Skeletal Muscle Myopathy in Heart Failure: the Role of Ejection Fraction

Purpose of Review

This review summarizes: (1) the structural and functional features coupled with pathophysiological factors responsible of skeletal muscle myopathy (SMM) in both heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction and (2) the role of exercise as treatment of SMM in these HF-related phenotypes.

Recent Findings

The recent literature showed two main phenotypes of heart failure (HF): (1) HFrEF primarily due to a systolic dysfunction of the left ventricle and (2) HFpEF, mainly related to a diastolic dysfunction. Exercise intolerance is one of most disabling symptoms of HF and it is shown that persists after the normalization of the central hemodynamic impairments by therapy and/or cardiac surgery including heart transplant. A specific skeletal muscle myopathy (SMM) has been defined as one of the main causes of exercise intolerance in HF.

Summary

The SMM has been well described in the last 20 years in the HFrEF; on the contrary, few studies are available in HFpEF. Recent evidences have revealed that exercise training counteracts HF-related SMM and in turn ameliorates exercise intolerance.

     

Imaging and Management of Heart Failure and Preserved Ejection Fraction

Purpose of review

The prevalence of heart failure with preserved ejection fraction (HFpEF) is rising and in some places, it is already the most prevalent form of heart failure. The usual treatments of HF do not improve mortality or outcomes in HFpEF, suggesting a distinct pathophysiology that remains poorly characterized. The neutrality of clinical trial results is also attributable to the heterogeneity of patient profiles, and by poor characterization offered by classical echocardiography parameters. Emerging imaging modalities may overcome this problem. We therefore aimed to summarize recent advances offered by cardiovascular imaging in disease characterization, and the implication of findings to new phenotype-specific treatment options.

Recent findings

Novel cardiovascular imaging techniques such as LV global longitudinal strain, left atrial strain, tissue characterization by magnetic resonance T1 time, as well as incorporation of systolic and diastolic stress testing offer greatly improved characterization, diagnosis, and stratification of disease pathogenesis. These techniques offer insight into identification of HFpEF sub-phenotypes that are resistant to, or responsive to therapies.

Summary

There is a growing body of evidence that novel cardiovascular imaging modalities are able to characterize HFpEF patients with much greater accuracy than current guideline-driven parameters. Whether this information can be synthesized to adequately stratify patients into sub-phenotypes with clearer disease pathogenesis amenable to targeted intervention will be of particular future interest.

     

Clinical Phenotyping of Transthyretin Cardiac Amyloidosis with Bone-Seeking Radiotracers in Heart Failure with Preserved Ejection Fraction

Purpose of Review

The two most common types of cardiac amyloidosis are caused by fibril deposits of immunoglobulin light chains (AL) and transthyretin (TTR), each with distinct prognosis and clinical management. Cardiac amyloidosis is under-recognized among heart failure patients with preserved ejection fraction (HFpEF). Bone-seeking tracers like ^99mTc-PYP and ^99mTc-DPD have long been used to identify cardiac amyloidosis, and more recently, to differentiate TTR from AL cardiac amyloidosis in symptomatic patients. However, results are mainly derived from single-center retrospective studies, with comparable but not standardized imaging protocols and interpretation criteria.

Recent Findings

The clinical scope of cardiac amyloidosis among HFpEF patients and current literature supporting the use of bone-seeking tracers for TTR cardiac amyloidosis are presented. The differences of imaging techniques for cardiac amyloid and bone disease evaluation, bone tracer pharmacodynamics, and imaging interpretation criteria for cardiac amyloidosis diagnosis are discussed. Finally, a diagnostic algorithm to use bone scintigraphy in cardiac amyloidosis diagnosis among HFpEF patients is proposed.

Summary

Bone scintigraphy with ^99mTc-PYP or ^99mTc-DPD can be a useful tool with high sensitivity and specificity for detecting TTR-related cardiac amyloidosis in patients with HFpEF. It is needed to standardize the imaging protocol and interpretation criteria and to perform prospective clinical studies.

     

Heart Failure with Recovered EF and Heart Failure with Mid-Range EF: Current Recommendations and Controversies

Purpose of review

This review explores key features and potential management controversies in two emerging populations in heart failure: heart failure with recovered ejection fraction (HF-recovered EF) and heart failure with mid-range ejection fraction (HFmrEF).

