Heart Rate in Coronary Syndromes and Heart Failure

In the past 2 decades, there have been growing evidences that resting heart rate might be a marker of risk or even a risk factor for cardiovascular morbidity and mortality. This article reviews current evidences concerning the relation between heart rate and patients' outcome in different clinical settings such as acute coronary syndromes, left ventricular systolic dysfunction, and heart failure. The relationship between resting heart rate and the development of coronary artery disease, as well as all-cause and cardiovascular mortality, has been found to be strong, graded, and independent from other risk factors. Several lines of research indicate that heart rate plays an important role in the pathophysiology of atherosclerosis and in the clinical manifestations of coronary artery disease and that it is an independent prognostic factor in all coronary syndromes. The prognostic value of elevated heart rate in patients with heart failure has been tested in several clinical trials evaluating pharmacologic heart rate–lowering agents (eg, β-blockers). It is difficult to determine which percentage of the clinical benefit obtained with β-blockers is related to induced bradycardia because cardiac slowing is only one of the effects of these drugs. In the BEAUTIFUL trial, a subgroup analysis conducted in patients with resting HR more than 70 beats per minute showed that treatment with ivabradine was able to improve outcome. According to the results presented in this review, we can conclude that heart rate is a predictor of death in both stable coronary artery disease and acute coronary syndromes. Elevated heart rate is also able to negatively predict clinical outcomes in patients with heart failure. However, it is still unclear if heart rate reduction per se can improve prognosis.     

Heart failure in elderly patients

Several structural and functional changes contribute to heart failure in elderly patients: an age dependent increase in sympathetic nervous activity, left ventricular wall diameter, myocardial fibrosis and apoptosis, micro- and macrovascular coronary sclerosis, aortic stiffness. As a consequence, diastolic, but also systolic heart failure is a frequent finding in elderly patients. The relation of systolic to diastolic heart failure is clearly shifted towards diastolic heart failure in elderly patients, especially in women. Mortality is increased with systolic dysfunction in elderly patients compared to younger heart failure patients. Mortality is less with diastolic dysfunction, but still higher compared to elderly without heart failure. In addition, morbidity is increased both with diastolic and systolic heart failure in elderly patients. Cognitive dysfunction is a frequent finding. After exclusion of specific cardiac and extracardiac reasons for dyspnoea, drug therapy of systolic heart failure in elderly is similar to younger patients. However, the physiological decrease of renal function and the more frequent renal impairment in elderly patients with heart failure needs to be considered. Guideline recommendations for drug therapy are based in most cases on studies conducted in younger systolic heart failure patients. A recent meta-analysis of randomized beta-blocker trials suggests improved survival with beta-blockers even in the elderly subgroup. Guidelines for the treatment of diastolic heart failure are available only recently. The term heart failure with normal left ventricular ejection fraction (LVEF) has been proposed instead of diastolic heart failure. Given the increased morbidity and mortality in elderly patients with heart failure and normal LVEF, therapy should include general measures, such as physical activity, weight reduction, volume restriction. Specific therapy includes optimal control of systolic and diastolic blood pressure, diuretics, nitrates, and frequency-control. However, randomized trials evaluating the efficacy of specific therapies in heart failure with normal LVEF are still missing.     

Role of Beta-Blocker Therapy in Heart Failure and Atrial Fibrillation

Heart failure is a serious disorder associated with substantial morbidity and mortality. Approximately 15-30% patients with systolic heart failure are in atrial fibrillation and the proportion increases with severity of heart failure. Patients with heart failure and atrial fibrillation have worse outcome than those in sinus rhythm. Beta-blockers, together with angiotensin-converting enzymes inhibitors, are the standard therapy in patients with chronic heart failure. Retrospective studies have suggested that despite the improvement in left ventricular systolic function after treatment with beta-blockers, the exercise capacity and symptoms in those heart failure patients with atrial fibrillation was not improved as much as those in sinus rhythm. Moreover, the use of bisoprolol in the Cardiac Insufficiency Bisoprolol Study II, unlike those in sinus rhythm, failed to produce any survival benefit in patients with poor systolic function and atrial fibrillation. It seems that those patients with heart failure and atrial fibrillation may have different response to beta-blocker therapy. Prospective trials to clarify the impact of beta-blocker therapy and the optimal therapeutic strategy in this high-risk group of patients are warranted.     

