The ESC Guidelines on heart failure, sacubitril–valsartan in resistant hypertension, and new therapeutic targets in myocardial hypertrophy

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on heart failure and cardiomyopathies contains the ‘2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure’.1 These Guidelines are extremely innovative. They introduce new concepts compared with the 2016 Guidelines including: (i) a change of the term ‘heart failure with mid-range ejection fraction’ to ‘heart failure with mildly reduced ejection fraction (HFmrrEF)’; (ii) a simplified diagnostic algorithm for heart failure with reduced ejection fraction (HFrEF); (iii) a treatment algorithm for HFrEF according to phenotypes; (iv) a modified classification for acute HF; (v) updated treatments for most non-cardiovascular comorbidities including diabetes, hyperkalaemia, iron deficiency, and cancer; (vi) the role of genetic testing in cardiomyopathies and new treatments; and (vii) the addition of quality indicators. DAPA-HF: trial design and main findings. BMI, body mass index; BP, blood pressure; CI, confidence interval; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NT-proBNP, N-terminal probrain natriuretic peptide (from Curtain JP, Docherty KF, Jhund PS, Petrie MC, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Bengtsson O, Langkilde AM, Sjöstrand M, Solomon SD, McMurray JJV. Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF. See pages 3727–3738). DAPA-HF: trial design and main findings. BMI, body mass index; BP, blood pressure; CI, confidence interval; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NT-proBNP, N-terminal probrain natriuretic peptide (from Curtain JP, Docherty KF, Jhund PS, Petrie MC, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Bengtsson O, Langkilde AM, Sjöstrand M, Solomon SD, McMurray JJV. Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF. See pages 3727–3738). Sodium–glucose co-transporter 2 (SGLT2) inhibitors have recently been shown to reduce both worsening heart failure and death from cardiovascular causes in patients with HFrEF.2–6 Ventricular arrhythmias are common and are one of the key causes of death in HFrEF, as indicated by the benefit of implantable cardioverter defibrillators (ICDs) in reducing the incidence of sudden death. Although rates of sudden death have been declining over the past three decades with improving pharmacological therapy, this mode of death remains the principal cause of mortality in ambulatory patients with HFrEF, particularly those with mild symptoms. In an ESC Fast Track clinical research article entitled ‘Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF’, John McMurray from the Western Infirmary in Glasgow, UK and colleagues examined the effect of dapagliflozin on the incidence of ventricular arrhythmias and sudden death in patients with HFrEF.7 In a post-hoc analysis of DAPA-HF trial, the authors examined reports of serious adverse events related to ventricular arrhythmias or cardiac arrest, in addition to adjudicated sudden death. The effect of dapagliflozin, compared with placebo, on the composite of the first occurrence of any of a serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death was examined using Cox proportional hazards models. A serious ventricular arrhythmia was reported in 115 (2.4%) of the 4744 patients in DAPA-HF; 206 (41%) of the 500 cardiovascular deaths occurred suddenly. Independent predictors of the composite outcome (first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death), ranked by χ2 value, were log-transformed NT-proBNP, history of ventricular arrhythmias, left ventricular ejection fraction, systolic blood pressure, history of myocardial infarction, male sex, body mass index, serum sodium concentration, non-white race, treatment with dapagliflozin, and cardiac resynchronization therapy. Of participants assigned to dapagliflozin, 5.9% experienced the composite outcome compared while the prevalenc was 7.4% in the placebo group (hazard ratio 0.79, P = 0.037), and the effect was consistent across each of the components of the composite outcome (Figure 1). McMurray and colleagues conclude that dapagliflozin reduces the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death when added to conventional therapy in patients with HFrEF. The manuscript is accompanied by an Editorial by Peter Light from the University of Alberta in Edmonton, Canada.8 The author concludes that the results presented advance our knowledge of this important class of drug and should be considered as proof of principle and hypothesis generating. Given the compelling evidence that has recently emerged—from clinical trials to cellular mechanisms, it seems that new trials and pre-clinical studies designed to specifically interrogate the antiarrhythmic efficacy of the SGLT2 inhibitors will be key avenues to pursue in the near future. These are indeed exciting times for SGLT2 inhibitor research. Almost one in six patients with HFpEF had apparent resistant hypertension in PARAGON-HF and this was associated with worse clinical outcomes; neprilysin inhibition reduced systolic blood pressure significantly in these patients (from Jackson AM, Jhund PS, Anand IS, Düngen HD, Lam CSP, Lefkowitz MP, Linssen G, Lund LH, Maggioni AP, Pfeffer MA, Rouleau JL, Saraiva JFK, Senni M, Vardeny O, Wijkman MO, Yilmaz MB, Saito Y, Zile MR, Solomon SD, McMurray JJV. Sacubitril-valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction. See pages 3741–3752). Almost one in six patients with HFpEF had apparent resistant hypertension in PARAGON-HF and this was associated with worse clinical outcomes; neprilysin inhibition reduced