Recent findings

While HF-recovered EF patients have better outcomes than heart failure with reduced ejection fraction (HFrEF), they continue to have symptoms, persistent biomarker elevations, and abnormal outcomes suggesting a continued disease process. HFmrEF patients appear to have features of HFrEF and heart failure with preserved ejection fraction (HFpEF), but have a high prevalence of ischemic heart disease and may represent a transitory phase between the HFrEF and HFpEF. Management strategies have insufficient data to warrant standardization at this time.

Summary

HF-recovered EF and HFmrEF represent new populations with unmet needs and expose the pitfalls of an EF basis for heart failure classification.

     

Effects of renin–angiotensin–aldosterone system inhibitors on mortality,hospitalization, and diastolic function in patients with HFpEF

Aim

The purpose of this meta-analysis was to evaluate the effects of renin–angiotensin–aldosterone system (RAAS) inhibitors on mortality, hospitalization, diastolic function, and exercise capacity in heart failure with preserved ejection fraction (HFpEF).

Methods

Thirteen randomized controlled trials (RCTs), totaling 12,532 patients with HFpEF, were selected. All-cause and cardiovascular mortality, all-cause and heart failure-related hospitalization, diastolic function, and the 6-min walk distance were assessed. The risk ratios (RR) of the dichotomous data, weighted mean difference (WMD) of continuous data, and 95?% confidence intervals (CI) were calculated to assess the effects of RAAS inhibitors.

Results

RAAS inhibitors significantly decreased heart failure-related hospitalization (RR 0.89; 95?% CI 0.82–0.97; p?=?0.01) and improved the diastolic function, as reflected in a reduced E/e’ index (MD ?1.38; 95?% CI ?2.01 to ?0.74; p?<?0.0001). However, there were no beneficial effects on all-cause cardiovascular mortality and all-cause hospitalization. Other diastolic parameters had few changes compared with the controls. The 6-min walk distance was not improved by the use of RAAS inhibitors.

Conclusion

In patients with HFpEF, RAAS inhibitors decreased heart-failure hospitalization and the E/e’ index without affecting mortality, all-cause hospitalization, other diastolic function parameters, and the 6-min walk distance.

     

Rationale and Design of the Multicenter Trial on Japan Working Group on the Effects of Angiotensin Receptor Blockers Selection (Azilsartan vs. Candesartan) on Diastolic Function in the Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE Trial

Background

Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial.

Methods

The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e’) assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study.

Conclusions

The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

     

Role of Cardiac Magnetic Resonance Imaging in Valvular Heart Disease: Diagnosis,Assessment, and Management

Purpose of Review

This article will review the current techniques in cardiac magnetic resonance imaging (CMR) for diagnosing and assessing primary valvular heart disease.

Recent Findings

The recent advancements in CMR have led to an increased role of this modality for qualifying and quantifying various native valve diseases. Phase-contrast velocity encoded imaging is a well-established technique that can be used to quantify aortic and pulmonic flow. This technique, combined with the improved ability for CMR to obtain accurate left and right ventricular volumetrics, has allowed for increased accuracy and reproducibility in assessing valvular dysfunction. Advancements in CMR technology also allows for improved spatial and temporal resolution imaging of various valves and their regurgitant or stenotic jets. Therefore, CMR can be a powerful tool in evaluation of native valvular heart disease.

Summary

The role of CMR in assessing valvular heart disease is growing and being recognized in recent guidelines. CMR has the ability to assess valve morphology along with qualifying and quantifying valvular disease. In addition, the ability to obtain accurate volumetric measurements may improve more precise management strategies and may lead to improvements in mortality and morbidity.

     

Heart Failure with Preserved Ejection Fraction Trials Have Heterogeneous Control Groups: a Comparison of Kaplan-Meier Curves

Purpose

Previous studies have evaluated intra-study heterogeneities of heart failure with preserved ejection fraction (HFpEF), but inter-study heterogeneities remain poorly understood. We investigate the heterogeneities of outcomes among control groups of HFpEF trials.

Methods

We included randomized controlled trials recruiting HFpEF patients with ejection fraction ≥?40% and reporting Kaplan-Meier curves for at least 36 months. The Kaplan-Meier curves of control groups were extracted and calculated for hazard ratios and 95% confidence intervals. Two virtual trials were developed to validate the reliability and accuracy of our method.