How Heart Rate Should Be Controlled in Patients with Atherosclerosis and Heart Failure

Purpose of Review

Resting heart rate is an independent risk factor for all-cause and cardiovascular mortality in patients with heart failure. The main objectives are to discuss the prognosis of heart rate, its association with coronary atherosclerosis, and the modalities of control of the heart rate in sinus rhythm and in the rhythm of atrial fibrillation in patients with chronic heart failure.

Recent Findings

As a therapeutic option for control heart rate, medications such as beta-blockers, digoxin, and finally ivabradine have been studied. Non-dihydropyridine calcium channel blockers are contraindicated in patients with heart failure and reduced ejection fraction. The influence of the magnitude of heart rate reduction and beta-blocker dose on morbidity and mortality will be discussed. Regarding the patients with heart failure and atrial fibrillation, there are different findings in heart rate control with the use of a beta-blocker. Patients eligible for ivabradine have clinical benefits and increased ejection fraction. Vagal nerve stimulation has low efficacy for the control of heart rate. Complementary therapies such as tai chi and yoga showed no effect on heart rate.

Summary

In this review, we discuss the main therapeutic options for the control of heart rate in patients with atherosclerosis and heart failure. More research is needed to examine the effects of therapeutic options for heart rate control in different population types, as well as their effects on clinical outcomes and impact on morbidity and mortality.

     

Heart rate and its reduction in chronic heart failure and beyond

Heart rate (HR) is associated with cardiovascular outcomes in all the stages of the cardiovascular continuum as well as in patients with pulmonary, cerebrovascular, and renal disease, sepsis, cancer, and erectile dysfunction. In patients with cardiovascular disease, but also in the general population, increased HR represents an important indicator of mortality with each acceleration of HR over 70 b.p.m. increasing the risk. In patients in sinus rhythm with chronic heart failure with reduced ejection fraction (HFrEF), a HR >70 b.p.m. increased the risk of hospitalization, and >75 b.p.m. the risk of cardiovascular death as shown in the Systolic Heart Failure Treatment with the I_f Inhibitor Ivabradine Trial (SHIFT). Reducing HR with ivabradine by 11 b.p.m. (placebo‐controlled) reduced the primary composite endpoint (cardiovascular death and hospitalization for worsening heart failure). Ivabradine was well tolerated showing benefit irrespective of age or diabetes status, and also in the presence of low systolic blood pressure and severe heart failure (SHIFT trial). Therefore, HR qualifies as a modifiable risk factor in heart failure. In patients with stable coronary disease, HR is a risk marker but HR reduction with ivabradine does not improve outcomes. The role of selective HR lowering remains unclear in patients with pulmonary, renal, cerebrovascular, and other diseases, as the potential benefit of interventions on HR has not been explored in these conditions. Future studies should scrutinize if HR reduction improves outcomes, defining HR as a potential risk factor and therapeutic target in other conditions beyond heart failure.     

Sex-Related Differences in Heart Failure and Beta-Blockers

Under-representation of women in heart failure trials has limited our knowledge of heart failure in women to extrapolation of findings from men. Significant sex related differences in clinical and laboratory characteristics exist in systolic heart failure including better survival in women. The value of various therapeutic interventions should be based on proven effect in women and not on an assumption based on proven benefit in men. Among the medications currently recommended for patients with systolic heart failure, beta-blockers have the strongest data supporting their efficacy in women.     

Atrial Fibrillation Ablation and Heart Failure

Atrial fibrillation (AF) worsens outcome in patients with systolic heart failure and the presence of heart failure (HF) predicts a 5- to 6-fold increase in risk of AF. In addition to loss of atrial systole, AF may contribute to left ventricular (LV) systolic dysfunction due a rapid ventricular rate, irregularity of rhythm and exacerbation of mitral regurgitation due to atrial dilatation. Elimination of atrial fibrillation with catheter ablation can improve ejection fraction and reduce heart failure symptoms and appears superior to AV node ablation and bi-ventricular pacing. AF ablation can restore sinus rhythm in most patients with heart failure. Additional study is warranted to identify which patients will receive maximum benefit from aggressive rhythm control and to determine efficacy in patients with diastolic heart failure.     

