Cardiologia Croatica. 2021;16(3-4)

Ingrid Prkačin

Mineralocorticoid receptor antagonists (MRA) play a significant role in the treatment of resistant arterial hypertension and heart failure. There is no clinical study proving that they are the first drug of choice in the treatment of these patients. The most common limitation of the use of this group of drugs, whose most common representative is spironolactone, is hyperkalemia and sexual dysfunction, as well as gynecomastia, which is significantly less pronounced when using eplerenone, a more selective drug. Despite proven efficacy, the use of MRAs like eplerenone in patients with CKD is still limited and it is insufficiently applied in everyday practice. Finerenone, a nonsteroidal, novel, and selective antagonists of mineralocorticoid receptors shows promising differences from steroidal MRA, with a mechanism of action distinct from other agents for cardiorenal medicine in chronic kidney disease and diabetes mellitus type 2, which results in less hyperkalemia. In the FIDELIO-DKD randomized study, finerenone significantly reduced the both composite endpoints vs. placebo, suggesting that is possible postpone progression to kidney damage, thus ushering a new era in the treatment of diabetic kidney disease, which represents the most common cause of end-stage kidney disease in the world.

Héctor Bueno, Brenda Moura, Patrizio Lancellotti, Johann Bauersachs

## Introduction Heart failure (HF) prevalence remains high worldwide with significant sex-related and regional differences in its presentation, management, and outcomes. In 2020, advances in biomarkers and imaging techniques were reported for the diagnosis and prognosis of diastolic dysfunction, HF with preserved ejection fraction or monitoring cardiotoxicity; a new definition of HF with recovered left ventricular ejection fraction (LVEF) was released. Benefits of renin–angiotensin–aldosterone system inhibitors and β-blockers may extend to patients with an LVEF up to 55%. Sacubitril–valsartan improved LV remodelling, biomarker levels, and rates of sudden cardiac death. Two studies investigating the sodium-glucose cotransporter 2 inhibitors empagliflozin and sotagliflozin in patients with HF were reported: the EMPEROR-Reduced trial in patients with HF with reduced EF with or without type 2 diabetes (T2DM) demonstrated a significant reduction in cardiovascular (CV) death and HF hospitalisations (HFH). In patients with T2DM and HF across the whole EF spectrum after a recent HFH, the SOLOIST trial showed a reduction in the primary endpoint of CV deaths, total HFH, and urgent visits for HF. In addition, in patients with kidney disease with or without diabetes mellitus (DAPA-CKD), dapagliflozin prevented the deterioration of renal function. Two novel drugs, the activator of soluble guanylate cyclase vericiguat and the myosin activator omecamtiv mecarbil, in the large outcome trials VICTORIA and GALACTIC-HF predominantly reduced HFH in high-risk patients with worsening HF. In the AFFIRM-AHF trial, intravenous ferric carboxymaltose reduced HFH in patients with iron deficiency after an HF decompensation. Year 2020 will be remembered as the year of coronavirus disease of 2019 (COVID-19). The pandemia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a massive impact on global health and economy. When this article is published, >80 million people will have been infected and >1.75 million will have died of the disease. Many others will have died or worsen of their diseases, many with cardiovascular (CV) disease, as an indirect effect of the fear to seek assistance or the collapse of healthcare systems. Yet, advances in science and medical care continued developing during the year. This article reviews important advances in the field of heart failure (HF) presented in 2020. ## Epidemiology More than 64 million people are living with HF in the world, with an estimated prevalence of 1–2% among adults in developed countries, most often with several comorbidities. (1) The incidence of HF may be stabilizing globally, with decreases in higher-income countries, (2) but increases in lower-income countries, and a shift towards HF with preserved ejection fraction (HFpEF), and increasing due to population ageing and the increase in obesity. (1) Age, traditional risk factors for HF, a sedentary lifestyle, and social deprivation are associated with incident HF. (3) Actually, lifestyle and social determinants of health are attracting more attention in the epidemiology and care of patients with HF. (4) In patients with new-onset HF, the most common first events are cardiac events (36%), recurrent HF (28%), and death (29%). (5) Non-traditional risk factors, such as pacemaker implantation may play a role in the development of HF: within the first 2 years after implantation in patients without known HF, the incidence of fatal and non-fatal HF is 10.6%, six times higher than for age- and gender-matched individuals without HF and pacemaker. (6) Mortality rates of HF seem to be declining less rapidly than previously in the general population. (1) Among patients with cardiac resynchronization therapy (CRT), a gradual decrease in sudden cardiac death risk has been observed since the early 2000s (7) with implications for the role of implantable defibrillators and the design of comprehensive HF care models. Significant regional differences in the management of acute HF have been identified, including timing and types of treatments used, (8) and rates and time trends of readmission. (2, 9, 10) However, the importance of distinguishing worsening/chronic HF from new-onset HF in patients with first hospitalization has been highlighted, as patients with worsening/chronic HF have a significantly greater comorbidity burden and higher adjusted risks of mortality and HF readmission. (10, 11) ## Clinical aspects ## Diagnostics and risk stratification ## Imaging Imaging is pivotal in the diagnosis and risk stratification of patients with HF. The European Society of Cardiology (ESC) Heart Failure Association (HFA) has recently highlighted in a position statement the central role of full echocardiographic examination in patients admitted for acute heart failure (AHF). (12) Once the patient is stabilized, the added value of routine cardiac magnetic resonance (CMR) over echocardiography alone to help diagnose the causes of HF not related to ischaemic heart disease has been questioned. (13) Selective rather than routine CMR for identifying specific HF aetiologies is more cost effective. Noteworthy, CMR could serve to better define HFpEF phenotypes and to select patient specific therapies, such as MRA may be for HFpEF patients with myocardial fibrosis. (14-17) The diagnosis of HFpEF remains challenging especially in patients with coexisting conditions that account for dyspnoea. Diastolic dysfunction, left atrial enlargement, elevated left atrial pressure, and pulmonary hypertension are common in these patients. (18, 19) The 2016 diastolic dysfunction grading algorithm proposed by the European Association of Cardiovascular Imaging has shown improved prognostic value compared to the 2009 one. (20) However, the high number of patients with doubtful classification renders clinical decision making challenging. (21) The analysis of LA mechanics, LA strain, and left ventricular (LV) global longitudinal strain (22) allows to better classify the degree of diastolic dysfunction and improves individual risk stratification. Two algorithms (H2FPEF and ESC HFA-PEFF) may facilitate HFpEF diagnosis. These two scores have equivalent predictive power of incident HF hospitalization or death among patients without a clinical diagnosis of HF. (23) Although LV ejection fraction (LVEF) is key for HF classification, it remains a crude estimate of LV function. Intriguingly, 17% of patients with initially preserved LV systolic function show a decrease in LVEF below 40% at 6 months follow-up, which is associated with more cardiac events. (24) Parameters of LV mechanics (LV strain, multilayer strain and myocardial work) provide incremental prognostic information over LVEF. (22, 25) The benefit of treatment [i.e. sacubitril/valsartan (SV)] on LV remodelling is also better captured by LV strain. (26) Myocardial mechanics is linked to coronary microvascular dysfunction in patients with hypertensive HF. (27, 28) In AHF, cardiac sympathetic nerve dysfunction, as evaluated by 123I-metaiodobenzylguanidine imaging, is associated with poor outcome irrespective of LVEF. (29) ## Biomarkers Biomarkers are key for diagnosis and prognostic evaluation in patients with HF. Circulating biomarkers related to extracellular matrix regulation were abnormal in patients with HFpEF, displayed prognostic value, and were influenced favourably by SV in PARAGON-HF. (30) In HF with reduced LVEF (HFrEF), absolute NT-proBNP, hs-TnT, and sST2 levels predict outcomes independent of age, sex, and LVEF category. (31) Differential circulating levels of biomarkers associated with ageing in patients with HF have been reported, with increasing levels of proteins associated with extracellular matrix organization, inflammatory processes, and tumour cell regulation and lower expression of tumour proliferation functions. (32) In AHF, a specific challenge is to identify infection as a trigger of AHF. Procalcitonin (PCT) has emerged as an alternative for C-reactive protein in diagnosing bacterial infection. In a recent randomized, multicentre, open study, a strategy of PCT-guided initiation of antibiotic therapy was more effective than standard care in improving clinical outcomes. (33) Omics phenotyping is likely the next frontier to unravel disease mechanisms and heterogeneity. (34) As a recent example, incorporating a panel of three metabolite-based biomarkers into a risk score improved the prognostic utility of NT-proBNP by predicting long-term CV death. (35) ## Heart failure during the COVID-19 pandemic The role of the angiotensin-converting enzyme (ACE) receptor 2 in the infection of human cells by SARS-CoV-2 and in the pathophysiology of COVID-19, (36) and the poor prognosis of cardiac patients with COVID-19 (37) raised the concern of a potential deleterious effect of the treatment with ACE inhibitors and angiotensin receptor blockers (ARB). These drugs may either decrease acute lung damage, prevent angiotensin-II-mediated pulmonary inflammation or increase the SARS-CoV-2 pulmonary damage by the up-regulation of ACE2 receptors. (38, 39) Observational studies refuted the hypothesis of a deleterious effect of ACEI/ARB. (40-43) The BRACE CORONA trial found no worse outcomes in patients with COVID-19 allocated to continuation or interruption of their chronic ACEI/ARB treatment (presented at the ESC Congress, data not published). The incidence of AHF or decompensation of chronic HF among patients with Covid-19 is high and with poor prognosis. (44) Indirect effects of the pandemic included the reduction in HF hospitalizations during local outbreaks (45-47) with increases in their hospital mortality, (45, 47) and major challenges for the management and Follow-up of HF patients, and the conduct of clinical trials. Recommendations to overcome these challenges have been released. (48-50) ## Sex and heart failure Women account for half of patients with HF with a lower incidence rate until the age of 75 years, a higher proportion of HFpEF, probably related to the higher prevalence of obesity and diabetes mellitus. (1) Women with HF present a greater symptom burden and poorer quality of life as compared with men. (51) Significant sex-related differences have been described in Europe in the management of acute and chronic HF (8, 52) including a lower use of guideline-directed medical therapies—which seem to be mostly explained by older age and comorbidity rather than by sex itself—with lower crude rates of death and HF hospitalization in women. The lack of sex-related differences in the clinical effect of HF therapies (53, 54) does not justify these differences, although the possibility has been suggested that women with HF might benefit from treatment to a higher level of LVEF than previously considered. (54) A different perspective of the gender gap in HF is the lower proportion of female authors in HF practice guidelines and trials, ranging between 11% and 24% only, with modest increases over time in European and US guidelines references but not in HF trials. Importantly, HF trials with a woman first or senior author are associated with a higher proportion of enrolled female participants. (55) ## Comorbidities Comorbidities are important because they impact the clinical presentation, management, and outcomes of HF patients. The burden of comorbidities is higher in older patients, women and those with HFpEF, (56-58) which are often ignored. (59) Particularly relevant conditions in HF patients include atrial fibrillation, (60) which has complex interrelations with HF needing more research. (61, 62) One example is the lack of increase in mortality risk associated with elevated heart rate in patients with HFrEF and atrial fibrillation, as compared to sinus rhythm. (60, 63) Renal disease is one other, with renal function often changing during the course of the disease or as a response to HF therapies. Clinical responses, including worsening renal function and pseudo-worsening renal function, and their pathophysiological correlates, i.e. tubular function (diuretic response) beyond estimated glomerular filtration rate (eGFR), need to be understood to be properly managed, adapting therapies to the changing situation. (64, 65) ## Specific situations ## Acute heart failure In patients with acute HFrEF, istaroxime, an inhibitor of the sarcolemmal Na+/K+ pump activating the SERCA2a pump, improved cardiac function without major adverse effects in a small mechanistic trial. (66) Cimlanod, a nitroxyl donor infused over 48 h, was reasonably well tolerated at a lower dose whereas higher doses caused unacceptable hypotension. There was improvement of NT-ProBNP but not on dyspnoea (presented at HFA Discoveries, data not published). A number of position papers have summarized the role of imaging (12) or the management of AHF in specific situations, such as acute coronary syndromes (67) or atrial fibrillation. (68) ## Cardiogenic shock While its incidence seems to be decreasing, cardiogenic shock still conveys a high mortality risk. (69) A new clinical classification, (70) and two position papers (71, 72) on cardiogenic shock have been published this year. The SWEdish evaluation of left Ventricular Assist Device (SweVAD) will examine the impact of mechanical circulatory support vs. guideline-directed medical therapy on survival in a population of AHF patients ineligible for heart transplant. (73) ## Peripartum cardiomyopathy Peripartum cardiomyopathy (PPCM) is the first cause of HF in women during/after pregnancy (74-76) The ESC EORP registry on PPCM enrolled >700 women with this condition from 49 countries. It showed that PPCM affects women from any region or ethnicity. Within 6 months after diagnosis, the average rates of maternal mortality, readmission, and neonatal mortality were, respectively, 6%, 10%, and 5%, with marked regional variations. Recovery of LVEF occurred in 46% of women. (77) The management of these patients is reviewed in a recent paper. (78) ## HF with recovered left ventricular ejection fraction This year, a working definition of HF with