anticoagulants (NOACs) in AF and is very relevant to countries with a high prevalence of rheumatic heart disease-related AF. (9) Patients with AF and echocardiographically documented rheumatic heart disease (including moderate to severe mitral stenosis in over 80%) were randomized to vitamin K antagonist (VKA) therapy or 20 mg rivaroxaban daily. Vitamin K antagonist led to a lower rate of the composite of cardiovascular events or death (in particular sudden death and mechanical or pump failure death) than rivaroxaban, without a higher rate of bleeding. Vitamin K antagonist patients were regularly monitored for INR and for that reason may have received better care overall, whilst randomized therapy (and any anticoagulation) was stopped more often in the NOAC arm. Nevertheless, trial results indicate that VKAs should be the preferred oral anticoagulants over NOACs. (9) The third study in this area was RAFAS, an open-label randomized clinical trial comparing early rhythm control with usual AF care in 273 patients with newly documented AF in the setting of an acute ischaemic stroke. (10) Re-stroke rate at 12 months after index stroke was lower in the early rhythm control group [3 (1.7%) vs. 6 patients (6.3%)] whilst overall mortality, any hospitalization, and arrhythmia-related events did not differ. Sustained AF at 12 months was less frequent under early rhythm control (34%) compared with usual care (63%). Although small-scale and open-label, the study addressed an important clinical problem since the re-stroke rate is high in acute ischaemic stroke particularly when it is complicated by new-onset AF. In these patients, rhythm control is generally not considered whilst RAFAS suggests early ablation may be beneficial. (10) Larger well-controlled clinical trials on catheter ablation in patients with AF detected early after acute ischaemic stroke are definitely needed to settle the issue. In conclusion, in 2022 several important trials and translational studies have been published in the top cardiovascular journals to push knowledge in the arrhythmia field promisingly forward. They will not only contribute to future cardiovascular guidelines but will also form stepping stones for novel translational research stimulating advances in our field.

Petar Medaković, Mladen Jukić, Zrinka Biloglav

According to morbidity and mortality indicators, cardiovascular diseases are the leading public health issue in the Republic of Croatia and the European Union. Although mortality rates from ischemic disease have been reduced, Croatia is still categorized among countries with high cardiovascular risk. The guidelines of the European Society of Cardiology from 2020 for acute coronary syndrome (ACS) in patients with low to intermediate risk of coronary atherosclerotic heart disease (CHD) recommend coronary computed tomography angiography (CCTA) as an alternative to invasive coronarography. In most patients with suspicion of CHD, CCTA leads to the diagnosis of non-obstructive diseases, which causes the majority of ACS cases. Multi-slice Computed Tomography scanners of the newest generation employ low doses of radiation and low contrast volume to reliably show the characteristics of vulnerable plaque: (i) positive remodeling, (ii) low attenuation plaque, (iii) spotty calcification, and the (iv) napkin-ring sign. Due to positive remodeling, these plaques are often non-obstructive, and according to the CAD-RADS 2.0 guidelines from 2022 all their characteristics should be specifically emphasized in CCTA findings. Based on the assessment of the prognostic value of vulnerable plaque characteristics for adverse cardiac events, CCTA has been shown to be equally valid as other invasive diagnostic methods. Additionally, it was shown to be useful in indicating the optimal medication therapy and monitoring its effects. The results of large international randomized trials indicate the direction of the treatment approach for vulnerable plaque.