Results

Of 4161 studies, we included six trials containing 7682 HFpEF patients in control groups. The DIG trial had the highest all-cause mortality, cardiovascular mortality, heart failure mortality, and composite endpoints of cardiovascular mortality and heart failure hospitalization (all p?<?0.001). The TOPCAT trial had the lowest all-cause mortality, cardiovascular mortality, heart failure hospitalization, and composite of cardiovascular mortality and heart failure hospitalization (all p?<?0.001). Adoption of different ejection fraction cut-off values for HFpEF diagnosis did not significantly change the outcomes of control groups in the DIG trial (45% vs. 50%: hazard ratio, 1.05, 95% confidence interval, 0.97–1.13, p?=?0.271), or in the CHARM-Preserved trial (40% vs. 50%: hazard ratio, 1.01, 95% confidence interval, 0.93–1.09, p?=?0.864) during 36-month follow-up.

Conclusions

The control groups of HFpEF trials have heterogeneous outcomes. Future trials should consider these heterogeneities when designing protocols.

     

The Role of Cardiovascular Magnetic Resonance in the Management of Patients with Cancer

Purpose of review

This article reviews the utility of cardiovascular magnetic resonance imaging (CMR) to detect abnormalities of the cardiovascular system that may result from cancer or its treatment.

Recent findings

With CMR, one may assess cardiac anatomy, function, myocardial perfusion, tissue composition, and blood flow. For those with cancer, these capabilities allow one to differentiate myocardial masses that may relate to the presence of cancer and evaluate diseases of the pericardium. These features facilitate measurement of left ventricular (LV) volumes, ejection fraction, mass, strain, T1 and T2 relaxation properties, and the extracellular volume fraction all of which may be useful for detecting subclinical cardiovascular injury that results from the receipt of potentially cardiotoxic cancer treatment.

Summary

CMR can provide an effective and efficient means to identify clinical abnormalities resulting from the diagnosis of cancer or subclinical cardiac injury that may be related to receipt of the therapy for cancer.

     

The Role of Cardiovascular Magnetic Resonance for Surveillance of Cardiac Performance upon Receipt of Potentially Cardiotoxic Cancer Therapeutics

Purpose of Review

Advancements in cancer treatment have resulted in improved cancer-related survival and consequently an increase in the number of cancer survivors. Unfortunately, associated with this increase in cancer-related survivorship, cardiac events have occurred with increasing frequency in cancer survivors. Recognition that cancer survivors are at increased risk for cardiovascular (CV) morbidity has generated interest to develop cardiac imaging techniques that identify subclinical CV disease during receipt of potentially cardiotoxic cancer treatment. Since subclinical cardiovascular disease precedes future cardiac events, early recognition of subclinical CV disease during receipt of potentially cardiotoxic cancer treatment offers the opportunity to initiate strategies that prevent further evolution of subclinical CV disease as well as cardiac events.

Recent Findings

Cardiovascular magnetic resonance imaging (CMR) is an advanced imaging technique that identifies imaging markers of subclinical cardiovascular disease in patients receiving potentially cardiotoxic cancer treatment regimens. In this article, we review the use of CMR for identifying subclinical cardiac disease in patients receiving potentially cardiotoxic cancer treatment regimens.

Summary

The ability of contemporary CMR to accurately define cardiac anatomy, function, and tissue characteristics may represent a critical tool to assess patients with cancer.

     

Low frequency of cardniac arrhythmias and lack of structural heart disease in medically-naïve acromegaly patients: a prospective study at baseline and after 1 year of somatostatin analogs treatment

Background

The incidence of arrhythmias may be increased in acromegaly, but the pathophysiologic mechanisms involved are still unclear, and it has never been correlated with structural heart changes analyzed by the gold-standard method cardiac magnetic resonance (CMR).

Aim

Evaluate the frequency of arrhythmias in drug-naïve acromegaly patients at baseline and after 1 year of somatostatin analogs (SA) treatment and to correlate the occurrence of arrhythmias with the presence of structural heart changes.