recovered left ventricular ejection fraction (HFrecEF) has been proposed. This includes: (i) documentation of a decreased LVEF 40%. (79) Reverse LV remodelling is associated with improved myocyte and LV chamber contractility and better clinical outcomes. However, a significant proportion of patients with HFrecEF develop recurrences of LV dysfunction and HF. Despite improvements in structural and functional abnormalities, many of the multilevel molecular changes occurring during LV remodelling remain dysregulated in reverse remodelled hearts. Therefore, guideline-directed medical and device therapy for patients with HFrecEF should be continued indefinitely with close clinical follow-up. (79) ## HF in cancer patients The role of CV imaging in cancer patients receiving cardiotoxic therapies has been highlighted in a position statement by the HFA (12) and in the European Society for Medical Oncology guidelines. (80) The role of focus echocardiography (81) and CMR (82) has also been recently discussed. In daily practice, caution should, however, be given if using late gadolinium enhancement or qualitative T2-weighted STIR imaging-only approach for the exclusion of checkpoint inhibitor-associated myocarditis. (83) Imaging is cornerstone for monitoring cardiotoxicity and identifying subtle impairment of myocardial function occurring prior crossing the traditionally defined threshold of LV systolic dysfunction (LVEF 40%), highest among chronic lung disease patients. (88) The presence of RVD at CRT implantation predicts worsening LV remodelling and survival. (89) ## Pharmacotherapies ## Angiotensin receptor–neprilysin inhibitors (paragon, paradigm, parallax) Angiotensin receptor–neprilysin inhibitor (ARNI) showed, in a sub-analysis of PARADIGM-HF, a reduction in sudden cardiac death risk regardless of the use of implantable cardiac defibrillators. (90) Reduction in ventricular volumes and increase in LVEF have been observed with standard echocardiography in patients after 6 months on SV, but improvement in global longitudinal strain is apparent after 3 months. (26) In a small cohort of patients with end stage renal disease, SV showed efficacy and safety. (91) The LIFE Trial, comparing SV to valsartan in NYHA Class IV HFREF patients, although prematurely interrupted because of the COVID 19 pandemia, will still provide information about ARNI as a treatment option for advanced HF patients. (92) The PARALLAX trial tested the efficacy of SV vs. optimal individualised background therapy in HFpEF patients and found a reduction in NT-proBNP from baseline to 12 weeks but no effect on six-minute walk distance from baseline to 24 weeks (presented at ESC 2020—data not published). In the PARAGON Trial in patients with HFpEF, SV did not result in a lower rate of total hospitalizations for HF and death. Of the 12 pre-specified subgroup analyses, sex and LVEF appeared to modify the effect of SV vs. valsartan on the primary composite outcome. Although no benefit was apparent in men, there was a significant reduction in HF hospitalizations in women. (93) Also, patients seemed to derive more benefit from SV when started early after hospitalization. (94) Baseline and mean achieved systolic blood pressure of 120–129 mm Hg identified the lowest risk HFpEF patients, but the blood pressure-lowering effects of SV did not account for its effects on outcomes, regardless of sex. (95) Compared with valsartan, SV reduced the risk of renal events and slowed the decline in estimated glomerular filtration rate. (96) Reduction in serum uric acid was also associated with improved outcomes. (97) A meta-analysis assessing the efficacy of different renin–angiotensin–aldosterone system (RAAS) antagonists in clinical trials performed in HFpEF patients (PEP-CHF, CHARM-preserved, I-PRESERVE, TOPCAT, PARAGON-HF) showed no statistical difference in all-cause and CV mortality among RAAS antagonists and placebo, but a significantly decreased risk in HF hospitalizations in patients allocated to receive ARNI compared with controls (OR, 0.73, 95% CI, 0.61–0.87) and ARB (OR 0.80, 95% CI, 0.71–0.91). (98) A patient-level data analysis from the PARADIGM-HF and PARAGON-HF trials (SV vs. enalapril in HFrEF and SV vs. valsartan in HFpEF, respectively), and the CHARM-Alternative and CHARM-Preserved trials (candesartan vs. placebo) showed that, compared with RAAS inhibitors, SV improved outcomes across the range of LVEF, with a risk reduction (RR) of 0.54 [95% confidence interval (CI) 0.45–0.65] for the recurrent primary endpoint compared with putative placebo (P 60%. (99) These results are in line with prior post hoc analyses from the TOPCAT study and β-blocker trials suggesting that the cut-off of LVEF for a beneficial treatment effects is 55%. These analyses show that in the sparsely studied population of patients with an LVEF of 40–55%, several HF treatments might provide benefit (**Figure 1**). (100) FIGURE 1. Results from different trials testing a number of drugs commonly used to treat heart failure, pointing to an extended benefit up to a left ventricular ejection fraction of 55%. For patients with left ventricular ejection fraction >55%, a population group usually presenting several comorbidities, there is still no evidence of a drug improving prognosis. Reprinted from Böhm et al. (100) (from Bueno H, Moura B, Lancellotti P, Bauersachs J. The year in cardiovascular medicine 2020: heart failure and cardiomyopathies. Eur Heart J. 2021 Feb 11;42(6):657-670. https://doi.org/10.1093/eurheartj/ehaa1061, by permission of OUP on behalf of the ESC) ## Sodium-glucose cotransporter 2 inhibitors (EMPEROR-Reduced, DAPA-HF, SOLOIST, VERTIS, SUGAR-DM-HF, EMPA-TROPISM [ATRU-4]) In patients with type 2 diabetes, the sodium-glucose cotransporter 2 (SGLT-2) inhibitors empagliflozin and dapagliflozin reduce the risk of HF hospitalization regardless of baseline CV risk or history of HF. (101, 102) In The VERTIS trial, ertugliflozin did neither significantly reduce CV events, nor the combined endpoint of CV death/HF hospitalization (103) but reduced HF hospitalizations. (104) In patients with HFrEF, DAPA-HF has demonstrated a significant reduction in CV mortality and HF events. (105, 106) This robust effect was analysed in more detail in several seminal papers published in 2020. The benefit of dapagliflozin was independent of the diabetes status, occurring across all levels of HbA1C, (107) as well as of baseline renal function or blood pressure, patient age, or background HF therapy. (108–111) Dapagliflozin improved symptoms, physical function, and quality of life (112) and was shown to be a cost-effective treatment for HFrEF in the UK, German, and Spanish healthcare systems. (113) Dapagliflozin also reduces the rate of decline in renal function in HFrEF patients. (111) as well as in patients with chronic kidney disease, as shown in the DAPA-CKD trial, where treatment with dapagliflozin reduced the risk of worsening renal function, end-stage kidney disease, or death. (111) This protective effect was observed in patients with or without diabetes. (111, 114) Empagliflozin also showed marked beneficial effects in HFrEF patients independently from diabetes status, with a significant reduction in the primary composite endpoint of CV death and HF events (hazard ratio (HR), 0.75; 95% CI, 0.65–0.86; P 2 of body-surface area per year, P 50%. (123) Sotagliflozin was also investigated in patients with type 2 diabetes, chronic kidney disease, and elevated CV risk (SCORED); (124) primary endpoint (changed during the study to a composite of CV death, total HF hospitalizations and urgent visits for HF) was significantly reduced in patients treated with sotagliflozin (HR, 0.67; 95% CI, 0.52–0.85; P 