Diagnosis and Management of Fetal Heart Failure

Congestive fetal heart failure, defined as inability of the heart to deliver adequate blood flow to organs such as the brain, liver, and kidneys, is a common final outcome of many intrauterine disease states that may lead to fetal demise. Advances in fetal medicine during the past 3 decades now provide the diagnostic tools to detect and also treat conditions that may lead to fetal heart failure. Fetal echocardiographic findings depend on severity of diastolic and systolic dysfunction of both ventricles. At an advanced stage, findings include cardiomegaly; valvar regurgitation; venous congestion; fetal edema and effusions; oligohydramnios; and preferential shunting of blood flow to the brain, heart, and adrenals in the distressed fetus. A useful diagnostic tool to quantify severity of heart failure is the cardiovascular profile score, which is a composite score based on 5 different echocardiographic parameters. To predict outcomes, the score should be interpreted in the context of the underlying disease, as different causes of intrauterine heart failure may have highly variable outcomes. Low fetal cardiac output may result from a myocardial disease (cardiomyopathy, myocarditis, ischemia), abnormal loading conditions (arterial hypertension, obstructive structural heart disease, atrioventricular malformations, twin-to-twin transfusion), arrhythmia, or external cardiac compression (pleural and/or pericardial effusions, cardiac tumours). Treatment options are available for several of these conditions.     

Recommendation of Low-Salt Diet and Short-term Outcomes in Heart Failure with Preserved Systolic Function

Background

Dietary sodium indiscretion frequently contributes to hospitalizations in elderly heart failure patients. Animal models suggest an important role for dietary sodium intake in the pathophysiology of heart failure with preserved systolic function. The documentation and effects of hospital discharge recommendations, particularly for sodium-restricted diet, have not been extensively investigated in heart failure with preserved systolic function.

Methods

We analyzed 1700 heart failure admissions to Michigan community hospitals. We compared documentation of guideline-based discharge recommendations between preserved systolic function and systolic heart failure patients with chi-squared testing, and used logistic regression to identify predictors of 30-day death and hospital readmission in a prespecified follow-up cohort of 443 patients with preserved systolic function. We hypothesized that patients who received a documented discharge recommendation for sodium-restricted diet would have lower 30-day adverse event rates.

Results

Heart failure patients with preserved systolic function were significantly less likely than systolic heart failure patients to receive discharge recommendations for weight monitoring (33% vs 43%) and sodium-restricted diet (42% vs 53%). Upon propensity score-adjusted multivariable analysis, patients with preserved systolic function who received a documented sodium-restricted diet recommendation had decreased odds of 30-day combined death and readmission (odds ratio 0.43, 95% confidence interval, 0.24-0.79; P = .007). No other discharge recommendations predicted 30-day outcomes.

Conclusions

Clinicians document appropriate discharge instructions less frequently in heart failure with preserved systolic function than systolic heart failure. Selected heart failure patients with preserved systolic function who receive advice for sodium-restricted diet may have improved short-term outcomes after hospital discharge.     

Clinical implications of an accurate problem list on heart failure treatment

CONTEXT: The premise of the problem-oriented medical record is that an accurately defined problem list will directly result in more thorough and efficient patient care. However, little empirical evidence exists demonstrating improved patient outcomes as a result of an adequately structured problem list. OBJECTIVE: To determine the impact of problem list documentation of heart failure on the likelihood that evidence-based pharmacotherapy has been prescribed. DESIGN: Cross-sectional study. SETTING: Community-based primary care clinics in Portland, Oregon. SUBJECTS: Active patients in the network with a left ventricular ejection fraction of 40% or less, with and without heart failure, in their structured problem list. MAIN OUTCOME MEASURES: The proportion of patients prescribed medications with known benefits for systolic dysfunction. RESULTS: In this group of patients with known systolic dysfunction, the likelihood of therapy with either an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker was higher in patients who had heart failure listed on their problem list compared to patients who did not (92.2% vs 76.7%; P<.05). This association remained after statistical adjustment for age, gender, and ejection fraction. Patients with accurate problem list entries were also more likely to receive digoxin (61.1% vs 36.7%; P=.001) and spironolactone (26.7% vs 13.3%; P=.025). There were no differences in the use of beta-blockers between the 2 groups. CONCLUSION: Accurate documentation of heart failure on the problem list of patients with known systolic dysfunction is associated with a significant increase in the likelihood of being prescribed medications with known clinical benefit.     