Patients and methods

Consecutive drug-naïve acromegaly patients were recruited. The occurrence of arrhythmias and structural heart changes were studied through 24-h Holter and CMR, respectively, at baseline and after 1-year SA treatment.

Results

Thirty-six patients were studied at baseline and 28 were re-evaluated after 1 year of SA treatment. There were 13 females and median age was 48 years (20–73 years). Nine patients (32 %) were controlled after treatment. No sustained arrhythmias were reported in the 24-h Holter. No arrhythmia-related symptoms were observed. Only two patients presented left ventricular hypertrophy and three patients presented fibrosis at baseline. There was no correlation of the left ventricular mass with the number of episodes of arrhythmias and they were not more prevalent in the patients presenting cardiac fibrosis.

Conclusion

We found no sustained arrhythmias and a lack of arrhythmia-related symptoms at baseline and after 1 year of SA treatment in a contemporary cohort of acromegaly patients that also present a low frequency of structural heart changes, indicating that these patients may have a lower frequency of heart disease than previously reported.

     

Impaired Exercise Tolerance in Heart Failure: Role of Skeletal Muscle Morphology and Function

Purpose of Review

To discuss the impact of deleterious changes in skeletal muscle morphology and function on exercise intolerance in patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), as well as the utility of exercise training and the potential of novel treatment strategies to preserve or improve skeletal muscle morphology and function.

Recent Findings

Both HFrEF and HFpEF patients exhibit a reduction in percent of type I (oxidative) muscle fibers and oxidative enzymes coupled with abnormal mitochondrial respiration. These skeletal muscle abnormalities contribute to impaired oxidative metabolism with an earlier shift towards glycolytic metabolism during exercise that is strongly associated with exercise intolerance. In both HFrEF and HFpEF patients, peripheral “non-cardiac” factors are important determinants of the improvement in exercise tolerance following aerobic exercise training. Adjunctive strategies that include nutritional supplementation with amino acids and/or anabolic drugs to stimulate anabolic molecular pathways in skeletal muscle show great promise for improving exercise tolerance and treating heart failure-associated sarcopenia, but these efforts remain early in their evolution, with no immediate clinical applications.

Summary

There is consistent evidence that heart failure is associated with multiple skeletal muscle abnormalities which impair oxygen uptake and utilization and contribute greatly to exercise intolerance. Exercise training induces favorable adaptations in skeletal muscle morphology and function that contribute to improvements in exercise tolerance in patients with HFrEF. The contribution of skeletal muscle adaptations to improved exercise tolerance following exercise training in HFpEF remains unknown and warrants further investigation.

     

The Evolving Role of Cardiorespiratory Fitness and Exercise in Prevention and Management of Heart Failure

Purpose of Review

This paper highlights the dynamic relationship between cardiorespiratory fitness (CRF) and heart failure (HF). As heart failure with preserved ejection fraction (HFpEF) surpasses heart failure with reduced ejection fraction (HFrEF) in prevalence, our void in understanding how to treat this syndrome becomes less justifiable. As such, significant attention has been given to the role that obesity and physical inactivity play, as both risk factors for heart failure, and therapeutic targets for its treatment.

Recent Findings

Previous findings have shown that low CRF, obesity, and physical inactivity are all risk factors for HF. More recently, it has been discovered that these factors are even more significant when applied to HFpEF, even after accounting for traditional cardiovascular risk factors. As such, new investigations have attempted to discover whether improvements in CRF could be utilized as a tool for prevention of HF. In addition, small studies have shown that interventions to improve CRF in patients with HF could improve both quality of life and fitness.

Summary

The role of CRF, PA, and obesity in the development of HF is now well established; however, our ability to attenuate that risk is yet to be determined. Observational data have signaled a correlation between improvements in PA, CRF and lower risk of HF however, large randomized controlled trials are still required to truly determine whether exercise training could be used in the prevention and treatment of HF, particularly HFpEF.

     

Diastolic Stress Testing Along the Heart Failure Continuum

Purpose of Review

This review summarizes recent developments highlighting the clinical utility of diastolic stress testing along the heart failure continuum.

Recent Findings

Invasive hemodynamic assessment of cardiac filling pressures during physiological stress is the gold-standard technique for unmasking diastolic dysfunction. Non-invasive surrogate techniques, such as Doppler ultrasound, have shown excellent agreement with invasive approaches and are now recommended by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. While cycle exercise is often advocated, recent evidence supports the use of isometric handgrip as a viable alternative stressor.