2 nor other predefined outcome parameters. (131) ## Cardiac myosin activators and inhibitors ## Omecantiv mecarbil (GALACTIC-HF, EXPLORER-HCM) Omecamtiv mecarbil, a cardiac myosin activator that enhances cardiomyocyte contraction, given twice daily on the basis of plasma levels of the drug, significantly reduced the primary endpoint of HF hospitalisation and CV death in patients with HFrEF and a recent HF event (HR, 0.92; 95% CI, 0.86–0.99; P = 0.03) but had no impact on any of the secondary outcomes (CV death, change in symptom score, first HF hospitalization, and death from any cause). (132) A similar compound, danicamtiv, increased stroke volume, improved global longitudinal and circumferential strain, decreased LA minimal volume index, and increased LA function index when compared to placebo in a small phase 2a trial in 40 patients with stable HFrEF. (133) On the other hand, mavacamten, a myosin inhibitor, significantly improved the combined primary endpoint of increase in peak oxygen consumption (pVO2) and reduction in NYHA class in a phase 3 trial in patients with obstructive hypertrophic cardiomyopathy. Also, outflow tract obstruction and health status were improved. (134) ## Other therapies ## Ferric carboxymaltose (AFFIRM-AHF) In iron-deficient patients hospitalized for acute HF (AFFIRM-AHF), (135) intravenous ferric carboxymaltose compared to placebo was associated with a trend to reduced total HF hospitalizations and CV death (rate ratio 0.79, 95% CI 0.62–1.01, P = 0·059). In a pre-specified sensitivity analysis considering the impact of the COVID-19 pandemic, a statistically significant difference in favour of ferric carboxymaltose was reported for the primary endpoint was reported, but not in CV death risk. (136) ## MicroRNA-132 inhibition In a first clinical trial limited by a small number of HF patients, the antisense oligonucleotide drug directed against miR-132, CDR132L, (137) was well tolerated and showed first hints for a cardiac functional improvement. (138) ## Comprehensive disease-modifying pharmacological therapies Using data from the EMPHASIS-HF, PARADIGM-HF, and DAPA-HF trials lifetime gains in survival have been estimated with comprehensive therapy (SV, β-blocker, MRA, and SGLT-2 inhibitor) vs. RAAS and β-blockers in patients with chronic HFrEF. (11, 139) The HR for the composite endpoint of CV death or hospitalisation for HF was 0.38 (95% CI 0.30–0.47). Favourable results were also calculated for CV death alone, hospitalization for HF alone, and all-cause mortality. Comprehensive therapy could prolong overall survival 6.3 years in average in a 55-year-old patient. These results support the combination use of SV, β-blockers, mineralocorticoid receptor antagonists, and SGLT-2 inhibitors as a new therapeutic standard. ## Device/interventional therapies ## Secondary (or functional) mitral regurgitation (COAPT) Secondary (or functional) mitral regurgitation (SMR) occurs frequently in HFrEF and is associated with progressive symptoms and worse prognosis. If SMR is treated by edge-to-edge repair, patients with optimal result at discharge and 12-month follow-up displayed best outcomes. (140) ## Cardiac resynchronization therapy (STOP-CRT) Cardiac resynchronization therapy (STOP-CRT) is an integral part of treatment in patients with HFrEF, especially with left bundle branch block and wide QRS. In a selected cohort of patients with LVEF >50% during CRT and neurohormonal blockade, the STOP-CRT study investigated the feasibility and safety of neurohormonal blocker withdrawal. The incidence of adverse LV remodelling or clinical outcomes was low after discontinuation of betablockade/RAAS inhibition. However, comorbidities prompted the continuation of neurohormonal blockers in many patients. (141) In patients with HFrEF who are ineligible for CRT, baroreflex activation therapy (BAT) may be useful in addition to optimal drug therapy. In the BeAT-HF study, BAT was safe and significantly improved symptoms, quality of life, exercise capacity, and NT-proBNP. (142) On the basis of these data, BAT was approved in the USA, while ongoing follow-up in the BeAT-HF study will assess effects on hard outcomes. ## Specific management issues ## Telemedicine and remote monitoring The role of telemedicine and remote monitoring in the management of HF patients is still controversial. An observational study in three European countries showed that pulmonary artery pressure-guided HF management is feasible and safe and associated with better outcomes haemodynamic and clinical outcomes. (143) Also, preliminary results testing non-invasive remote physiological monitoring from a wearable sensor showed promising results in the early detection of impending HF rehospitalisation. (144) However, different modes of remote monitoring failed to show a benefit in improving treatment, quality of life, (145) or clinical outcomes. (146) Moreover, remote monitoring with a cardiac implanted electronic device increased clinical activity for patients with HF and AF, with no associated reduction in mortality, and conversely, greater risk of CV hospitalisation amongst patients with persistent/permanent AF. (147) In the COVID-19 era, remote monitoring is a useful tool for managing HF patients. (148) ## Self-care and palliative care Self-care is essential in the management of chronic HF. Practical advice for key activities and priorities for self-care is given in an HFA manuscript. (149) At the end of the HF pathway, palliative care should be introduced early, focusing on symptom management, (150) regardless of prognosis, but actually only a minority in Europe receive it. (151) Providing palliative care substantially reduces hospitalizations, with no clear adverse effect on survival. (152)

Krešimir Gabaldo, Domagoj Vučić, Ivan Bitunjac, Marijana Knežević Praveček, Katica Cvitkušić Lukenda, Tomislav Krčmar, Blaženka Miškić

Diabetes and its complications causes up to 9% of total mortality worldwide. Peripheral arterial disease is, in addition to cardiovascular diseases, the most common complication of diabetes with a prevalence that increases with age and the duration of diabetes. The specificity of peripheral artery disease in diabetics is the diffuse involvement of the arterial system, especially the popliteal arteries. Consequently, diabetes is still the main cause of small and large limb amputations, which, in addition to a reduction in the quality of life, significantly affects the survival of patients. Since the developed of atherosclerotic disease involves a number of complications from the professional domain of various subspecialties, such as diabetic foot, it is necessary to organize multidisciplinary teams for the diagnostic and therapeutic purposes. For this purpose, the General Hospital “Dr. Josip Benčević” in Slavonski Brod organized a multidisciplinary team with the goal of early recognition of peripheral artery disease and application of timely treatment. Experience from everyday clinical practice indicates that proper functioning of the team requires an accurate diagnostic and therapeutic algorithm to avoid long waiting lists for imaging, which includes Color Doppler and multislice computed tomography. The diagnostic algorithm was based on the ankle-brachial index, and its value and clinical picture guided and determined the degree of urgency and the type of image processing. By integrating the algorithm into the online database registry, we were able to more easily monitor the incidence rate, treatment success, and dependence on the entered variables. We hope that this approach will result in earlier detection of symptomatic disease and thus a significant reduction in lower limb amputations and, ultimately, mortality.

