The year in cardiovascular medicine 2025: the top 10 papers in heart failure.

Digitalis is the oldest compound in cardiovascular medicine that continues to be used in contemporary clinical practice.1 Evidence supporting the beneficial effects of digoxin on hemodynamic, neurohormonal, and electrophysiological parameters has been accumulated from >200 years of clinical experience and research (Table 1).2 View this table: TABLE 1. Effects of Digoxin Digoxin was approved for heart failure in 1998 under current regulations by the Food and Drug Administration on the basis of the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED), Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme (RADIANCE), and Digitalis Investigators Group (DIG) clinical trials.3–5 It was also approved for the control of ventricular response rate for patients with atrial fibrillation. The most recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend digoxin for symptomatic chronic heart failure for patients with reduced systolic function (Class IIa recommendation: weight of evidence/opinion is in favor of usefulness/efficacy), preserved systolic function (Class IIb: usefulness/efficacy is less well established by evidence/opinion), and/or rate control for atrial fibrillation with a rapid ventricular response (Class IIa).6 The new Heart Failure Society of America guidelines for heart failure provide similar recommendations.7 Despite its relatively recent approval by the Food and Drug Administration and the guideline recommendations, digoxin use is decreasing in patients with heart failure.8 In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry, only 30% of patients with left ventricular systolic dysfunction were being treated with digoxin before admission. Digoxin was added in only 8% of patients before discharge despite the fact that they had signs and symptoms of heart failure while receiving diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs) and β-blockers.9,10 This decrease in digoxin use is likely the result of several factors. …

Figures of the Heart Failure Association: Professor Dr. med. Johann Bauersachs, Chair of the Clinical Science Section.

Background Recurrent somatic mutations in blood stem cells cause the emergence of mutated blood cell clones, known as clonal hematopoiesis (CH). Mutations in the most prevalent driver genes DNMT3A and TET2 with a variant allele frequency (VAF)≥2% have been associated with atherosclerosis and chronic heart failure (CHF). However, the effects of mutations in other driver genes for CH with low VAF (<2%) on CHF is still unknown. Purpose To assess the potential prognostic significance of mutations in distinct genes other than DNMT3A and TET2 causing CH at low VAF in patients with CHF due to post-ischemic origin. Methods We analyzed mononuclear bone marrow and peripheral blood cells from 400 CHF patients by deep error-corrected targeted amplicon sequencing allowing for the detection of very low VAF of ≥0.5% in 56 CH driver genes and associated such with the long-term mortality in these patients. Results Median age of the patients was 63 and median follow-up time was 4.8 years. We detected 1116 mutations with a VAF≥0.5% in 348 of 400 patients (87%). 21% of the patients carried 1 mutation, whereas 66% showed 2 and more mutations. Only 52 (13%) patients had no detectable mutation at all. Despite a high prevalence of mutations in the most frequently mutated driver genes DNMT3A (165 patients) and TET2 (107 pts), mutations in the genes CBL (8 pts), CEBPA (10 pts), PHF6 (22 pts), SMC1A (18 pts) and SRSF2 (14 pts) were associated with increased death compared to the average death rate of all patients (18.8%). To avoid confounding effects caused by the presence of DNMT3A and TET2 CHIP mutations, we excluded patients with DNMT3A-, TET2- and other CHIP-related mutations with a VAF≥2% for further analyses. Kaplan-Meier survival curve analyses revealed a significantly higher mortality in patients with mutations in either of the five genes, combined as the CH risk gene set for CHF (Fig. 1). Patients with mutations in the risk gene set (44 pts) did not differ from patients with mutations in other CH driver genes or without mutations with respect to age, cardiovascular risk factors, disease severity or CH clone size. By multivariate Cox proportional regression analysis, including the Seattle heart failure model (SHFM) score (as tertiles), death remained independently associated with the presence of mutations in the risk gene set (HR, 2.57; 95% CI, 1.30–5.10; p=0.007), in addition to SHFM score tertiles (tertile 2, HR, 2.36; 95% CI, 0.73–7.65 and tertile 3, HR, 7.96; 95% CI, 2.77–22.90). Conclusions Somatic mutations with low VAF in a distinct set of genes, namely in CBL, CEBPA, PHF6, SMC1A and SRSF2, are significantly associated with mortality in CHF, independently of the classical CHIP-driver mutations DNMT3A and TET2. Mutations in the CH risk gene set are prevalent in young CHF patients and comprise an independent risk factor for the outcome of CHF, potentially providing a novel tool for cardiovascular risk assessment and precision medicine in CHF. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Research Foundation (DFG)

To Infuse or Not?