Ivabradine in Management of Heart Failure: a Critical Appraisal

Elevated resting heart rate has been linked to poor outcomes in patients with chronic systolic heart failure. Blockade of funny current channel with ivabradine reduces heart rate without inotropic effects. Ivabradine was recently approved by US Food and Drug Administration for patients with stable, symptomatic chronic heart failure (HF) with left ventricular ejection fraction (LVEF) ≤35 %, who are in sinus rhythm with resting heart rate (HR)?≥?70 bpm and either are on maximally tolerated doses of beta-blockers, or have a contraindication to beta-blockers. This article will review and evaluate the data supporting the use of ivabradine in patients with HF and explore its mechanisms and physiologic effects.     

Treatment of Diabetes in Patients with Heart Failure

Purpose of Review

This review aims to summarize and discuss heart failure outcomes for current glucose-lowering agents in patients with type 2 diabetes mellitus.

Recent Findings

Current regulations require cardiovascular outcomes trials for new glucose-lowering therapies to establish that there is no unacceptable increase in cardiovascular risk prior to approval. These cardiovascular outcomes trials include glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors. Overall, 87,162 patients have been studied in 10 published cardiovascular outcomes trials. There was no significant increase in major adverse cardiovascular events including cardiovascular mortality, myocardial infarction, and stroke in any of these trials. Heart failure was a component of the secondary endpoint of all of these trials, but only two of these studies show a significant improvement in rates of hospitalization for heart failure.

Summary

Expanded regulatory labeling for reduction in cardiovascular mortality (empagliflozin) and reduction in major adverse cardiovascular events (liraglutide) has recently been established. Saxagliptin and to a lesser part alogliptin have been associated with an increased rate of hospitalization for heart failure. Canagliflozin and empagliflozin are the only two medications that have shown a clear benefit in rates of heart failure hospitalization in treatment of patients with type 2 diabetes mellitus.

     

Rationale and design of a randomized trial to assess the effects of beta-blocker in diastolic heart failure; Japanese Diastolic Heart Failure Study (J-DHF)

BACKGROUND: Heart failure consists of two phenotypes: systolic heart failure and diastolic heart failure (DHF). A growing body of evidence demonstrated benefits of beta-blocker, angiotensin-converting enzyme inhibitor, and angiotensin II receptor blocker in systolic heart failure; however, evidence leading to therapeutic strategy of DHF is lacking. METHODS AND RESULTS: The Japanese Diastolic Heart Failure Study (J-DHF) is a multicenter, prospective, randomized trial designed to assess effects of beta-blocker in patients with DHF. A total of 800 patients (400 patients in each group) will be enrolled. The primary outcome is a composite of cardiovascular death and unplanned admission to hospital for congestive heart failure. Other outcomes include all-cause mortality, worsening of the symptoms of heart failure, or a need for modification of the treatment for heart failure. Serial assessment of echocardiographic and neurohumoral parameters and cost analysis of the treatment regimen will be conducted. The follow-up period is a minimum of 2 years. CONCLUSION: This study will provide important evidences for the treatment of DHF.     