Jean-Jacques Monsuez, Plamen Gatzov, Ignacio Ferreira-Gonzalez, Fernando Alfonso

Several challenging issues with regards to the very large amount of percutaneous coronary interventions (PCI) performed and the numerous clinical settings they apply have been addressed by studies published in National Societies of Cardiology Journals (NSCJs). A large Spanish study showed that survival of patients discharged from hospital after primary PCI for ST-elevation myocardial infarction (STEMI) is quite similar to an age-adjusted population life expectancy (1). However, several differences in success of PCIs and subsequent outcomes have been observed across selected populations. Women included in a Polish nationwide registry have more procedural-related complications after rotational atherectomy and a higher mortality rate (2). A large multinational survey of patients with ACS found similar differences. Women were older than men, with more co-morbidities and were less often revascularized. Compared with men, a higher percentage of women died during follow-up (3). Failure and complications of PCI also worsen clinical outcomes of patients, as reported in another large multinational study. Among patients with a non-ST elevation ACS, 5% experienced at least one complication. Procedural complications were associated with early mortality, acute myocardial infarction (AMI) or stroke (4). More reassuringly, neurological complications following AMI decreased overtime, as reported by the SWEDEHEART registry. Within 10 years the relative risk of ischemic stroke was reduced by 20% at 1-year post AMI. The reduction coincides with the shift of reperfusion therapy from thrombolysis to primary PCI for STEMI and the increased use of evidence-based secondary preventive therapy according to the ESC guidelines (5). Invasive physiological assessment of coronary lesions with fractional flow reserve (FFR), which is increasingly used, remains a subject of concern. A retrospective analysis of PCI performed in two large volume centers in Portugal showed that it was performed in few patients with either stable CAD or ACS only. However, the release of the 2014 ESC guidelines on myocardial revascularization was followed by 2-fold increase in its adoption (6). The usefulness of instantaneous wave-free ratio (iFR) was assessed using the newly developed Syncvision software to guide the iFR-pullback study and the final decision-making process in long, diffuse, or sequential lesions. Similar results with regards to outcomes of patients, including mortality, AMI, stent thrombosis and target vessel revascularization (TVR) confirmed the safety of this approach too (7). Distal radial access for PCI is more difficult than conventional radial access. A Turkish study among patients with ACS found no difference between the success rate of both approaches, but distal access was associated with fewer rates of radial spasm and radial occlusion (8). According to the 2018 ESC guidelines, PCI for left main (LM) stenosis is increasingly performed after careful staging of lesions using the SYNTAX score. In a study from Bulgaria showing real world results, successful maximal revascularization was obtained after unprotected PCI of LM in all patients with only few unfavorable clinical outcomes during follow up (9). PCI of LM bifurcation lesions carries a harmful risk of side-branch closure. Two different strategies for provisional side branch interventions have been compared in another study. For non-true bifurcation lesions, a 1-stent technique with (aggressive strategy) or without (conservative strategy) mandatory kissing balloon inflation was applied. For true bifurcation lesions, an elective 2-stent technique (aggressive strategy) was compared to a 1-stent approach followed by a stepwise additional balloon inflation/stenting depending on the residual stenosis of the side branch (conservative strategy). Aggressive and conservative strategies for a side branch provisional stenting had similar results with regards to 1-year TVR (10). An Egyptian study of patients with STEMI and totally occluded culprit-lesion artery by a heavy thrombus burden compared outcomes of patients in whom thrombus aspiration was performed or not. Thrombus aspiration was associated with better TIMI flow, myocardial blush grade and ST-segment resolution and with reduced 1-month mortality rates (11). According to the 2018 ESC guidelines on myocardial revascularization, PCI for chronic total occlusions (CTOs) has increasingly been performed using the recommended calculation of the SYNTAX score. This increased rate was clearly seen in a multicenter study from Belgium and Luxembourg in which procedures achieved technical success in 80% of cases. High-volume centers progressively tackled more complex CTOs while keeping success rates stable overtime (12). Another issue of concerns pertains to aorto-ostial CTOs since they are often associated with unfavorable anatomic characteristics and unclear vessel course. Procedural success was achieved in 78% PCI of