Diabetes mellitus and heart failure: insights from a toxic relationship

Until the 1970s, treatment options for heart failure were limited to digitalis and diuretics.1 Although effective for symptoms, there was no evidence of mortality benefit with this combination, and it was an inadequate option for many patients with advanced symptoms. The search for more effective options led to strategies that modulated hemodynamics.1 Numerous physiological studies showed the dependence of ventricular function on vascular resistance, and drugs that reduced systemic vascular resistance improved cardiac performance.2,–,5 A pivotal study by Franciosa et al6 showed that sodium nitroprusside in patients with heart failure in the setting of acute myocardial infarction reduced left ventricular filling pressures from 22.7±2.0 to 11.3±1.6 mm Hg and led to a modest increase in cardiac output. A subsequent study revealed more striking improvements in patients with refractory heart failure, in whom nitroprusside reduced systemic vascular resistance by 50%, increased cardiac output by 56%, and reduced left ventricular filling pressure by 47%.7 These hemodynamic benefits with nitroprusside led to studies with oral agents, including hydralazine, isosorbide dinitrate (ISDN), prazosin, phentolamine, and minoxidil. Although these drugs did affect hemodynamics, none was as effective as nitroprusside individually.8,–,12 In 1977, Massie et al13 studied the combination of 2 oral agents, hydralazine and ISDN (H-ISDN) in class III to IV heart failure patients, proposing that simultaneously reducing preload with ISDN and afterload with hydralazine would result in a better response than with either drug individually. They found that H-ISDN reduced left ventricular filling pressure by 36%, increased cardiac index by 58%, and reduced systemic vascular resistance by 34%. Later, Pierpont et al14 compared H-ISDN with nitroprusside and showed that the 2 therapies had similar effects on wedge pressure reduction and cardiac index increase. Considering these hemodynamic benefits with …

Recurrent orthostatic syncope due to left atrial and left ventricular collapse after a continuous-flow left ventricular assist device implantation

Acute decompensated heart failure (ADHF) is a common and highly morbid cardiovascular disorder. Most hospitalizations for ADHF are related to symptoms of congestion, and the vast majority of ADHF patients are treated with intravenous loop diuretics. Despite this nearly ubiquitous use, data supporting the safety and efficacy of loop diuretics in ADHF are limited, and controversy exists about the best way to use loop diuretics with regard to both dosing and means of administration (continuous infusion vs. intermittent boluses). We reviewed the data supporting the safety and efficacy of loop diuretics in patients with ADHF. A large body of observational literature suggests that loop diuretics, especially at higher doses, may be associated with increased mortality in patients with heart failure even after detailed adjustment for other measures of disease severity. Additionally, multiple small underpowered trials suggest that continuous infusion may be equivalent or superior to intermittent bolus dosing. In summary, there is a critical need to develop more robust data on the use of loop diuretics in ADHF. In that context, the NIH Heart Failure Clinical Research Network has begun the Diuretics Optimization Strategies Evaluation (DOSE) study, a multi-center, double-blind, randomized controlled trial that will enroll 300 patients with ADHF. The DOSE study will randomize patients using a 2 × 2 factorial design to low dose vs. high dose furosemide, and intermittent bolus vs. continuous infusion. Successful completion of the DOSE study will provide important data on the optimal clinical use of loop diuretics in ADHF.

More than 4000 patients have been evaluated in randomized controlled trials of cardiac resynchronization therapy (CRT). These studies have demonstrated that CRT with or without an implantable cardioverter-defibrillator (ICD) consistently improves quality of life, functional status, exercise capacity, and cardiac structure and function and reduces morbidity and mortality in heart failure patients with ventricular dyssynchrony. The magnitude of benefit seen with CRT is comparable to or exceeds that seen with evidence-based drug therapies for heart failure but occurs in patients who are already receiving such medications. Thus, CRT has been added to the list of evidence-based therapies that make heart failure patients feel better and live longer (the Table). Consequently, a strong ethical mandate exists for the use of CRT in heart failure. This mandate is reflected in our current practice guidelines for the management of chronic heart failure, which state that all eligible patients should receive CRT unless contraindicated.1,2 End of debate! CRT should be a routine part of any evidence-based treatment regimen for heart failure. View this table: Major Benefits of Evidence-Based Heart Failure Therapies Of course, things are never quite so simple, so let us take a look at the evidence supporting this clinical mandate for CRT and address patient selection, some of the limitations of CRT, and some of the unanswered questions about the use of CRT in heart failure. None of this discussion will lessen the role of CRT in the treatment of heart failure; rather, it will guide the selection of appropriate patients and speculate on the future application of CRT to an even broader group of heart failure patients. Response by Greenberg and Mehra p 2698 Approximately one third of patients with systolic heart failure exhibit ventricular dyssynchrony, defined as a QRS duration >120 ms on the surface ECG.3,4 Ventricular dyssynchrony produces suboptimal ventricular …