José Luis Zamorano, Fausto J. Pinto, Jorge Solano-López, Chiara Bucciarelli-Ducci

## Introduction The past year has been a unique one owing to the outbreak of COVID-19, which has affected the population worldwide, with the ensuing economic and social consequences. The field of cardiology has not escaped this reality bringing with it changes in our everyday clinical praxis. The contribution of different imaging techniques to the cardiac involvement of COVID-19 with diagnostic and prognostic implications has been published very expeditiously. It is still pending to ascertain the long-term outcome of the different degrees of cardiac injury. The recent publication of the ISCHEMIA trial (1) has resulted in a heated debate on the role of ischaemia testing in patients with stable coronary artery disease (CAD), with some colleagues advocating that ISCHEMIA has sanctioned the limited role of myocardial ischaemia in patients with stable CAD. However, this is not the conclusion of the trial, nor its primary hypothesis nor the study design and extrapolation beyond these boundaries could be incorrect. Ischaemia imaging will continue to play a major role in the diagnosis and management of stable CAD as both physicians and patients still need to clarify the cause of symptoms, coronary anatomy does not infer ischaemia or explains symptoms, and chest pain can also be of non-coronary origin. Most importantly, there is no randomized trial demonstrating that an imaging approach of coronary anatomy is superior to functional testing. In fact, PROMISE (2) is the only trial that compared the two strategies and it did not demonstrate any difference in outcome between the two approaches. Furthermore, advances in the knowledge and application of artificial intelligence (AI) are consolidating the need for greater attention and interest regarding a tool that in a few years will become part of our daily clinical practice. Finally, we highlight the introduction of new recommendations in the use of imaging techniques in the new practice guidelines. We then summarize the most outstanding studies from the last year relating to the most relevant imaging techniques in current cardiology (**Figure 1**). FIGURE 1. Graphical Abstract - Raw 3D data were streamed from standard echocardiograph using custom connection to 3D DICOM viewer workstation (CarnaLife Holo, MedApp, Krakow, Poland) for real-time, dynamic 3D rendering and wirelessly transferred into HoloLensmixed reality display (Microsoft, Redmond, USA) to overlay non-obstructive 3D data hologram upon reality view. Data were visible as a semitransparent holographic cube positioned in a convenient sector of visual field of echocardiographist and shared by interventional cardiologist. Reproduced with permission from Kasprzak et al. (7) (from Zamorano JL, Pinto FJ, Solano-López J, Bucciarelli-Ducci C. The year in cardiovascular medicine 2020: imaging. Eur Heart J. 2021 Feb 14;42(7):740-749. https://doi.org/10.1093/eurheartj/ehaa1035, by permission of OUP on behalf of the ESC) ## Echocardiography Echocardiography continues to be one of the most used methods to better understand cardiac pathophysiology and different pathological and even normal aspects of cardiac function and also plays a central role in daily patient management. Several papers have been published in 2020, and here, we highlight just a small proportion of the large amount of literature that has been produced during this year, a very unusual one, considering the COVID-19 pandemic that affected all of us. One area of great current interest is transthyretin amyloidosis cardiomyopathy (ATTR-CM), an increasingly recognized cause of heart failure (HF) and with the new treatment strategies underway, some already with important clinical results; its recognition is becoming a must in clinical scenarios. Echocardiography has always played a role in the diagnosis of amyloidosis and that role is further strengthened with the exponential increase in relevance of amyloidosis. Chacko et al. (3) in an international network characterized the structural and functional echocardiographic phenotype across the spectrum of wild-type (wtATTR-CM) and hereditary (hATTR-CM) transthyretin cardiomyopathy and the echocardiographic features predicting prognosis. They studied 1240 patients with ATTR-CM, comprising 766 with wtATTR-CM and 474 with hATTR-CM, of whom 314 had the V122I variant and 127 the T60A variant. At diagnosis, patients with V122I-hATTR-CM had the most severe degree of systolic and diastolic dysfunction across all echocardiographic parameters and patients with T60A-hATTR-CM the least; patients with wtATTR-CM had intermediate features. Stroke volume index, right atrial area index, longitudinal strain, and E/e′ were independently associated with mortality (P 50%) were divided into five groups according to the type of BAV dysfunction: (i) normal function BAV, (ii) mild AS or aortic regurgitation (AR), (iii) ≥ moderate isolated AS, (iv) ≥ moderate isolated AR, and (v) ≥moderate mixed AS and AR. LV systolic dysfunction based on 2D speckle-tracking echocardiography was defined as a cut-off value of left ventricular global longitudinal strain [LVGLS (−13.6%)]. The primary outcome was aortic valve intervention or all-cause mortality. The proportion of patients with LVGLS ≤−13.6% was the highest in the normal BAV group (97%) and the lowest in the group with moderate and severe mixed AS and AR (79%). During a median follow-up of 10 years, 210 (41%) patients underwent aortic valve replacement and 17 (3%) died. Patients with preserved LV systolic function (LVGLS ≤−13.6%) had significantly better event-free survival compared to those with impaired LV systolic function (LVGLS >−13.6%). LVGLS was independently associated with increased risk of events (mainly aortic valve replacement): hazard ratio (HR) 1.09; P 10-fold higher rate of coronary revascularization during the first year after CMR. The implication is that patients without ischaemia or LGE on CMR have a low incidence of cardiac events, little need for coronary revascularization, and low spending on subsequent ischaemia testing. The cost-effectiveness study of SPINS demonstrated that, stress CMR can be a cost-effective gatekeeping tool prior to invasive coronary angiography (ICA) in patients at risk for obstructive CAD. (16) In particular, the incremental cost-effectiveness ratio for the CMR-based strategy compared with the no-imaging strategy was $52 000/quality-adjusted life years (QALY), whereas the incremental cost-effectiveness ratio for the immediate ICA strategy was $12 million/QALY compared with CMR. Recent developments on quantitative CMR stress perfusion with automated measurements using AI (17) have been validated clinically. (18) The advances in computation power permit inline automated annotation and the use sophisticated myocardial perfusion models (e.g. the blood-tissue exchange model) to be solved with low variability in real time during scanning vs. hours of complex analysis with potentially variable results. Knott et al. assessed the prognostic significance of this new technology in 1 049 patients with known or suspected coronary artery disease reduced myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) quantified automatically inline were strong independent predictors of adverse cardiovascular outcome. For each 1 mL g−1 min−1 decrease in stress MBF, the adjusted HRs for death and major cardiovascular event (MACE) were 1.93 (95% CI 1.08–3.48; P = 0.028) and 2.14 (95% CI 1.58–2.90; P 2 weeks from original diagnosis and resolution of the respiratory symptoms and negative results on a swab test at the end of the isolation period) of whom n = 67 recovered at home (n = 18 asymptomatic, n = 49 minor-to-moderate symptoms) and only n = 33 with severe symptoms requiring hospitalization. The cohort was compared to 50 healthy and risk factor-matched controls. They showed that 78 patients (78%) had abnormal CMR findings, including raised myocardial native T1 (n = 73), raised myocardial native T2 (n = 60), presence of myocardial LGE (n = 32), or presence of pericardial enhancement (n = 22). At the time of the CMR, high-sensitivity troponin T (hsTnT) was detectable (>3 pg/mL) in 71 patients recently recovered from COVID-19 (71%) and significantly elevated (>13.9 pg/mL) in 5 patients (5%). Compared with healthy controls and risk factor-matched controls, patients recently recovered from COVID-19 had lower LVEF, higher left ventricle volumes, and raised native T1 and T2. Whilst the results of widespread cardiac changes detected by CMR in asymptomatic patients previously infected by the SARS-CoV-2 virus are intriguing, the clinical significance of these findings is unclear and still needs to be determined. Unfortunately, the results of this study have been overemphasized, and in part sensationalized, by the media with the inevitable results of creating concerns among members of the public, confusion among physicians, and a degree of scepticism among imaging experts internationally. Multicentre large-scale prospective CMR studies to detect and measure acute and chronic cardiac damage of the COVID-19 infection are currently underway, COVID-Heart and COVID-PHOSP among others. The recommendations for the use of CMR in the diagnosis and management of patients with cardiovascular disease are increasing. In the latest release of ESC guidelines in 2020, the Guidelines for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-segment Elevation (12) includes for the first time CMR as a class I recommendation, level of evidence B in all patients with MI and unobstructed coronary arteries without an obvious cause. ## Computed tomography Over the past year, studies concerning computed tomography (CT) in the cardiovascular scenario have strengthened its ability as a predictor of cardiovascular events, and as a therapeutic guide in primary prevention. Recently, ROBINSCA trial assessed the effectiveness of cardiovascular disease (CVD) screening in asymptomatic participants using the SCORE model (n = 12 185) or coronary artery calcium (CAC) scoring (n = 12 950). Both arms were stratified into low, intermediate, or high 10-year risk for developing fatal and non-fatal cardiovascular disease. SCORE screening arm identified 45.1% at low risk (SCORE 20%. Based on PCE the number needed to treat at 5 years (NNT5) was greater than or similar to the number needed to harm (NNH5) among the three estimated cardiovascular risk strata. Conversely, CAC ≥100 and CAC ≥400 identified subgroups in which NNT5 was lower than NNH5. This was true both overall (for CAC ≥100, NNT5 = 140 vs. NNH5 = 518) and within all cardiovascular risk strata. Also, CAC = 0 identified subgroups in which the NNT5 was much higher than the NNH5. (28) Olesen et al. stratified 48 731 patients by diabetes status and CAD severity (no, non-obstructive, or obstructive) assessed by coronary CT angiography (CCTA). With the median follow-up of 3.6 years, they found that diabetic patients had higher death rates than non-diabetic patients, irrespective of CAD severity. Still, those diabetic patients without CAD have a low risk of MI similar to non-diabetic patients. (29) Finck et al. conducted a study with 1615 patients with suspected CAD who underwent a CCTA with morphological analysis of the atheromatous plaque. After an average of 10.5 years, there were 36 cardiac deaths and 15 non-fatal MI. Among characteristics of the plaque; the spotty or gross calcification pattern and the napkin ring sign (NRS) (low-attenuating central portion with ring-like higher attenuation) were predictive for events. Yet, only spotted calcified plaques and NRS convey further prognostic value above clinical features and the severity of coronary stenosis. In a stepwise approach, the prediction of endpoint beyond clinical risk could be improved by including the severity of CAD (x2 of 27.5, P 2 of 3.89, P = 0.049). (30) Another study assessed whether non-calcified low-attenuation plaque burden on CCTA might have a better predictor of MI than CAC or coronary stenosis severity. They followed up 1769 patients with suspected angina for median 4.7 years finding that low-attenuation plaque burden was the strongest predictor of MI (P = 0.014), irrespective of cardiovascular risk score, CAC score, or coronary artery stenosis. Patients with low-attenuation plaque burden >4% were almost five times more likely to have subsequent MI (P 50%). On multivariate analysis, only the baseline total PAV and %DS independently predicted the development of obstructive lesions (P 0.05). (32) The investigators of the ICONIC study performed a nested case–control study of patients who underwent a CCTA prior developing an acute coronary syndrome. Culprit lesions were confirmed by invasive coronary angiography and coregistered to baseline CCTA images. They found that HRPs on baseline CCTA were less prevalent in non-obstructive plaques (19.7%) than in obstructive plaques (46.8%). Even though non-obstructive plaque comprised 81.3% of HRP lesions overall. Among patients with identifiable culprit lesion precursors, the adjusted HR was 1.85 (95% CI 1.26–2.72) for HRP, with no interaction between %DS and HRP. Compared to non-obstructive HRP lesions, obstructive lesions without HRP exhibited a non-significant HR of 1.41 (95% CI 0.61–3.25) (**Figure 2**). (33) FIGURE 2. Coronary computed tomography angiograms demonstrating high-risk plaque (HRP) in culprit lesion precursors. A 61-year-old male exsmoker exhibited a high-risk plaque extending from the (A) left main to the (B) proximal left anterior descending artery with (C) 41% diameter stenosis severity, (D) positive remodelling (white arrow), and low-attenuation plaque (green arrow). There is also diffuse calcification. One month later, the patient presented with a non-ST-elevation myocardial infarction. A 55-year-old male with hypertension and hyperlipidaemia exhibited a high-risk plaque with (E) only 35% DS severity, but (F) positive remodelling, low-attenuation plaque, and napkin-ring sign. The patient presented with a non- ST-elevation myocardial infarction 2months later. Reproduced with permission from Ferraro et al. (33) (from Zamorano JL, Pinto FJ, Solano-López J, Bucciarelli-Ducci C. The year in cardiovascular medicine 2020: imaging. Eur Heart J. 2021 Feb 14;42(7):740-749. https://doi.org/10.1093/eurheartj/ehaa1035, by permission of OUP on behalf of the ESC) Recently, the ADVANCE Registry presented its 1-year results of 4288 patients with suspected CAD in whom a 30% coronary stenosis was identified by CCTA. They evaluated the relationship of fractional flow reserve derived from CCTA (FFRCT) with clinical outcomes. There were 55 events; 78% of them occurred in patients with an FFRCT ≤0.80 (P = 0.06). Time to first event (cardiovascular death or MI) occurred more in patients with an FFRCT ≤0.80 compared with FFRCT >0.80 patients (25 [0.80%] vs. 3 [0.20%]; relative risk (RR): 4.22; 95% CI: 1.28–13.95; P = 0.01). Concerning the downstream care, the majority of patients in whom medical therapy was the recommended treatment strategy following FFRCT continued on only medical therapy at 1 year (92.9%), and when the site recommendation was for revascularization, the majority (68.9%) were revascularized. (34) An innovative study introduces a new parameter of dynamic CT perfusion (CTP) called stress MBF rate (SFR). This is defined as the ratio of hyperaemic (ATP infusion) MBF in an artery with stenosis to the hyperaemic MBF in a non-diseased artery. Eighty-two patients were derived to invasive angiography for suspected CAD. Stress dynamic CTP and CCTA was performed before invasive angiography. Out of 101 vessels with 30–90% stenosis on invasive angiography, FFR resulted hemodynamically significant (50% stenosis in quantitative ICA) vs. SPECT. 