aorto-ostial CTOs among patients included in a large multinational study. There were only few procedural complications. During follow-up, subsequent TVR and cardiovascular mortality rate remained very low (13). Treatment of in-stent restenosis is another challenging anatomic scenario. In a 3-year clinical follow-up of patients presenting with bare-metal stent (BMS) in-stent restenosis, a study from Czech Republic showed more favorable outcomes in patients treated with iopromide paclitaxel-coated balloons as compared with those treated with seal-wing paclitaxel-eluting balloons. Major cardiac adverse events and the need for TVR were seen in 2- and 3-fold fewer patients, respectively (14). A single center study from Turkey reported the results on concomitant PCI or not in transaortic valve implantation (TAVI). Postprocedural complications including pericardial effusion, stroke, major vascular complications, bleeding, and emergency arrhythmias were similar in patients in whom coronary revascularization was performed simultaneously or performed as a staged procedure before or after TAVI. Although 30-day mortality was higher in simultaneously performed than in staged coronary revascularization, 1-year mortality rates were not statistically different (15). Another new field for percutaneous procedures relates to patients with refractory angina in whom revascularization is not suitable. The coronary sinus reducer (CSR) is intended to relief these disabling symptoms. Among patients in whom the device was implanted in a 5-year Dutch experience, two third of them showed improvements of at least 1 Canadian Cardiovascular Society (CCS) class, and about one half in at least 2 CCS class (16). As metoprolol was recently shown to reduce progression of ischemic injury in a pig model of STEMI, this effect was assessed in patients with ongoing STEMI. Compared with controls, those who received IV metoprolol before reperfusion had narrower QRS, a lower prevalence of QRS distortion, and a lower sum of ST-elevation, suggesting that IV metoprolol may reduce ischemic injury. The improvement by metoprolol in the ECG parameters correlated with improvement in magnetic resonance imaging (MRI) parameters of infarct size, coronary microvascular obstruction, and left ventricular function (17). Publications on PCI released by NSCJs provide real world insights on the current evolving challenges in management of patients with CAD across countries whose national cardiac societies are affiliated to the ESC. They highlight the advancements taking place in this dynamic field with ongoing procedural improvements and how ESC guidelines are progressively adopted and implemented in a real-world setting. ## Acknowledgments †List of authors: Jean-Jacques Monsuez (Editor-in-Chief of Archives des Maladies du Cœur et des Vaisseaux Pratique), France; Plamen Gatzov (Editor-in-Chief of Forum for Interventional Cardiology Journal), Bulgaria; Michael Aschermann (Editor-in-Chief of Cor et Vasa), Czech Republic; Hala Mahfouz Badran (Editor-in-Chief of Egyptian Heart Journal), Egypt; Nuno Cardim (Editor-in-Chief Revista Portuguesa de Cardiologia), Portugal; Ariel Cohen (Editor-in-Chief of Archives of Cardiovascular Diseases), France; Jose M De La Torre Hernandez (Editor-in-Chief REC Interventional Cardiology), Spain; Cetin Erol (Editor-in-Chief Anatolian Journal of Cardiology), Turkey; Claes Held (Editor-in-chief Svensk Cardiologi), Sweden; Gerd Heusch (Editor-in-Chief of Basic Resarch in Cardiology), Germany; Patrizio Lancellotti (Editor-in-chief Acta Cardiol), Belgium; Jan Piek (Editor-in-chief Neth Heart J), Netherland; Juan Sanchis (Editor-in-Chief of Revista Española de Cardiología), Spain; Anetta Undas (Editor-in-Chief Kardiologia Polska), Poland; Dilek Ural (Editor-in-Chief of Archives of The Turkish Society of Cardiology), Turkey; Fernando Alfonso (past- Chairman of the Editors’ Network of the European Society of Cardiology), Spain; Ignacio Ferreira-Gonzalez (past-Chairman of the Editors’ Network of the European Society of Cardiology), Spain.

Helmut Baumgartner, Bernard Iung, David Messika-Zeitoun

## Introduction This new format of the ‘Year in Cardiovascular Medicine’ series brings the challenge to select only 10 papers published in 2022 the authors believe to be the most important in their topic. We restricted our search to the New England Journal of Medicine, British Medical Journal, Journal of the American Medical Association, Lancet, European Heart Journal, Circulation and Journal of the American College of Cardiology. The selection is a consensus of the three authors. There are of course definitely more papers that would deserve to be cited. Our selection remains subjective and besides quality, we also considered the potential impact on clinical practice and future research, as well as publications we felt may be of most interest to our readers (**Figure 1**). FIGURE 1. Graphical Abstract (from Baumgartner H, Iung B, Messika-Zeitoun D. The year in cardiovascular medicine 2022: the top 10 papers in