Summary

Diastolic stress testing is a powerful tool to enhance detection of diastolic dysfunction, is able to differentiate between cardiac and non-cardiac pathology, and should be incorporated into routine clinical assessment.

     

Prevalence of Prediabetes and Undiagnosed Diabetes in Patients with HFpEF and HFrEF and Associated Clinical Outcomes

Purpose

The prevalence and consequences of prediabetic dysglycemia and undiagnosed diabetes is unknown in patients with heart failure (HF) and preserved ejection fraction (HFpEF) and has not been compared to heart failure and reduced ejection fraction (HFrEF).

Methods

We examined the prevalence and outcomes associated with normoglycemia, prediabetic dysglycemia and diabetes (diagnosed and undiagnosed) among individuals with a baseline glycated hemoglobin (hemoglobin A1c, HbA1c) measurement stratified by HFrEF or HFpEF in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity programme (CHARM). We studied the primary outcome of HF hospitalization or cardiovascular (CV) death, and all-cause death, and estimated hazard ratios (HR) by use of multivariable Cox regression models.

Results

HbA1c was measured at baseline in CHARM patients enrolled in the USA and Canada and was available in 1072/3023 (35%) of patients with HFpEF and 1578/4576 (34%) patients with HFrEF. 18 and 16% had normoglycemia (HbA1c < 6.0), 20 and 22% had prediabetes (HbA1c 6.0–6.4), respectively. Finally among patients with HFpEF 22% had undiagnosed diabetes (HbA1c > 6.4), and 40% had known diabetes (any HbA1c), with corresponding prevalence among HFrEF patients being 26 and 35%. The rates of both clinical outcomes of interest were higher in patients with undiagnosed diabetes and prediabetes, compared to normoglycemic patients, irrespective of HF subtype, and in general higher among HFrEF patients. For the primary composite outcome among HFpEF patients, the HRs were 1.02 (95% CI 0.63–1.65) for prediabetes, HR 1.18 (0.75–1.86) for undiagnosed diabetes and 2.75 (1.83–4.11) for known diabetes, respectively, p value for trend across groups < 0.001. Dysglycemia was also associated with worse outcomes in HFrEF.

Conclusions

These findings confirm the remarkably high prevalence of dysglycemia in heart failure irrespective of ejection fraction phenotype, and demonstrate that dysglycemia is associated with a higher risk of adverse clinical outcomes, even before the diagnosis of diabetes and institution of glucose lowering therapy in patients with HFpEF as well as HFrEF.

     

The Role of Cardiovascular Magnetic Resonance in Sports Cardiology; Current Utility and Future Perspectives

Purpose of review

Cardiovascular magnetic resonance (CMR) is frequently used in the investigation of suspected cardiac disease in athletes. In this review, we discuss how CMR can be used in athletes with suspected cardiomyopathy with particular reference to volumetric analysis and tissue characterization. We also discuss the finding of non-ischaemic fibrosis in athletes describing its prevalence, distribution and clinical importance.

Recent findings

The strengths of CMR include high spatial resolution, unrestricted imaging planes and lack of ionizing radiation. Regular physical exercise leads to cardiac remodeling that in certain situations can be clinically challenging to differentiate from various cardiomyopathies. Thorough morphological assessment by CMR is fundamental to ensuring accurate diagnosis. Developments in tissue characterization by late gadolinium enhancement and T1 mapping have the potential to be powerful additional tools in this challenging clinical situation. Using late gadolinium enhancement, it is also possible to detect non-ischaemic fibrosis in athletes who do not have overt cardiomyopathy. The mechanisms of this fibrosis are unclear; however, it does appear to be clinically important. We also review data on the prevalence of non-ischaemic fibrosis in athletes.

Summary

CMR is a powerful tool to aid in the diagnosis of cardiomyopathy in athletes. It may also have a future role in assessing fibrosis related to long-term participation in sport.

