Role of Cardiac Contractility Modulation in Heart Failure With a Higher Ejection Fraction

Cardiac contractility modulation (also known as CCM) is a novel device therapy that delivers nonexcitatory electric stimulation to cardiac myocytes during the absolute refractory period, and it has been shown to improve functional status and clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF). CCM therapy is currently recommended for a subset of patients with advanced HFrEF who are not candidates for cardiac resynchronization therapy. A growing body of evidence demonstrates the benefit of CCM therapy in patients with HFrEF and with ejection fraction at the upper end of the spectrum and in patients with HF and with mildly reduced ejection fraction (HFmrEF). Experimental studies have also observed reversal of pathological biomolecular intracellular changes with CCM therapy in HF with preserved ejection fraction (HFpEF), indicating the potential for clinically meaningful benefits of CCM therapy in these patients. In this review, we sought to discuss the basis of CCM therapy and its potential for management of patients with HF with higher ejection fractions.     

Update on renin-angiotensin-aldosterone blockade in heart failure

There is convincing evidence that the renin-angiotensin-aldosterone system (RAAS) plays an important role in heart failure (HF), from the events that result in its inception through advanced disease. In particular, RAAS activation is one of the major pathways involved in maladaptive cardiac remodeling, a process that results in progressive cardiac dysfunction. Not surprisingly, strategies targeting the RAAS have substantial benefits in HF. These therapies, which include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone receptor antagonists, have emerged as cornerstones of HF therapy, particularly in patients with systolic dysfunction. Their role in HF with preserved ejection fraction, however, is less certain. New information and approaches targeting RAAS activation continue to emerge. Direct renin inhibitors are hypothesized to have beneficial effects in HF, but further studies are needed to evaluate their efficacy.     

CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation,SGLT2 Inhibitors,ARNI in HFpEF,and Tafamidis in Amyloidosis

In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes.     

Heart Failure Duration and Mechanistic Efficacy of Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction

BackgroundAlthough sacubitril/valsartan (Sac/Val) is indicated for the treatment of heart failure with reduced ejection fraction (HFrEF), gaps in care continue to exist for those with newer onset HFrEF vs those with longer durations of disease.Methods and ResultsWe categorized 794 persons with HFrEF (EF of ≤40%) according to a HF duration of less than 12 months, 12–24 months, 24–60 months, and more than> 60 months. After the initiation of Sac/Val, concentrations of N-terminal pro-B type natriuretic peptide, high sensitivity cardiac troponin T, and soluble ST2 were measured, and Kansas City Cardiomyopathy Questionnaire 23 scores were obtained serially from baseline to 12 months. The left ventricular ejection fraction was measured by echocardiography. Significant decreases in the concentrations of N-terminal pro-B type natriuretic peptide, high sensitivity cardiac troponin T, and soluble ST2 were observed regardless of HF duration (P < .001). Comparable gains in Kansas City Cardiomyopathy Questionnaire 23 scores were achieved in all HF duration categories. Moreover, consistent reverse cardiac remodeling in all HF duration categories occurred, with the absolute left ventricular ejection fraction improvement by 12 months across HF duration groups of 12.2%, 6.9%, 8.5%, and 8.6% for HF duration of less than 12 months, 12–24 months, 24–60 months, and more than 60 months, respectively.ConclusionsThe initiation of Sac/Val decreases prognostic biomarkers, improves health status, and reverses cardiac remodeling processes, regardless of HF duration.Brief lay summaryWe categorized 794 persons with heart failure owing to a low ejection fraction according to disease duration into 4 groups: less than 12 months, 12–24 months, 24–60 months, and more than 60 months. After the initiation of sacubitril/valsartan (Entresto), we found that regardless of the duration of heart failure significant improvements occurred in cardiac biomarkers, patients felt better with improved health status and on testing with cardiac ultrasound examination, improvement in heart size, and function occurred. These results suggest that, regardless of heart failure duration, patients with a reduced ejection fraction would benefit from use of sacubitril/valsartan for their care.     