systolic blood pressure significantly in these patients (from Jackson AM, Jhund PS, Anand IS, Düngen HD, Lam CSP, Lefkowitz MP, Linssen G, Lund LH, Maggioni AP, Pfeffer MA, Rouleau JL, Saraiva JFK, Senni M, Vardeny O, Wijkman MO, Yilmaz MB, Saito Y, Zile MR, Solomon SD, McMurray JJV. Sacubitril-valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction. See pages 3741–3752). Patients with heart failure and preserved ejection fraction (HFpEF) frequently have difficulty in controlling hypertension.9 In a clinical research article entitled ‘Sacubitril–valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction’, Alice Jackson from the University of Glasgow in the UK, and colleagues examined the effect of neprilysin inhibition on ‘apparent resistant hypertension’ in patients with HFpEF in the PARAGON-HF trial, which compared the effect of sacubitril–valsartan with valsartan.10 In this post-hoc analysis, patients were categorized according to systolic blood pressure at the end of the valsartan run-in (n = 4795). ‘Apparent resistant hypertension’ was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if with diabetes) despite treatment with valsartan, a calcium channel blocker, and a diuretic. ‘Apparent mineralocorticoid receptor antagonist (MRA)-resistant’ hypertension was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if with diabetes) despite the above treatments and an MRA. The primary outcome in the PARAGON-HF trial was a composite of total hospitalizations for HF and death from cardiovascular causes. The authors examined clinical endpoints and the safety of sacubitril–valsartan according to the hypertension category. They also examined reductions in blood pressure from the end of valsartan run-in to Weeks 4 and 16 after randomization. Overall, 731 patients (15.2%) had resistant hypertension and 135 (2.8%) had MRA-resistant hypertension. The rate of the primary outcome was significantly higher in patients with apparent resistant hypertension (17.3 per 100 person-years) compared with those with a controlled systolic blood pressure (13.4 per 100 person-years), with an adjusted rate ratio of 1.28. The reduction in systolic blood pressure at Weeks 4 and 16, respectively, was greater with sacubitril–valsartan vs. valsartan in patients with resistant hypertension (−4.8 and –3.9 mmHg) and MRA-resistant hypertension (−8.8 and −6.3 mmHg). The proportion of patients with apparent resistant hypertension achieving a controlled systolic blood pressure by Week 16 was 47.9% in the sacubitril–valsartan group and 34.3% in the valsartan group (adjusted odds ratio 1.78). In patients with MRA-resistant hypertension, the respective proportions were 43.6% vs. 28.4% (adjusted odds ratio 2.63) (Figure 2). The authors conclude that sacubitril–valsartan may be useful in treating resistant hypertension in patients with HFpEF, even in those who continue to have an elevated blood pressure despite treatment with at least four antihypertensive drug classes, including an MRA. The manuscript is accompanied by an Editorial by Massimo Volpe and Giovanna Gallo from the Università degli Studi di Roma La Sapienza in Italy.11 The authors conclude that the current analysis performed by Jackson et al. supports such an approach as it documents better control of blood pressure and potentially better outcomes in patients with resistant hypertension and HFpEF when treated with sacubitril–valsartan. This paves the way to more formal prospective studies to investigate the potential double-hit benefits of sacubitril–valsartan in a tough and challenging clinical field such as resistant hypertension and HFpEF. While myocardial ischaemia plays a major role in the pathogenesis of HF, the indications for coronary angiography during acute HF are not established. In a Clinical Research article entitled ‘Early invasive coronary angiography and acute ischaemic heart failure outcomes’, Leah Kosyakovsky from the University of Toronto in Canada, and colleagues determined the association of early coronary angiography during acute HF hospitalization with 2-year mortality, cardiovascular death, HF readmissions, and coronary revascularization.12 In a two-stage sampling process, the authors identified acute HF patients who presented to 70 emergency departments in Ontario (April 2010 to March 2013) and determined, using administrative databases, whether they underwent early coronary angiography within 14 days after presentation. After clinical record review, they defined a cohort with acute ischaemic HF as patients with at least one factor suggesting underlying ischaemic heart disease, including previous myocardial infarction, troponin elevation, or angina on presentation. They oversampled patients undergoing angiography and used inverse probability of treatment weighting (IPTW) to adjust for baseline differences. Of 7239 patients with acute HF, 2994 met the inclusion criteria. Early angiography was performed in 1567 patients (52%) and was associated with lower all-cause mortality [hazard ratio (HR) 0.74, P = 0.002], cardiovascular death (HR 0.72, P = 0.012), and HF readmissions (HR 0.84, P = 0.042) after IPTW. Those undergoing early angiography experienced higher rates of percutaneous coronary intervention (HR 2.58, P < 0.001) and coronary artery bypass grafting (HR 2.94, P < 0.001) within 2 years. The authors conclude that early coronary angiography is associated with lower all-cause mortality, cardiovascular death, HF readmissions, and higher rates of coronary revascularization in acute HF patients with possible ischaemia. This manuscript is accompanied by an Editorial by Mehmet Birhan Yilmaz from the Dokuz Eylul University in Izmir, Turkey.13 