Metformin Therapy and Outcomes in Patients With Advanced Systolic Heart Failure and Diabetes

BackgroundAlthough 25% to 44% of patients with heart failure (HF) have diabetes mellitus (DM), the optimal treatment regimen for HF patients with DM is uncertain. We investigated the association between metformin therapy and outcomes in a cohort of advanced, systolic HF patients with DM.Methods and ResultsPatients with DM and advanced, systolic HF (n = 401) were followed at a single university HF center between 1994 and 2008. The cohort was divided into 2 groups based on the presence or absence of metformin therapy. The cohort had a mean age of 56 ± 11 years, left ventricular ejection fraction (LVEF) of 24 ± 7%, with 42% being New York Heart Association (NYHA) III and 45% NYHA IV. Twenty-five percent (n = 99) were treated with metformin therapy. The groups treated and not treated with metformin were similar in terms of age, sex, baseline LVEF, medical history, and baseline glycosylated hemoglobin. Metformin-treated patients had a higher body mass index, lower creatinine, and were less often on insulin. One-year survival in metformin-treated and non-metformin-treated patients was 91% and 76%, respectively (RR = 0.37, CI 0.18-0.76, P = .007). After multivariate adjustment for demographics, cardiac function, renal function, and HF medications, metformin therapy was associated with a nonsignificant trend for improved survival.ConclusionIn patients with DM and advanced, systolic HF who are closely monitored, metformin therapy appears to be safe. Prospective studies are needed to determine whether metformin can improve HF outcome.     

From Hypertension to Heart Failure

The prevalence of heart failure is increasing in modern societies. Hypertension is a major contributor to the development of heart failure, whether through the development of left ventricular hypertrophy and diastolic dysfunction or by promoting atherosclerosis and myocardial infarction, which eventually leads to systolic dysfunction and left ventricular dysfunction. Effective therapy for hypertension can prevent more than 50% of heart failure events. Most studies done in the last three decades have used β blockers with diuretics as the modality of therapy. These agents have been shown to effectively prevent the development of heart failure. More recent comparative studies have shown that use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are also effective in preventing heart failure. Calcium channel blockers, however, seem to be less effective in preventing development of heart failure in patients with hypertension. It needs to be emphasized that the most important variable in preventing heart failure is the appropriate treatment of hypertension.     

Renin Inhibitors in Chronic Heart Failure: The Aliskiren Observation of Heart Failure Treatment Study in Context

Renin‐angiotensin aldosterone system (RAAS) activation is a key neurohormonal contributor to the progression of chronic heart failure. Strategies that block this activation have consistently demonstrated major beneficial impacts on morbidity and mortality in this setting. Direct renin inhibitors (DRIs) present a novel opportunity to block at an additional or alternative step in this pathway, that being conversion of angiotensinogen to angiotensin I. Theoretical benefits of blocking at the level of renin include: inhibition of the reflex activation of plasma renin activity induced by conventional downstream RAAS blockers. Minimization of angiotensin II and/or aldosterone escape and blocking upstream at the rate‐limiting step of angiotensin I production. Preclinical and early‐phase clinical studies have largely supported this hypothesis. In the Aliskiren Observation of Heart Failure Treatment study, patients with systolic chronic heart failure receiving background angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers and β‐blockers benefited from aliskiren in reduction vs placebo of plasma levels of brain natriuretic peptide, the primary efficacy endpoint of that study. Large‐scale outcome trials are, however, required to definitively determine the benefits of a DRI strategy additional to, or as an alternative to, conventional approaches such as ACE inhibitors in the systolic chronic heart failure setting. Copyright © 2010 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.     

Heart failure with preserved systolic function

Optional statement At least 30% of patients with congestive heart failure have preserved systolic function in the absence of significant valvular heart disease. These patients have diastolic dysfunction. Patients are frequently older and hypertensive. The rate of hospitalization in these patients is similar to that in patients with systolic dysfunction. Mortality is intermediate between that of patients with systolic dysfunction heart failure and normal subjects. Diagnosis requires a clear demonstration of the presence of the heart failure syndrome, normal systolic function, and the absence of valvular disease that could increase left atrial pressures. The diagnosis is supported by evidence of diastolic dysfunction that, from a practical point of view, will be provided most frequently by tissue Doppler imaging. Few randomized data are available on efficacy of therapeutic approaches. Acute treatment centers on reducing central blood volume with diuretics and nitrates and controlling heart rate, particularly in the setting of atrial fibrillation. Further treatment centers on reversing underlying pathophysiologic changes, particularly left ventricular hypertrophy. Control of hypertension and antagonism of the renin-angiotensin-aldosterone system appear to be promising therapeutic approaches.     