Gender Differences in the Pathophysiology, Clinical Presentation, and Outcomes of Ischemic Heart Failure

Despite advances in the treatment of acute myocardial infarction (MI), heart failure (HF) remains a frequent acute and long-term outcome of ischemic heart disease (IHD). In response to acute coronary ischemia, women are relatively protected from apoptosis, and experience less adverse cardiac remodeling than men, frequently resulting in preservation of left ventricular size and ejection fraction. Despite these advantages, women are at increased risk for HF- complicating acute MI when compared with men. However, women with HF retain a survival advantage over men with HF, including a decreased risk of sudden death. Sex-specific treatment of HF has been hindered by historical under-representation of women in clinical trials, though recent work has suggested that women may have a differential response to some therapies such as cardiac resynchronization. This review highlights the sex differences in the pathophysiology, clinical presentation and outcomes of ischemic heart failure and discusses key areas worthy of further investigation.     

Hiding in Plain Sight: Cardiac Amyloidosis,an Emerging Epidemic

Amyloidosis is a term used to describe a group of rare heterogeneous diseases that ultimately result in the deposition and accumulation of misfolded proteins. These misfolded proteins, known as amyloids, are associated with a variety of precursor proteins that have amyloidogenic potential. Ultimately, the specific type of amyloidosis is dependent on multiple factors including genetic variability of precursor proteins and the tissue or organ in which the amyloid accumulates. Several types of amyloid have a predilection for the heart and thus contribute to cardiac amyloidosis, a major cause of restrictive cardiomyopathy. Individuals with cardiac amyloidosis present clinically with heart failure with preserved ejection fraction. Although improved diagnostics and increased awareness of cardiac amyloidosis have led to a relative increase in diagnosis, cardiac amyloidosis remains an underrecognized and underdiagnosed cause of heart failure with preserved ejection fraction. It is essential to properly identify cases of cardiac amyloidosis and determine the pathology responsible for the formation of amyloid to appropriately provide management. This review aims to encourage physician awareness of cardiac amyloidosis by focusing on clinical presentation and the distinctions between types. Furthermore, epidemiology is central to understanding the affected demographics and sometimes hereditary nature of the disease. Improved understanding of cardiac amyloidosis will ideally lead to earlier diagnosis and interventions to improve patient outcomes.     

Prevention, diagnosis, and treatment of hypertensive heart disease

Hypertensive heart disease (HHD), a result of long-standing hypertension, is characterized by changes in the myocardial structure and function in the absence of other primary cardiovascular abnormalities. Although increased blood pressure is the initiating stimulus, neurohormonal factors, particularly the renin-angiotensin system, play a key role in remodeling of cardiac chamber geometry and walls. Optimal antihypertensive therapy in the setting of therapeutic lifestyle changes is crucial in the prevention and control of HHD. Regression of left ventricular hypertrophy (LVH) is achievable and associated with improved prognosis. However, prevention of myocardial remodeling before LVH establishes would further increase the benefits to cardiac function and prognosis. Antihypertensive agents exhibit variable effectiveness in inducing LVH regression. Currently, renin-angiotensin system blocking agents seem to be the most effective approach for LVH regression and reverse remodeling in these patients.     

Ischemia/Infarction

Myocardial infarction (MI) accounts for most incidences of heart failure (HF) and low ejection fraction. Evidence suggests that acute MI leads to early cardiac remodeling, with changes in ventricular geometry and structure that in turn lead to a vicious cycle of ventricular dilation, increased wall stress, hypertrophy and more ventricular dilation and dysfunction, and worsening of HF. The early geometric and structural changes contribute to early mechanical complications and subsequent progressive ventricular remodeling and the development of chronic HF. A clear understanding of the underlying mechanisms is helpful in developing optimal preventive and therapeutic strategies for HF.     

STEMI and heart failure in the elderly: role of adverse remodeling

The elderly population (age ≥ 65 years) has been increasing worldwide. In North America and Europe, both heart failure (HF) and ST-segment elevation MI (STEMI) are more prevalent in the elderly. Morbidity, hospitalizations and costs associated with HF are higher in the elderly. Despite improved therapies, the bulk of cardiovascular deaths occur in the elderly. Survivors of acute STEMI develop progressive ventricular remodeling that leads to HF. There are several reasons for the increased HF burden in the elderly. First, there is a lack of clinical trial data exclusively in elderly patients for specific therapy of adverse remodeling post-STEMI and HF with low ejection fraction (HF/low-EF) or HF with preserved ejection fraction (HF/PEF). Second, there is the lack of data on the impact of aging on remodeling during healing post-STEMI and HF. Third, HF therapy in the elderly is more challenging because of aging-specific biological changes and associated comorbidities and polypharmacy. More research on aging and post-STEMI remodeling and clinical trials on post-STEMI remodeling and HF in the elderly are needed, especially in the “older-elderly” population segment aged ≥75 years.     