755 patients (mean age 62.3 ± 9.5 years) were included. The PET MPI with the novel tracer demonstrated to have superior sensitivity than SPECT [71.9%, 95% CI 67.0–76.3%; P 35% (P = 0.0014) and early H/M for LVEF improvement of at least 10% from basal. (42) CA implies ominous prognosis for patients. Early diagnosis with sufficient accuracy and safety remain still challenging. Rosengren et al. published the largest study of CA patients (both AL and ATTR) examined with Pittsburgh compound (11C-PIB) PET. In this study, the diagnostic accuracy of 11C-PIB PET is remarkable with high sensitivity (94%) and specificity (93% to 100%) for distinguishing CA patients from both non-amyloid hypertrophic and healthy controls. 11C-PIB uptake was significantly higher in AL-CA patients than in ATTR-CA patients (P < 0.001). In the study from Lee et al., they also demonstrate correlation between 11C-PIB uptake and myocardial histology in CA. In addition, after a median follow-up of 423 days, the degree of myocardial 11C-PIB uptake was a significant predictor of clinical outcome (death, heart transplantation, and acute decompensated HF) on multivariate Cox regression analysis (adjusted HR: 1.185; 95% CI 1.054–1.332; P = 0.005). (43) Roque et al. used serial 18F-fluorodeoxyglucose (FDG PET/CT) after 1, 6, and 12 months in 37 post-aortic or mitral valve replacement patients. They obtained the standardized uptake values (SUVs) and a new proposed value denominate valve uptake index [(SUVmax − SUVmean)/SUVmax]. Of the 111 PET/CT performed, FDG uptake was visually detectable in 79.3% of patients, presenting a diffuse, homogeneous distribution pattern in 93%. No patient presented endocarditis during follow-up (**Figure 3**). Surprisingly, no significant differences were encountered in FDG distribution or uptake values between 1, 6, or 12 months, questioning the 3-month post-surgical period for the assessment of prosthetic infection. (44) FIGURE 3. 18F-fluorodeoxyglucose uptake distribution patterns (visual assessment). 18F-fluorodeoxyglucose uptake in non-infected prostheses (left panel), compared with an example of prosthetic valve endocarditis (right panel). Positron emission tomography/CTA fusion images of the valve plane (upper row), and their corresponding attenuation-corrected positron emission tomography images (lower row). From left to right, the characteristic inflammation patterns in order of descending frequency: diffuse homogeneous (93%), diffuse heterogeneous (7%), and focal/multifocal (2%). The diffuse homogeneous pattern is characteristic of inflammation and clearly differentiable from infection, whereas more focal. 18F-fluorodeoxyglucose uptake may overlap with infective endocarditis. No anatomic lesions were detected in any patient. Reproduced with permission from Roque et al. (44) (from Zamorano JL, Pinto FJ, Solano-López J, Bucciarelli-Ducci C. The year in cardiovascular medicine 2020: imaging. Eur Heart J. 2021 Feb 14;42(7):740-749. https://doi.org/10.1093/eurheartj/ehaa1035, by permission of OUP on behalf of the ESC) Tam et al. presented a study of FDG PET/CT in suspected LV assist devices (LVAD) associating their single-centre retrospective cases between September 2015 and February 2018 with a systematic review of PubMed from database inception through March 2018 involving in total 119 scans. Pooled sensitivity was 92% (95% CI: 82%–97%) and specificity was 83% (95% CI: 24%–99%) for FDG PET/CT in diagnosing LVAD infections. The ROC curve analysis demonstrated an AUC of 0.94 (95% CI 0.91–0.95). (45) Another infectious scenario in which nuclear imaging techniques play an important diagnostic role is cardiac device-related infected endocarditis (CDRIE). Holcman et al. assessed the diagnostic accuracy of the hybrid technique of SPECT CT with technetium99mhexamethylpropyleneamine oxime-labelled leucocytes (99mTc-HMPAO-SPECT/CT). In a single-centre prospective study, 103 patients with suspected CDRIE who underwent 99mTc-HMPAO-SPECT/CT were included. They found that adding this nuclear technique improves the sensitivity of the modified Duke criteria alone (87% vs. 48%, P < 0.001), whereas a negative scan excludes CDRIE with high probability. This yielded a reduction in possible CDRIE diagnoses. (46)

Harry J.G.M. Crijns, Frits Prinzen, Pier D. Lambiase, Prashanthan Sanders, Josep Brugada

## Introduction The Year in Cardiovascular Medicine: Arrhythmias 2020 reviews the most relevant studies in the field of arrhythmias and pacing. The past year has shown a significant progress: landmark clinical trials in atrial fibrillation (AF) and implantable defibrillator (ICD) therapy, new guidelines, integrated care, life style and arrhythmias, His bundle pacing, risk prediction in sudden cardiac death, and advances in cardiogenetics. ## New guidelines The guidelines on supraventricular tachycardia (SVT) and AF brought many new insights and recommendations. (1, 2) The former dealt with SVT ablation as an early strategy and invasive risk assessment in ventricular preexcitation. Its focus also was on what-to-avoid in management of SVT. (2) The new guidelines on AF promote the slogan ‘CC to ABC’, indicating that electrical Confirmation of AF is mandatory together with in-depth Characterisation of AF (**Figure 1**). (1) For management the AF guidelines advise to follow the Atrial fibrillation Better Care (ABC) pathway, which represents care to (i) avoid stroke, (ii) better symptom control, and (iii) take care of co-morbidities and cardiovascular risk factors. Despite the lack of data to show clinical effectiveness, AF screening is advocated saying that once AF is detected outcome worsens. It is also recommended to measure the quality of care over time and when needed improve care in an iterating cycle of improvement. The guidelines also highlight the importance of longitudinal rather than one-time cross-sectional assessment of stroke and bleeding risks since patients may outgrow their low risk status quite rapidly over time. Catheter ablation is advocated to ameliorate AF symptoms and to manage AF-associated heart failure and may be applied after one antiarrhythmic drug failure including failure on beta-blockade. FIGURE 1. The CC to Atrial fibrillation Better Care paradigm in the latest European Society of Cardiology (ESC) guidelines provides a comprehensive and holistic approach towards diagnosis and management of atrial fibrillation. CC stands for Confirmation (first C) and Characterisation (second C) of atrial fibrillation according to the structured 4S-AF scheme including assessment of stroke risk, symptom severity, severity of atrial fibrillation burden, and substrate severity. Reproduced with permission from Ref. (1) (from Crijns HJGM, Prinzen F, Lambiase PD, Sanders P, Brugada J. The year in cardiovascular medicine 2020: arrhythmias. Eur Heart J. 2021 Feb 1;42(5):499-507. https://doi.org/10.1093/eurheartj/ehaa1091, by permission of OUP on behalf of the ESC) ## Randomized trials on integrated care in atrial fibrillation Interesting randomized trials on integrated AF management included the ALL-IN trial, a cluster randomized trial in elderly AF patients in primary care, which showed that integrated care delivered by practice nurses supervised by general practitioners reduced all-cause mortality by 45% compared to usual-care. (3) This is impressive and highlights the power of ‘simple’ interventions if deployed systematically. The integrated care pathway included quarterly AF check-ups by the practice nurse, case management of antithrombotic treatment, and easy-access consultation of a cardiologist. This represents patient-centered shared responsibilities between primary care, anticoagulation clinics, cardiologists, and patients. Similarly, RACE 4 reported that nurse-led, information and communication technology (ICT)-supported, and physician-supervised integrated care reduces morbidity and mortality in experienced centres but not in less-experienced centres and emphasized the