Heart Failure with Reduced Ejection Fraction—Does Sex Matter?

Purpose of Review There is an increasing recognition of the importance of sex in susceptibility, clinical presentation, and outcomes for heart failure. This review focusses on heart failure with reduced ejection fraction (HFrEF), unravelling differences in biology, clinical and demographic features and evidence for diagnostic and therapeutic strategies. This is intended to inform clinicians and researchers regarding state-of-the-art evidence relevant to women, as well as areas of unmet need. Recent Findings Females are well recognised to be under-represented in clinical trials, but there have been some improvements in recent years. Data from the last 5 years reaffirms that women presenting with HFrEF women are older and have more comorbidities like hypertension, diabetes and obesity compared with men and are less likely to have ischaemic heart disease. Non-ischaemic aetiologies are more likely to be the cause of HFrEF in women, and women are more often symptomatic. Whilst mortality is less than in their male counterparts, HFrEF is associated with a bigger impact on quality of life in females. The implications of this for improved prevention, treatment and outcomes are discussed. Summary This review reveals distinct sex differences in HFrEF pathophysiology, types of presentation, morbidity and mortality. In light of this, in order for future research and clinical medicine to be able to manage HFrEF adequately, there must be more representation of women in clinical trials as well as collaboration for the development of sex-specific management guidelines. Future research might also elucidate the biochemical foundation of the sex discrepancy in HFrEF.

SGLT2 Inhibitors and Their Mode of Action in Heart Failure—Has the Mystery Been Unravelled?

Purpose of review SGLT2 inhibitors (SGLT2i) are new drugs for patients with heart failure (HF) irrespective of diabetes. However, the mechanisms of SGLT2i in HF remain elusive. This article discusses the current clinical evidence for using SGLT2i in different types of heart failure and provides an overview about the possible underlying mechanisms. Recent findings Clinical and basic data strongly support and extend the use of SGLT2i in HF. Improvement of conventional secondary risk factors is unlikely to explain the prognostic benefits of these drugs in HF. However, different multidirectional mechanisms of SGLT2i could improve HF status including volume regulation, cardiorenal mechanisms, metabolic effects, improved cardiac remodelling, direct effects on cardiac contractility and ion-homeostasis, reduction of inflammation and oxidative stress as well as an impact on autophagy and adipokines. Summary Further translational studies are needed to determine the mechanisms of SGLT2i in HF. However, basic and clinical evidence encourage the use of SGLT2i in HFrEF and possibly HFpEF.

Optimal CRT Implantation—Where and How To Place the Left-Ventricular Lead?

Purpose of Review Cardiac resynchronization therapy (CRT) represents a well-established and effective non-pharmaceutical heart failure (HF) treatment in selected patients. Still, a significant number of patients remain CRT non-responders. An optimal placement of the left ventricular (LV) lead appears crucial for the intended hemodynamic and hence clinical improvement. A well-localized target area and tools that help to achieve successful lead implantation seem to be of utmost importance to reach an optimal CRT effect. Recent Findings Recent studies suggest previous multimodal imaging (CT/cMRI/ECG torso) to guide intraprocedural LV lead placement. Relevant benefit compared to empirical lead optimization is still a matter of debate. Technical improvements in leads and algorithms (e.g., multipoint pacing (MPP), adaptive algorithms) promise higher procedural success. Recently emerging alternatives for ventricular synchronization such as conduction system pacing (CSP), LV endocardial pacing, or leadless pacing challenge classical biventricular pacing. Summary This article reviews current strategies for a successful planning, implementation, and validation of the optimal CRT implantation. Pre-implant imaging modalities offer promising assistance for complex cases; empirical lead positioning and intraoperative testing remain the cornerstone in most cases and ensure a successful CRT effect.

Insights Into Genetics and Pathophysiology of Arrhythmogenic Cardiomyopathy

Purpose of Review Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy young adults. Mutations in genes encoding for cellular junctions can be found in about half of the patients. However, disease onset and severity, risk of arrhythmias, and outcome are highly variable and drug-targeted treatment is currently unavailable. Recent Findings This review focuses on advances in clinical risk stratification, genetic etiology, and pathophysiological concepts. The desmosome is the central part of the disease, but other intercalated disc and associated structural proteins not only broaden the genetic spectrum but also provide novel molecular and cellular insights into the pathogenesis of ACM. Signaling pathways and the role of inflammation will be discussed and targets for novel therapeutic approaches outlined. Summary Genetic discoveries and experimental-driven preclinical research contributed significantly to the understanding of ACM towards mutation- and pathway-specific personalized medicine.

Sex Differences in Hypertrophic Cardiomyopathy: Interaction With Genetics and Environment

Purpose of Review We explore the sex-specific interaction of genetics and the environment on the clinical course and outcomes of hypertrophic cardiomyopathy (HCM). Recent Findings Women account for approximately one-third of patients in specialist HCM centres and reported in observational studies. As a result, evidence informing clinical guideline recommendations is based predominantly on risk factors and outcomes seen in men. However, disease progression appears to be different between the sexes. Women present at a more advanced stage of disease, are older at diagnosis, have higher symptom burden, carry greater risk for heart failure and are at greater risk of mortality compared to men. Women are more likely to be gene-positive, while men are more likely to be gene-negative. The risk of sudden cardiac death and access to specialised care do not differ between the sexes. Summary Reporting sex-disaggregated results is essential to identify the mechanisms leading to sex differences in HCM.