Cardiac Resynchronization Therapy in Mild Heart Failure: A Review of the REVERSE and MADIT-CRT Trials

Cardiac resynchronization therapy has become part of the treatment strategy for advanced, symptomatic heart failure, but newly published trials show that more patients than previously realized may benefit from this therapy, including those with mild heart failure symptoms. The REVERSE and MADIT-CRT trials showed that cardiac resynchronization therapy reduces risk of hospitalization for heart failure and leads to beneficial reverse remodeling of the left ventricle in mild heart failure, especially in patients with prolonged QRS complexes. Ongoing studies aim to expand the indications for this therapy even further, including in patients with normal ejection fractions and a need for frequent ventricular pacing. The current body of evidence favors cardiac resynchronization therapy in patients with a depressed ejection fraction and prolonged QRS, even with minimal or no heart failure symptoms.     

Biventricular and novel pacing mechanisms in heart failure

Biventricular pacing, often referred to as cardiac resynchronization therapy (CRT), improves subjective and objective measures and promotes reverse ventricular remodeling in patients with chronic New York Heart Association (NYHA) class III or IV heart failure despite optimal medical therapy, QRS duration of more than 130 ms, and left ventricular ejection fraction of less than 35%. However, there are many nonresponders and other patients who do not meet criteria for CRT, limiting the efficacy of therapy. Recent investigations (eg, the REVERSE trial) have shown that patients with minimal symptoms (NYHA class I-II) can benefit from the mechanical and functional effects of CRT, specifically reverse remodeling. Ongoing investigations include the possibility of earlier intervention in the postinfarct period with CRT. Additionally, a novel pacing mechanism known as cardiac contractility modulation has also shown promise in improving remodeling of the failing heart. In this article, we review CRT’s effects on reverse remodeling in an expanding patient population and as a novel pacing mechanism, its cardiac contractility modulation, and its benefits in patients with heart failure.     

Cardiac resynchronization therapy for heart failure: biventricular pacing and beyond

In the early 1990s, attempts at treating patients with dilated cardiomyopathy and end-stage heart failure by using right-sided, dual-chamber pacing met with equivocal results. Although initially discouraging, this work did provide further insight into the electromechanical consequences of advanced heart failure and suggested that atrial-synchronized biventricular pacing, or cardiac resynchronization therapy, might provide better and more consistent symptomatic and hemodynamic improvement. Several studies have recently validated the safety and efficacy of cardiac resynchronization therapy in advanced heart failure. Data from these studies have shown statistically significant improvements in left ventricular ejection fraction, New York Heart Association class, exercise tolerance, and quality of life. Observed reductions in morbidity and mortality await confirmation from ongoing large-scale outcomes studies. This article reviews the evolution of pacing in heart failure and discusses the underlying mechanisms that are potentially responsible for the improvement seen in patients receiving cardiac resynchronization therapy. In addition, the results of recently completed clinical trials, as well as the status of ongoing clinical trials, are reviewed.     

Ventricular Reverse Remodeling and 6-Month Outcomes in Patients Receiving Cardiac Resynchronization Therapy: Analysis of the MIRACLE Study

Objective: The objective of this analysis was to determine if there were differences in ventricular reverse remodeling and 6-month outcome with cardiac resynchronization therapy (CRT) among specific subgroups enrolled in the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) Study.Background: Analysis of major subgroups receiving CRT is important in determining who may be most likely to benefit, since all patients who receive CRT do not demonstrate improvement.Methods: Differences in response to CRT between subgroups based on baseline echocardiographic parameters, New York Heart Association (NYHA) class, age, gender, beta blocker use, and etiology of heart failure (HF) were analyzed for the clinical end points of the study as well as 6-month HF re-hospitalization or death.Results: The benefit of CRT over control was similar in all subgroups with respect to all clinical endpoints. However, non-ischemic HF patients had greater improvements with CRT compared to ischemic HF patients in left ventricular end diastolic volume (P < 0.001) and ejection fraction (EF) (6.7% increase vs. 3.2% [P < 0.001]). Greater improvements in EF were also seen in those patients with less severe baseline mitral regurgitation (MR) (P < 0.001). Women but not men receiving CRT were more likely to be event-free from first HF hospitalization or death compared to the control group (Hazard Ratio = 0.157).Conclusions: The benefits of CRT with respect to EF and reverse remodeling were greater in patients with non-ischemic HF and less severe MR. Women may also derive more benefit than men with respect to the occurrence of HF hospitalization or death.     