The traditional paradigm for heart failure management centered on mitigating the hemodynamic changes that occur in response to the failing heart. Subsequently, pharmacological modulation of neurohormonal activation and more recently cardiac resynchronization have been shown to reverse ventricular remodeling and to slow disease progression. Despite these advances in therapy, successful treatment of heart failure remains challenging, with rates of hospitalization in the United States exceeding 1 million per year and the annual number of heart failure–related deaths increasing steadily.1 Unfortunately, the history of drug development for heart failure has been marked by many disappointments, most notably the excess mortality associated with oral positive inotropes that were targeted at improving hemodynamics. In addition, more recent interventions aimed at interrupting endothelin and cytokine signaling or reducing oxidative stress have yet to fulfill hopes for novel biological therapies. Thus, new therapeutic strategies are needed to alter the natural history of the disease and to slow or reverse current epidemiological trends. The report by Lee and colleagues2 in this issue of Circulation points toward the promise of an alternative approach based on favorably influencing the efficiency of myocardial energetics, thereby increasing cardiac performance without depending on changes in oxygen consumption or improvement in hemodynamics. Article p 3280 The study of agents aimed at enhancing myocardial energy efficiency has focused principally on shifting myocardial substrate use toward more oxygen-efficient pathways.3 Although the complete oxidation of fatty acids to CO2 yields more adenosine triphosphate (ATP) per molecule of CO2 produced than does complete oxidation of glucose, a greater amount of oxygen is required to completely oxidize a fatty acid of equivalent carbon-chain length. Therefore, for a given amount of oxygen consumed, metabolism of glucose is more “oxygen efficient,” producing ≈15% more ATP (Figure).3,4 Production of ATP and consumption of …

Elderly people insidiously manifest the symptoms of heart failure, such as dyspnea and/or physical disabilities in an age-dependent manner. Although previous studies suggested that oxidative stress plays a pathological role in the development of heart failure, no direct evidence has been documented so far. In order to investigate the pathological significance of oxidative stress in the heart, we generated heart/muscle-specific manganese superoxide dismutase-deficient mice. The mutant mice developed progressive congestive heart failure with specific molecular defects in mitochondrial respiration. In this paper, we showed for the first time that the oxidative stress caused specific morphological changes of mitochondria, excess formation of superoxide (O(2)(*)(-)), reduction of ATP, and transcriptional alterations of genes associated with heart failure in respect to cardiac contractility. Accordingly, administration of a superoxide dismutase mimetic significantly ameliorated the symptoms. These results implied that O(2)(*)(-) generated in mitochondria played a pivotal role in the development and progression of heart failure. We here present a bona fide model for human cardiac failure with oxidative stress valuable for therapeutic interventions.

In the article by Yancy et al, “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America,” which published online May 20, 2016, and appeared in the September 27, 2016, issue of the journal ( Circulation. 2016;134:e282–e293. DOI: 10.1161/CIR.0000000000000435), several corrections were needed. 1. On page e282, …

Cardiac Autonomic Nerve Stimulation in the Treatment of Heart Failure

The cardiac ryanodine receptor (RyR2)/Ca2+ release channel on the sarcoplasmic reticulum (SR) is regulated by evolutionarily highly conserved signaling pathways that control excitation-contraction (EC) coupling in the heart. Phosphorylation of RyR2 by cAMP-dependent protein kinase (PKA) plays a key role in regulating the channel in response to stress via activation of the sympathetic nervous system (the “fight-or-flight response”).1 Maladaptive PKA hyperphosphorylation of RyR2 in failing hearts alters channel function, which may cause depletion of SR Ca2+ and diastolic release of SR Ca2+. This can initiate delayed afterdepolarizations that trigger ventricular arrhythmias.1 Mutations in RyR2 recently have been identified in patients with catecholaminergic induced sudden cardiac death (SCD).2–4⇓⇓ There may be a direct link between the PKA hyperphosphorylation of RyR2 that occurs during the progression of heart failure and fatal cardiac arrhythmias. Regulation of cardiac EC coupling by the release of Ca2+ from the SR via RyR2 in cardiomyocytes, known as Ca2+-induced Ca2+ release (CICR), has been appreciated for more than a decade.5,6⇓ Furthermore, it is well known that the amplitude of the Ca2+ transient generated by SR Ca2+ release determines contractile force in cardiomyocytes. The systems that regulate SR Ca2+ release include: (1) the triggers (predominantly Ca2+ influx through the voltage-gated Ca2+ channel on the plasma membrane); (2) the SR Ca2+ release channel or type 2 RyR2; and (3) the SR Ca2+ reuptake pump (SERCA2a) and its regulator phospholamban. These systems (trigger, release, and reuptake) are modulated by signaling pathways, including the β-adrenergic receptor (β-AR) signaling pathway (ie, phosphorylation by PKA). Activation of the sympathetic nervous system in response to stress results in elevation of cAMP levels and activation of PKA. Phosphorylation of RyR2 may not correlate directly …