importance of training in an integrated environment. (4) Key elements of integrated care in these trials were the multidisciplinary team approach, education, and empowerment of patients and where possible application of decision support technology. Recent mHealth solutions include TeleCheck-AF (5, 6) and a mobile AF application incorporating the ABC pathway (**Figure 1**). (7) The mAFA II trial reported a significant reduction in all-cause death and adverse cardiovascular events compared to routine management in high-risk AF. (7) Notably, single elements of integrated care such as application of a clinical decision support system, (8) an educational (9) or a motivational (10) intervention to improve anticoagulation or introduction of shared decision-making (11) improve the level of care but not prognosis. In integrated care, patient-driven life-style changes targeting obesity, alcohol, and blood pressure control is important before performing rhythm control with catheter ablation. In a large cohort of 402 406 individuals from the UK Biobank, regular physical activity was related with a lower incidence of AF (especially in women) and ventricular arrhythmias but not of bradyarrhythmias. (12) Also, a randomized trial provided proof-of-concept data to support alcohol cessation as secondary prophylaxis against AF in regular drinkers. (13) Per nature of the trial, it focused on one element of life style whilst a more comprehensive multi-level modification of AF risk factors may be needed to abrogate risks of AF in daily life. (14) ## Randomized trials on rhythm control in atrial fibrillation The EAST-AFNET 4 trial compared a rhythm with a rate control strategy in patients with early AF lasting 55%. These authors found that permanent LBBAP is safe and feasible. A better maintenance of synchrony of contraction, determined using SPECT MPI phase analysis, was observed when the left bundle branch was captured. Three studies comprising a total of 116 patients with LBBAP, 49 with HBP, and 75 with BVP consistently showed a larger reduction in QRS-complex (QRS) duration in combination with a larger increase in LV ejection fraction. (45, 47, 48) FIGURE 3. Schematic representation (upper right) and X-ray and computed tomography images (lower right) of positioning the pacing lead at the left side of the septum. Left panels show the electrocardiogram (ECG) during intrinsic rhythm of a patient with atrial fibrillation that received a pacemaker. Middle row of ECGs shows signals when pacing the lead at its initial position at the right of the septum and right row shows signals during pacing at final position. Note almost normalization of signals, QRS duration, and QRS area during LBB pacing. (from Crijns HJGM, Prinzen F, Lambiase PD, Sanders P, Brugada J. The year in cardiovascular medicine 2020: arrhythmias. Eur Heart J. 2021 Feb 1;42(5):499-507. https://doi.org/10.1093/eurheartj/ehaa1091, by permission of OUP on behalf of the ESC) Salden et al. (44) compared the acute hemodynamic and electrophysiological effects of ‘LV septum pacing’ with that of BVP and HBP. The three pacing modes were comparable with regards to increase in LVdP/dtmax, whilst HBP and LV septum pacing tended to provide better electrical resynchronization. An important finding was also that similar effects were observed when pacing the LV septum at the basal, equatorial and apical part of the septum. To show feasibility, safety (including lead extraction) and clinical effectiveness of these new pacing modalities, randomized studies are required comparing LBBP with HBP and BVP. A prospective randomized study is currently performed in China. (49) ## Inherited cardiac conditions, risk assessment, implantable defibrillators, and sudden death A novel approach to the diagnosis of Brugada syndrome (BrS) described the utilization of autoantibody screening for α-cardiac actin, α-skeletal actin, keratin, and connexin-43. In total, 18/18 BrS subjects demonstrated this autoantibody profile vs. 0/8 normal controls and 0/20 cardiomyopathy cases, which included arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) patients. (50) In a subgroup of BrS patients, each of these proteins and the sodium channel protein type 5 alpha subunit (NaV1.5) aggregated in the sarcoplasm of myocardial cells. The mechanism as to why antibodies to these proteins identified BrS cases is unclear but could relate to sarcolemmal membrane damage either due to a myocarditic process in the disease course or abnormal cell adhesion resulting in an immune response. The novelty of this study is the utilisation of a serological test to identify BrS subjects, which can be challenging given the transient nature of the electrocardiogram (ECG) pattern. This paper is complemented by a study investigating polygenic risk (PRS) of ECG markers to predict a positive ajmaline response. (51) PRS for BrS, baseline QRS duration, presence of Type II or III BrS ECG at baseline and family history of BrS were independently associated with the occurrence of a Type I BrS ECG, with good predictive accuracy (optimism-corrected C-statistic 0.74). This provides the first data to enable the combination of genetic and clinical screening to predict ajmaline responses and has implications for risk stratification. A combined clinical and electrophysiological mapping study showed that SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation than non-carriers. (52) Recent data support the use of drug therapy to manage patients with catecholaminergic polymorphic VT (CPVT). In a provocative paper by Van der Werf et al., (53) no survival benefit from ICDs was shown in young CPVT patients surviving cardiac arrest. There are a number of caveats to this study, but the main learning point was that such patients can be treated without an ICD. PRAETORIAN compared transvenous and subcutaneous ICDs in 849 patients >18 years with a class I or Iia indication for ICD therapy for primary or secondary prevention, followed for 49.1 months. (54) S-ICD demonstrated non-inferiority of the composite primary endpoint of device-related complications and inappropriate shocks. This provides the first multicentre trial evidence that the S-ICD is as effective and safe as transvenous ICD in preventing SCD for patients not requiring brady-pacing, anti-tachycardia VT pacing, or CRT, but challenges remain including longevity of leads and ICD, and inappropriate shocks. Concerning the latter, the UNTOUCHED study of primary prevention ICD therapy supports the PRAETORIAN data by showing an inappropriate shock-free rate of 95.9%, suggesting that the new SMART PASS filter technology and appropriate high rate S-ICD programming may minimize inappropriate shocks in S-ICD recipients. (55) Two primary prevention ICD registries applying propensity scoring showed beneficial effects but differed concerning efficacy of ICD in women and elderly. (56, 57) To predict sudden arrhythmic death (SAD) in coronary artery disease, the PRE-DETERMINE investigators integrated an ECG risk score with conventional cardiovascular parameters. A high-risk ECG score incorporating contiguous Q waves, LV hypertrophy, QRS duration, and JTc prolongation was more strongly associated with SAD than non-SAD (adjusted hazard ratios 2.87 vs. 1.38) and the proportion of deaths due to SAD was greater in the high vs. low risk groups (24.9% vs. 16.5%). (58) The addition of ECG markers to a clinical risk factor model including LVEF improved discrimination and reclassification, including correct reclassification of 28% of patients in the validation cohort. The strength of this approach is the utilization of simple bedside biomarkers to determine management, but it needs clinical validation in a randomized trial. To conclude, The Year in Cardiovascular Medicine 2020—Arrhythmias shows significant progress in the field, much of it incremental, some of it attention gathering, and some of it clearly needing further work.