Biomarkers to Predict Reverse Remodeling and Myocardial Recovery in Heart Failure

Left ventricular remodeling appears to be a critical link between cardiac injury and the development and progression of heart failure with reduced ejection fraction (HFrEF). Several drug and device therapies that modify and reverse the remodeling process in patients with HFrEF are closely associated with improvement in clinical outcomes. Reverse remodeling, including partial or complete recovery of systolic function and structure, is possible but its determinants are incompletely understood. Methods to predict reverse remodeling in response to therapy are not well defined. Though non-invasive imaging techniques remain the most widely used methods of assessing reverse remodeling, serum biomarkers are now being investigated as more specific, mechanistically driven, and clinically useful predictors of reverse remodeling. Biomarkers that reflect myocyte stretch and stress, myocyte injury and necrosis, inflammation and fibrosis, and extracellular matrix turnover may be particularly valuable for predicting pathophysiologic changes and prognosis in individual patients. Their use may ultimately allow improved application of precision medicine in chronic HF.     

Cardiac function in patients on chronic amiodarone therapy

Antiarrhythmic agents may depress cardiac contractility and worsen heart failure. Few data are available describing the chronic effects of amiodarone on myocardial function. To assess the effects of amiodarone on cardiac function, we studied 41 consecutive patients with first-pass or equilibrium radionuclide angiography prior to and 3 months after drug therapy was initiated. The mean heart rate, systolic blood pressure (BP), and diastolic BP were not significantly altered by treatment. The mean ejection fraction was 36% +/- 19 (mean +/- 1 SD) at the time of drug initiation and 36% +/- 17 3 months later (p less than 0.05). Nineteen patients had an ejection fraction greater than 30% and 16 had an ejection fraction less than 30%. The mean change in ejection fraction for these two subgroups showed no statistically significant difference, although a decrease in EF greater than 10% was seen in three patients (symptomatic in two), necessitating an increase in diuretic dose. No correlation between amiodarone dose and change in ejection fraction (r = -0.12, p greater than 0.05) was noted. There was no correlation between baseline ejection fraction and change in ejection fraction over this 3-month period (r = -0.36, p greater than 0.05). In summary, amiodarone does not depress left ventricular function and as a result can be used safely in patients with mild to moderate impairment of left ventricular function. In patients with stable left ventricular function, serial tests of left ventricular function may not be necessary.     

Cardiac amyloidosis: An underdiagnosed/underappreciated disease

Cardiac amyloidosis or amyloid cardiomyopathy (ACM), commonly resulting from extracellular deposition of amyloid fibrils consisted of misfolded immunoglobulin light chain (AL) or transthyretin (TTR) protein, is an underestimated cause of heart failure and cardiac arrhythmias. Among the three types of cardiac amyloidosis (wild-type or familial TTR and light-chain), the wild-type (Wt) TTR-related amyloidosis (ATTR) is an increasingly recognized cause of heart failure with preserved ejection fraction (HFpEF), and amyloidosis should be considered in the differential diagnosis of this heart failure group of patients. Recent advances in the diagnosis and drug treatment of ACM have ushered in a new era in early disease detection and better management of these patients. Certain clues in cardiac and extracardiac manifestations of ACM may heighten clinical suspicion and guide further confirmatory testing. Newer noninvasive imaging methods (strain echocardiography, cardiac magnetic resonance and bone scintigraphy) may obviate the need for endomyocardial biopsy in ATTR patients, while newer targeted therapies may alter the adverse prognosis in these patients. Early recognition of ACM is crucial in halting the disease process before irreversible organ damage occurs. Chemotherapy and stem-cell transplantation combined with immunomodulatory therapy may also favorably affect the course and prognosis of light chain ACM. Finally, in select patients with end-stage disease, heart transplantation may render results comparable to non-ACM patients. All these issues are herein reviewed.     

Cardiac resynchronization therapy and valvular cardiomyopathy after corrective surgery

Cardiac resynchronization therapy (CRT) has been shown to have clinical benefits in certain groups of patients with advanced heart failure (HF). However, patients with valvular cardiomyopathy are underrepresented in randomized clinical studies. The aim of this study was to assess the medium-term (i.e., at 6 months) effects of CRT in patients with HF exclusively due to valvular disease. The study included 40 consecutive patients who underwent CRT device implantation. At 6 months, there were improvements in functional class, left ventricular remodeling, and intraventricular dyssynchrony parameters in treated patients. In this particular subgroup of patients, the benefits of CRT were similar to those observed in patients with HF due to other etiologies.     