Introduction: Heart failure is a major public health problem, affecting over 26 million people worldwide. It is associated with a high rate of mortality, symptom burden and diminished quality of life. Best practice guidelines for the management of chronic heart failure recommend that patients and carers/family members are educated about heart failure self-care. Effective heart failure self-care has the potential to improve health outcomes. Studies conducted in Thailand addressing heart failure self-care are limited and none have investigated the potential benefits of education programs on the health outcomes of both parties within the dyad: the patient with heart failure and their carer. Aims: The primary aim of this research was to examine the effectiveness of a family-based education program for patients with heart failure and their carers in rural Thailand. The research comprises a series of studies, each with specific aims: i) to investigate current heart failure family-based education provision – a global review, ii) to develop a family-based heart failure education program, and iii) to evaluate the effectiveness of this program in rural Thailand. Methods: After completing a systematic review of the literature, a study protocol for development and evaluation of a culturally specific family-based education program was developed. A randomised controlled trial was then conducted in rural Thailand to examine the effectiveness of the program. For patients, the primary outcome was heart failure knowledge as measured by the Dutch Heart Failure Knowledge Scale (DHFKS). The main outcome for carers was perceived control over managing patients’ heart failure symptoms as measured by the Control Attitudes Scale-Revised (CAS-R). Secondary outcomes for patients were self-care as measured by the Self-Care of Heart Failure Index (SCHFI) and health-related quality of life as measured by the Minnesota Living with Heart Failure (MLHF) questionnaire. For carers, additional outcomes were heart failure knowledge as measured by the Dutch Heart Failure Knowledge Scale (DHFKS) and health-related quality of life as measured by the Short Form 12-Item (SF-12) Health Survey. In total, 100 dyads from two public hospitals in Thailand were randomly assigned in a 1:1 ratio in blocks of 10 to the intervention (family-based education program) or usual care (control) group. The education group received usual care in addition to a family-based education program, which consisted of face-to-face education and counselling sessions, a manual, a DVD, and telephone support. Data were collected at baseline, three months, and six months. Results: The systematic review identified six trials reported in nine papers. A dearth of HF studies was found that specifically developed and evaluated an education intervention for both patient and carer. There was a wide variation in the quality of the studies. A family-based HF education program, underpinned by adult learning theory, was developed in strict adherence to CONSORT guidelines. This comprised a culturally specific heart failure manual and DVD that were reviewed for content and cultural validity by a Thai cardiologist and heart failure nurses; minimal changes were recommended. Patients and carers in the education group (those who received the heart failure manual and DVD) had higher knowledge scores than the usual care group at three and six months (p < 0.01). Patients in the education group had better self-care maintenance, confidence, and quality of life scores than the usual care group (p < 0.05) at three and six months, as well as better self-care management scores (p < 0.05) at six months. Carers in the education group had higher perceived control over managing patients’ heart failure symptom scores than the usual care group (p < 0.05) at three months. Conclusion: This is the first ramdonised controlled trial to evaluate a family-based heart failure education program developed for patients and their carers in rural Thailand. The education program improved heart failure knowledge (in patients and carers), patients’ self-care behaviours and emotional dimension of quality of life, and carers’ perceived control over managing patients’ heart failure symptoms. This program provides evidence supporting the positive influence of self-care education by engaging family members/carers. Despite the lack of access to heart failure disease management programs in rural Thailand, it may be possible to improve patient engagement in self-care through educational programs that can be easily introduced, guided and followed-up by a Thai nurse, and which are predominantly self-administered (i.e. manual and DVD) in the patient’s home.