     

Updates on the Role of Imaging in Cardiac Sarcoidosis

Purpose of review

The non-specific symptom profile and subclinical nature of disease along with variable region of cardiac involvement in systemic sarcoidosis make the diagnosis particularly challenging. The yield of endomyocardial biopsy, a gold standard for diagnosis, is not high unless coupled with additional imaging modalities to detect regional involvement. This review is focused on highlighting the major recent advances in imaging modalities and diagnosis of cardiac sarcoidosis.

Recent findings

There has been much interest and increasing research focused on developing newer and improved imaging modalities to establish diagnosis. CMR and ¹⁸F- FDG-PET are now considered imaging modalities of choice in most centers worldwide, but the data comparing both methodologies head-to-head is limited. Nevertheless, novel radiotracers (i.e. ⁶⁸Ga-DOTANOC, ¹⁸F-Flurpiridaz, ¹³N-Ammonia) and hybrid combination PET/CMR imaging are coming to spotlight with improved sensitivity and specificity for earlier detection of myocardial sarcoid.

Summary

As CMR and PET are showing increased utilization in cardiac sarcoidosis, ²⁰¹Th-SPECT, ^99mTc MDP SPECT, ⁶⁷Ga Scintigraphy, and ⁸²Rb PET are falling out of favor. Newer imaging modalities, radionuclide tracers, and hybrid PET/CMR combinations have been promising in better detecting cardiac sarcoidosis and are currently being evaluated in larger trials.

     

Novel Insights and Treatment Strategies for Right Heart Failure

Purpose of Review

The function of the right ventricle (RV) is intimately linked to its preload (systemic volume status) and afterload (pulmonary vasculature). In this review, we explore current knowledge in RV physiology, RV function assessment, causes of right heart failure (RHF), and specific treatment strategies for RHF.

Recent Findings

We examine the evidence behind new pharmacological therapies available, such as macitentan and riociguat in the treatment of specific etiologies of RHF. We will also focus on RHF in the setting of heart failure with preserved ejection fraction (HFpEF) and in the presence of left ventricular assist devices (LVAD), looking at current treatment recommendations, including mechanical circulatory support. Lastly, we will look to the horizon for the latest research on RHF, including the molecular basis of RHF and potential novel treatment methods for this old yet poorly understood syndrome.

Summary

Disturbances in this complex relationship result in the clinical syndrome of RHF. Despite advances in the management of left heart diseases, much work remains to be done to understand and manage RHF.

     

Multiple Avenues of Modulating the Nitric Oxide Pathway in Heart Failure Clinical Trials

Purpose of review

This review discusses the integral role of the nitric oxide (NO) pathway in the pathophysiology of heart failure (HF). We emphasize potential therapeutic targets in the NO pathway and review contemporary clinical trials evaluating these novel therapeutic options.

Recent findings

Nitrates, neprilysin inhibitors, and phosphodiesterase (PDE) inhibitors have all proven to be efficacious in HF patients with systolic dysfunction, with the former two classes of medications producing a net mortality benefit. However, neither PDE inhibitors nor nitrates have demonstrated significant clinical benefit in patients with HF with preserved ejection fraction (HFpEF), and neprilysin inhibitors have yet to be evaluated in this population. Soluble guanylate cyclase (sGC) stimulators have shown significant promise in all HF patients, leading to improvements in both quality of life scores and exercise capacity. Conversely, sGC activators have limited clinical utility in HF, owing largely to safety concerns of hypotension. Inorganic nitrates and nitrites, meanwhile, may be emerging as potential therapies for the HFpEF population.

Summary

The advent of novel therapies targeting the NO pathway is beginning to create a paradigm shift in the treatment of the HF patient. These therapies offer a promising outlook for the future, with hopes of reducing HF-associated morbidity and mortality.

     

Evolving Landscape of Clinical Trials in Heart Failure: Patient Populations,Endpoint Selection,and Regions of Enrollment

Purpose of Review

Clinical trial design and execution are evolving as increasingly important considerations with respect to the success of heart failure trials. The current review highlights temporal trends in characteristics of heart failure clinical trials.

Recent Findings

Recent trials in heart failure have required longer recruitment phases, displayed inefficient enrollment rates, increased use of composite and nonfatal endpoints, undergone rapid globalization, and gradually increased focus on heart failure with preserved ejection fraction.

Summary

Understanding patterns and trends in clinical trial design and execution may inform future planning and conduct of trials of heart failure therapeutics.