The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure

Background

Heart failure is commonly associated with vascular disease and a high rate of athero-thrombotic events, but the risks and benefits of antithrombotic therapy are unknown.

Methods

The current study was an open-label, randomized, controlled trial comparing no antithrombotic therapy, aspirin (300 mg/day), and warfarin (target international normalized ratio 2.5) in patients with heart failure and left ventricular systolic dysfunction requiring diuretic therapy. The primary objective was to demonstrate the feasibility and inform the design of a larger outcome study. The primary clinical outcome was death, nonfatal myocardial infarction, or nonfatal stroke.

Results

Two hundred seventy-nine patients were randomized and 627 patient-years exposure were accumulated over a mean follow-up time of 27 ± 1 months. Twenty-six (26%), 29 (32%), and 23 (26%) patients randomized to no antithrombotic treatment, aspirin, and warfarin, respectively, reached the primary outcome (ns). There were trends to a worse outcome among those randomized to aspirin for a number of secondary outcomes. Significantly (P = .044) more patients randomized to aspirin were hospitalized for cardiovascular reasons, especially worsening heart failure.

Conclusions

The Warfarin/Aspirin Study in Heart failure (WASH) provides no evidence that aspirin is effective or safe in patients with heart failure. The benefits of warfarin for patients with heart failure in sinus rhythm have not been established. Antithrombotic therapy in patients with heart failure is not evidence based but commonly contributes to polypharmacy.     

Renal dysfunction in heart failure patients: what is the evidence?

Congestive heart failure (CHF) is an increasingly common medical condition and the fastest growing cardiovascular diagnosis in North America. Over one-third of patients with heart failure also have renal insufficiency. It has been shown that renal insufficiency confers worsened outcomes to patients with heart failure. However, a majority of the larger and therapy-defining heart failure medication and device trials exclude patients with advanced renal dysfunction. These studies also infrequently perform subgroup analyses based on the degree of renal dysfunction. The lack of information on heart failure patients who have renal insufficiency likely contributes to their being prescribed mortality and morbidity reducing medications and receiving diagnostic and therapeutic procedures at lower rates than heart failure patients with normal renal function. Inclusion of patients with renal insufficiency in heart failure studies and published guidelines for medication, device, and interventional therapies would likely improve patient outcomes.     

Heart failure with preserved ejection fraction. Effect of etiology on prognosis

INTRODUCTION AND OBJECTIVES: Heart failure with preserved systolic function accounts for almost 40% of heart failure cases. Prognosis is similar to that in patients with a low left ventricular ejection fraction (LVEF). However, it is not clear whether the etiology of heart failure with preserved systolic function has an effect on prognosis. METHODS: We assessed 95 consecutive patients admitted to our hospital with heart failure and a LVEF>45%. Twenty-five (26%) had an ischemic etiology and 70 (74%), a non-ischemic etiology. RESULT: The patients' mean age was 73 (6) years, 60% were female, and their mean LVEF was 61 (7)%. These characteristics were similar in the two etiological groups. After a mean follow-up period of 53 (8) months (4-69 months; median 46 months), mortality was higher in ischemic patients (17.88 vs 2.37/100 patient-years; P<.0001), as was the rate of cardiovascular admissions (24.58 vs 4.14/100 patient-years; P<.0001). The rates of mortality due to heart failure and sudden death were also higher in ischemic patients, at 7.82 vs 0.59/100 patient-years, and 7.82 vs 0.30/100 patient-years, respectively (P<.0001). The higher overall admission rate found in the ischemic group was due to higher rates of admission for heart failure (14.53 vs 0.89/100 patient-years; P<.0001) and acute coronary syndrome (8.94 vs 1.78/100 patient-years; P=.003). CONCLUSIONS: In terms of prognosis, heart failure with preserved systolic function is not a homogeneous disease entity. Morbidity and mortality rates are higher in patients with an ischemic etiology. Moreover, different mechanisms are involved.