Control of autocrine and paracrine myocardial signals: an emerging therapeutic strategy in heart failure

A growing body of evidence supports the hypothesis that autocrine and paracrine mechanisms, mediated by factors released by the resident cardiac cells, could play an essential role in the reparative process of the failing heart. Such signals may influence the function of cardiac stem cells via several mechanisms, among which the most extensively studied are cardiomyocyte survival and angiogenesis. Moreover, besides promoting cytoprotection and angiogenesis, paracrine factors released by resident cardiac cells may alter cardiac metabolism and extracellular matrix turnover, resulting in more favorable post-injury remodeling. It is reasonable to believe that critical intracellular signals are activated and modulated in a temporal and spatial manner exerting different effects, overall depending on the microenvironment changes present in the failing myocardium. The recent demonstration that chemically, mechanically or genetically activated cardiac cells may release peptides to protect tissue against ischemic injury provides a potential route to achieve the delivery of specific proteins produced by these cells for innovative pharmacological regenerative therapy of the heart. It is important to keep in mind that therapies currently used to treat heart failure (HF) and leading to improvement of cardiac function fail to induce tissue repair/regeneration. As a matter of facts, if specific autocrine/paracrine cell–derived factors that improve cardiac function will be identified, pharmacological-based therapy might be more easily translated into clinical benefits than cell-based therapy. This review will focus on the recent development of potential pharmacologic targets to promote and drive at molecular level the cardiac repair/regeneration in HF.     

Effect of statins, angiotensin-converting enzyme inhibitors, and beta blockers on survival in patients >or=65 years of age with heart failure and preserved left ventricular systolic function

About half of all patients with heart failure (HF) have preserved left ventricular systolic function. Statins, angiotensin-converting enzyme inhibitors, and beta blockers have been shown to improve survival in patients with HF and low ejection fraction. However, no large national study has investigated these agents in patients with HF and preserved left ventricular ejection fraction. We evaluated a nationwide sample of 13,533 eligible Medicare beneficiaries aged >or=65 years who were hospitalized with a primary discharge diagnosis of HF and had chart documentation of preserved left ventricular ejection fraction between April 1998 and March 1999 or between July 2000 and June 2001. In Cox proportional hazard model accounting for demographic profile, clinical characteristics, treatments, physician specialty, and hospital characteristics, discharge statin therapy was associated with significant improvements in 1- and 3-year mortality (RR 0.69, 95% confidence interval [CI] 0.61 to 0.78; RR 0.73, 95% CI 0.68 to 0.79, respectively). Irrespective of total cholesterol level or coronary artery disease status, diabetes, hypertension, and age, statin therapy was associated with significant differences in mortality rates. Similarly, angiotensin-converting enzyme inhibitors were associated with better survival at 1 year (RR 0.88, 95% CI 0.82 to 0.95) and 3 years (RR 0.93, 95% CI 0.89 to 0.98). Beta-blocker therapy was associated with a nonsignificant trend at 1 year (RR 0.93, 95% CI 0.87 to 1.10) and significant survival benefits at 3 years (RR 0.92%, 95% CI 0.87 to 0.97). In conclusion, our data demonstrate that statins, angiotensin-converting enzyme inhibitors, and beta blockers are associated with better short- and long-term survival in patients >or=65 years with HF and preserved left ventricular ejection fraction.     

Cardiac resynchronization pacing therapy

Approximately one third of patients with congestive heart failure and systolic dysfunction have an intraventricular conduction delay that is manifested as a QRS duration >120 ms. An intraventricular conduction delay adversely affects ventricular performance by causing dyssynchrony in ventricular activation. When ventricular dyssynchrony is present, simultaneous left and right ventricular pacing or cardiac resynchronization therapy can improve ventricular synchrony. This can lead to an improvement in hemodynamics, ventricular remodeling, mitral regurgitation, exercise capacity and quality of life. Candidates for cardiac resynchronization therapy include patients with advanced congestive heart failure that is refractory to medical therapy, a QRS duration >130 ms, left ventricular ejection fraction <0.35 and sinus rhythm. Because patients who are candidates for biventricular pacing are at high risk of sudden death, they should be considered for implantation of a biventricular pacing device that also provides defibrillation therapy. This paper reviews biventricular pacing for congestive heart failure, including results of acute hemodynamic studies and randomized clinical trials, patient and device selection, and procedural issues.