valvular heart disease. Eur Heart J. 2023;44:551-3. https://doi.org/10.1093/eurheartj/ehac777, by permission of OUP on behalf of the ESC) ## Role of lipoprotein (a) in calcific aortic stenosis There is strong evidence of a causal role of lipoprotein (a) [Lp(a)] in the pathogenesis of calcific aortic valve disease but its impact on aortic stenosis (AS) progression remained elusive. Kaiser et al. (1) assessed the association of Lp(a) with incidence and progression of aortic valve calcium (AVC) in 922 individuals of the population-based Rotterdam Study with available Lp(a) measurements and repeated non-contrast computed tomography [median follow-up (FU) 14 years]. Like LDL-cholesterol and prior experience with statins, Lp(a) was robustly associated with baseline and new-onset of AVC but not with AVC progression. These results have important implications for the design of future trials with Lp(a) lowering agents suggesting to focus on patients with elevated Lp(a) and/or the pre-calcific disease phase. ## Vitamin K2 and D in calcific aortic stenosis Vitamin K2 is the most effective cofactor for the carboxylation of proteins involved in the inhibition of arterial calcification and has been suggested to reduce the progression of AVC. Diederichsen et al. (2) studied in a randomized, placebo-controlled trial, the effect of 720μg vitamin K2 plus 25μg vitamin D daily over 24 months in 365 men (71±4 years) with an AVC score >300 arbitrary units (AU). There was no difference in ΔAVC score (primary outcome), overall and in subsets with AVC scores 300–600 or >600 AU. Although the potential benefit of higher dosages and longer treatment duration cannot be excluded, this study rather discourages further trials with vitamin K2. ## Aortic valve replacement in asymptomatic aortic stenosis The timing of surgery in asymptomatic AS remains controversial. In the AVATAR Trial, (3) 157 patients with severe asymptomatic AS confirmed by a negative exercise test and preserved left ventricular ejection fraction (LVEF) were randomly allocated to early surgery or conservative treatment. After a median FU of 32 months, the early surgery group had a significantly lower incidence (15 vs. 35%) of the primary composite endpoint (all-cause mortality, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure) than the conservative treatment group. There was no difference in cardiovascular deaths (9.5 vs. 9.1%) but a trend towards lower all-cause death (10 vs. 20%, P=0.16). These results require confirmation in larger populations, ongoing studies evaluating transcatheter therapies instead of surgery, and the identification of subsets that might benefit the most from an early intervention strategy (e.g. myocardial fibrosis). ## Transcatheter aortic valve implantation vs. surgical aortic valve replacement for aortic stenosis The choice of treatment modality for AS remains controversial. The randomized UK transcatheter aortic valve implantation (TAVI) Trial (4) with the primary endpoint of all-causemortality included 913 patients aged 70 years or older (median 81 years) with severe symptomatic AS and low-to-moderate operative risk (median STS score 2.6%). The trial confirms the non-inferiority of TAVI. There was no difference in stroke, and the rate of severe bleeding was higher with surgical aortic valve replacement, while vascular complications, pacemaker implantation, and paravalvular regurgitation were more frequent with TAVI. In contrast to previous trials, this trial was pragmatic, publicly funded, and designed to compare a TAVI strategy using any valve type and access route vs. surgery in a broad range of patients included according to clinical equipoise regarding the treatment options and not bound by prespecified risk score. ## Cerebral embolic protection during transcatheter aortic valve implantation Stroke due to embolization of debris during the procedure remains a devastating complication of TAVI. Kapadia et al. (5) randomized 3000 transfemoral TAVI patients to use or no use of the Sentinel embolic protection device. The use of the protection device appeared to be safe but the incidence of all stroke within 72 h post-intervention or before discharge (primary endpoint) was overall low and did not differ between groups (2.3 vs. 2.9%). No subgroup by age or potential risk factors could be identified that demonstrated a benefit of cerebral embolic protection. This study does not support the routine use of embolic protection devices. A more selective individualized approach in high-risk–risk patients and its impact on disabling stroke deserve further evaluation. ## Transcatheter edge-to-edge repair (TEER) in older patients with severe, symptomatic degenerative mitral regurgitation Current guidelines recommend TEER in patients with severe degenerative mitral regurgitation (DMR) deemed inoperable or at high risk for surgery without definitive evidence. It is, however, unlikely that a randomized trial will ever be conducted to compare TEER, which is a Class II recommendation in high-risk patients with