The author concludes that anatomical evaluation of coronary artery disease via early angiography seems to yield improved outcomes for patients with acute HF having ischaemic signals, i.e. elevation of troponin or angina, or previous history of MI. Hence, differential identification of the ischaemic phenotype of acute HF seems to enable early coronary angiography advantageous for patient outcomes, though it remains to be established whether there are more specific signals to be added, and further validation cohorts are needed. Despite considerable therapeutic advances, there is still a dearth of evidence on the molecular determinants of cardiac hypertrophy that culminates in HF.9,14 Neuraminidases (NEUs) are a family of enzymes that catalyse the cleavage of terminal sialic acids from glycoproteins or glycolipids. In a translational research article entitled ‘Neuraminidase 1 is a driver of experimental cardiac hypertrophy’, Qian-Qian Chen from the China Pharmaceutical University in Nanjing, China, and colleagues sought to characterize the role of NEUs in pathological cardiac hypertrophy and identify pharmacological inhibitors targeting mammalian NEUs.15 NEU1 was highly expressed in hypertrophic hearts of mice and rats, and this elevation was confirmed in patients with hypertrophic cardiomyopathy compared with healthy controls. The increased NEU1 was mainly co-localized with cardiac troponin T in cardiomyocytes. Cardiomyocyte-specific NEU1 deficiency alleviated hypertrophic phenotypes in response to transverse aortic constriction or isoproterenol hydrochloride infusion, while NEU1 overexpression exacerbated the development of cardiac hypertrophy. Mechanistically, co-immunoprecipitation coupled with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated that NEU1 translocated into the nucleus and interacted with GATA4, leading to foetal gene (Nppa and Nppb) expression. Virtual screening and experimental validation identified the novel compound C-09 from millions of compounds that showed favourable binding affinity for human NEU1 (KD = 0.38 μM) and effectively prevented the development of cardiac remodelling in cellular and animal models. Interestingly, the anti-influenza drugs zanamivir and oseltamivir effectively inhibited mammalian NEU1 and showed new indications for cardioprotection. Chen and colleagues conclude NEU1 is a critical driver of cardiac hypertrophy, and inhibition of NEU1 opens up an entirely new field of treatment for cardiovascular diseases. The contribution is accompanied by an Editorial by Konstantinos Stellos and Simon Tual-Chalot from the Newcastle University in the UK.16 The authors conclude that repurposing of anti-influenza drugs may offer a potential therapeutic opportunity for cardioprotection in pressure overload-induced cardiac hypertrophy and remodelling. Future studies are warranted to investigate the therapeutic efficacy of anti-influenza drugs in heart failure. In a second Translational Research article entitled ‘3′ untranslated region of Ckip-1 inhibits cardiac hypertrophy independently of its cognate protein’, Yinlong Zhao from the Hebei Normal University in Shijiazhuang, China, and colleagues note that the 3′ untranslated region (3′ UTR) of mRNA is more conserved than other non-coding sequences in vertebrate genomes, and its sequence space has substantially expanded during the evolution of higher organisms, which substantiates their significance in biological regulation. However, the independent role of the 3′ UTR in cardiovascular disease is largely unknown.17 Using bioinformatics, RNA fluorescent in situ hybridization, and quantitative real-time PCR, the authors found that the 3′ UTR and coding sequence regions of Ckip-1 mRNA exhibited diverse expression and localization in cardiomyocytes. They then generated cardiac-specific Ckip-1 3′ UTR-overexpressing mice under the wild-type and casein kinase 2 interacting protein-1 (CKIP-1) knockout background. Cardiac remodelling was assessed by histological, echocardiographic, and molecular analyses at 4 weeks after transverse aortic constriction (TAC) surgery. The results showed that the cardiac Ckip-1 3′ UTR significantly inhibited TAC-induced cardiac hypertrophy independently of CKIP-1 protein. To determine the mechanism of action of the Ckip-1 3′ UTR in cardiac hypertrophy, the authors performed transcriptome and metabolomics analyses, RNA immunoprecipitation, biotin-based RNA pull-down, and reporter gene assays. They found that the Ckip-1 3′ UTR promoted fatty acid metabolism through the AMPK–PPARα–CPT1b axis, leading to protection against pathological cardiac hypertrophy. Moreover, Ckip-1 3′ UTR RNA therapy using adeno-associated virus noticeably alleviated cardiac hypertrophy and improved heart function. The authors conclude that these findings disclose that the Ckip-1 3′ UTR inhibits cardiac hypertrophy independently of its cognate protein. The Ckip-1 3′ UTR might be an effective RNA-based therapy tool for treating cardiac hypertrophy and heart failure. The manuscript is accompanied by an Editorial by Gabriela Kuster and Riccardo Bernasconi from the University Hospital Basel in Switzerland.18 The authors note that Zhao and colleagues show a specific function of a 3' UTR is independent from the expression of its cognate protein in a setting of cardiovascular disease. Although still a long way away from clinical implication, their work directs our focus on an additional layer of gene regulation, adding to its complexity and opening the door to a new and intriguing landscape worthy of further exploration. The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.

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