primary MR, with medical therapy. Benfari et al. (6) analysed large registries (MitraSwiss, Minneapolis Heart Institute, MIDA) including 1187 patients≥65 years with symptomatic severe DMR. TEER was associated with lower mortality adjusted for age, sex, EuroSCORE II, NYHA class, atrial fibrillation, and LVEF. After propensity matching (247 pairs with median EuroSCORE II of 3.0%), TEER consistently showed better survival compared with unoperated patients (49±6 vs. 37±3% at 4 years). Procedural failure was infrequent in this registry of experienced operators but associated with excess mortality. These findings suggest extending indications of TEER in patients aged older than 65 years with severe DMR beyond the current recommendation in inoperable or high-risk patients. ## Prediction of mortality after isolated tricuspid valve surgery Isolated tricuspid valve surgery (ITVS) in non-congenital severe tricuspid regurgitation (TR) is considered a high-risk procedure but outcomevaries markedly depending on patient characteristics and appropriate risk assessment is crucial for decision-making. From data of 466 consecutive patients undergoing ITVS, Dreyfus et al. (7) derived and internally validated a new scoring system (TRI-SCORE – http://www.tri-score.com/) for in-hospital mortality prediction based on eight variables: age ≥70 years, NYHA Class III–IV, right-sided heart failure signs, daily dose of furosemide ≥125 mg, glomerular filtration rate <30 mL/min, elevated bilirubin, LVEF <60%, and moderate/severe right ventricular dysfunction. The TRI-SCORE provided excellent discrimination and calibration with observed and predicted in-hospital mortality increasing from 0% to 60% and from 1% to 65% with a score increase from 0 to ≥9. This score using easily available variables may guide the clinical decision-making process of patients with severe TR. ## Concomitant tricuspid valve repair in patients with degenerative mitral regurgitation Concomitant tricuspid valve repair (TVR) is liberally recommended in patients undergoing mitral valve (MV) surgery as persistent or developing severe TR has been demonstrated to be an important cause of late morbidity and mortality, but the evidence is weak. Gammie et al. (8) randomly assigned 401 patients with moderate TR or less-than-moderate TR but annular dilatation undergoing MV surgery for DMR to a mitral procedure with or without TVR. The primary 2-year endpoint—a composite of reoperation for TR, progression of TR by two grades from baseline or the presence of severe TR, or death was met but mainly driven by the progression of TR (particularly in patients with moderate TR at baseline) while mortality and morbidity were not significantly different. Remarkably, the patients with concomitant TVR had a significantly higher pacemaker implantation rate. While the latter remains a matter of concern, the negative impact of significant TR occurrence on long-term outcomes may not be detected with the short FU of 2 years. ## Thombolysis or surgery in patients with obstructive mechanical valve thrombosis The optimal treatment of obstructive mechanical valve thrombosis remains controversial. Current guidelines favour surgery as long as it can be performed with acceptable risk. Özkan et al. (9) aimed to prospectively evaluate the outcomes of thrombolytic therapy (TT) using slow (6 h) and/or ultraslow (25 h) infusion of low-dose tissue plasminogen activator (25 mg) and surgery. The success rate of TT was 90%. Event rates in the surgical (n = 75) and TT (n = 83) groups were as follows: minor complications 39 vs. 8%, major complications 41 vs. 6%, and 3-month mortality 19 vs. 2%, respectively. Although the study is observational with inherent selection and confounding bias and the number of patients is relatively small, the high success rate and markedly low complication rate of the proposed TT regime may influence our practice in obstructive mechanical valve thrombosis. ## Non-vitamin K antagonist oral anticoagulation in rheumatic heart disease associated atrial fibrillation Patients with rheumatic mitral stenosis and AF were excluded from prior studies comparing vitamin K antagonists (VKAs) and non-vitamin K antagonist oral anticoagulation in AF. The INVICTUS trial (10) randomly assigned 4565 patients with rheumatic heart disease associated atrial fibrillation (mean age: 51 years, 72% women and 85% with mitral stenosis) to standard doses of rivaroxaban or dose-adjusted VKA (open-label trial with blinded assessment of outcomes). Unexpectedly, VKA therapy led to lower rates of the primary endpoint (composite of cardiovascular events or death), stroke, all-cause death, and sudden death than rivaroxaban, without a higher bleeding rate. Possible explanations for these findings include the lower-than-expected stroke rate thereby reducing trial power, closer clinical monitoring, and better compliance in theVKAgroup.Differences in mortality were large and unlikely to be due to chance. The study supports current recommendations of VKA use in mitral stenosis.