The role of cardiovascular magnetic resonance in heart failure

Cardiovascular Magnetic Resonance (CMR) is an accepted gold standard for non-invasive, accurate, and reproducible assessment of cardiac mass and function. The interest in its use for viability, myocardial perfusion and coronary artery imaging is also widespread and growing rapidly as the hardware and expertise becomes available in more centres, and the scans themselves become more cost effective. In patients with heart failure, accurate and reproducible serial assessment of remodelling is of prognostic importance and the lack of exposure to ionizing radiation is helpful. The concept of an integrated approach to heart failure and its complications using CMR is fast becoming a reality, and this will be tested widely in the coming few years, with the new generation of dedicated CMR scanners.     

The role of cardiovascular magnetic resonance imaging in the diagnosis and prognosis of patients with heart failure

Cardiovascular magnetic resonance (CMR) imaging is a tomographic technique, which allows three-dimensional slice orientation without limitations from acoustic windows inherent to echocardiography. Further advantages of CMR are its high temporal and spatial resolution, its excellent soft tissue resolution and its high blood-to-tissue contrast. Cardiovascular magnetic resonance is currently the only imaging technique, which provides a comprehensive study of both structure and function of the heart as well as myocardial perfusion and viability. Moreover, post-processing of CMR images does not require any geometric assumptions as in echocardiography to determine ventricular dimensions. This is particularly important when evaluating ventricles of patients with chronic heart failure with severely altered morphology that may have regional variations in wall thickness and contractility at least in ischemic cardiomyopathy. The highly reproducible results of CMR imaging have turned this technique into a reference standard for the non-invasive assessment of ventricular dimensions, mass and function. In cases with indeterminate results of clinical, electrocardiographic and particularly echocardiographic findings CMR should be used early in the process of diagnosis of patients with heart failure. Not only can altered structure and degree of ventricular and valvular dysfunctions be accurately assessed but also regional perfusion deficits and/or myocardial scars are easily detected. For therapeutic and prognostic reasons a simple differentiation between ischemic and non-ischemic cardiomyopathy should be achieved as the first diagnostic step. In addition, the type and localization of the late gadolinium enhancement (LGE) phenomenon may aid in non-invasively differentiating the etiology of non-ischemic cardiomyopathy. CMR may also improve the assessment and extent of interventricular and intraventricular dyssynchrony in patients to be selected for cardiac resynchronization therapy (CRT). Lastly, the LGE phenomenon may provide independent prognostic information in patients with a CRT system implanted, as well as in patients with ischemic and non-ischemic cardiomyopathy. Thus, CMR imaging should be implemented early in the diagnostic process of patients with heart failure to significantly improve the speed and accuracy of diagnostic procedures, to control the effect of therapeutic measures, and to select patients with a limited prognosis by assessing the degree of ventricular dysfunction and the extent of myocardial scarring.     

The role of cardiovascular MRI in heart failure and the cardiomyopathies

Heart failure (HF) is a common syndrome related to varied pathophysiologic processes. Individualization of care according to the patient's pathologic and modifiable substrate is of increasing importance. The use of modern cardiovascular MRI (CMR) provides for the centralization of diagnostic testing with the ability to assess cardiac morphology, function, flow, perfusion, acute tissue injury, and fibrosis in a single setting. This offers the potential for a paradigm shift in the noninvasive diagnosis and monitoring of patients with HF. This article outlines a diagnostic approach for the primary use of CMR in the phenotypic characterization, risk stratification, and therapeutic management of patients with HF.     

Conduct of clinical trials in acute heart failure: regional differences in heart failure clinical trials

Clinical trials are often conducted globally. Differences in standard of care, patient populations including genetic and phenotypic differences, disease etiologies, rates of comorbidities, ascertainment of endpoints, and differences in concomitant therapies and medical culture may influence subsequent outcomes. There has been little consensus on how clinical trial results should be evaluated. This article reviews the differences in cardiovascular trial results by geographic region, offers potential explanations for these differences, and suggests methods for standardization of trial results.     

The role of apelin in cardiovascular function and heart failure

Apelin is a novel peptide that acts through the APJ receptor, sharing similarities with the angiotensin II-angiotensin II type 1 receptor pathway. It is a peripheral vasodilator, powerful inotrope and may affect central fluid homeostasis. Animal and human studies suggest that it may play a role in the pathogenesis of heart failure by modulating the harmful effects of angiotensin II. Apelin is reduced in patients with heart failure and up regulated following favourable left ventricular remodelling. It is widely distributed in a number of tissues, mainly restricted to vascular endothelium. This comprehensive review of the literature highlights the important studies that have led to the discovery of apelin and its role in cardiovascular function and heart failure.     

"BNP" for heart failure: role of nesiritide in cardiovascular therapeutics

B-type natriuretic peptide, or nesiritide, recently gained US Food and Drug Administration approval as the first new parenteral agent approved for heart failure therapy in more than a decade. Nesiritide refers to a peptide identical to endogenous B-type natriuretic peptide, currently manufactured by recombinant DNA technology. Nesiritide has been evaluated in clinical trials involving more than 700 subjects. The drug produces a prompt fall in systemic vascular resistance and pulmonary capillary wedge pressure, associated with rapid clinical improvement in decompensated heart failure. Nesiritide represents an attractive choice for first-line therapy of acutely decompensated heart failure patients. In this review, the authors summarize the currently available data regarding the use of nesiritide, and offer recommendations for its use based on our experience with the compound in clinical trials.     

Heart failure as an endpoint in heart failure and non-heart failure cardiovascular clinical trials: the need for a consensus definition.

Specific criteria have been established to define the occurrence of myocardial infarction (MI) and stroke in cardiovascular clinical trials, but there is not a consistent definition for heart failure. Heart failure events appear to occur at a rate that is similar to stroke and MI in trials of hypertension, hyperlipidaemia, diabetes, and coronary heart disease, yet a consistent approach to defining heart failure events has not yet been realized. The wide range of definitions used in clinical trials makes it difficult to interpret new data in the context of existing literature. This inconsistency has led to challenges in determining the incidence of heart failure in cardiovascular studies and the effects of interventions on these endpoints. This paper examines issues related to defining heart failure events in cardiovascular clinical trials and presents a definition to formally address this issue.     

Pharmacogenetics in heart failure trials

There is ongoing research into potential pharmacogenetic targets in heart failure. Several challenges exist despite the potential benefits, and questions remain on the level of evidence needed to support product approval or labeling. High annual mortality, high morbidity, and heterogeneity of response to treatment underscore the need for predictability of response in this patient population. Although prime time testing and application of pharmacogenetics is not currently being used in heart failure, we believe this treatment approach is not too distant. The data are supportive, and further research is warranted to strengthen the approach.     

The panacea for cardiovascular diseases: the role of statins in the management of heart failure

Early antithrombotic therapy after biological aortic valve replacement (AVR) is controversial. The aim of this study was to determine the rate of thromboembolic events (TE) without anticoagulation treatment during the first 3 months after surgery. Out of 143 consecutive patients who underwent biological AVR from January 1998 to December 2004, 127 patients who did not receive anticoagulation were included (89%). Events during the first 3 months after surgery included: 2 strokes (1.5%), 2 major bleedings (1.5%) and 9 deaths (7%) (none of them due to TE). In conclusion, the management of patients without antithrombotic treatment after biological AVR seems to be safe due to a low rate of TE.     

The cardiovascular physiologic actions of urocortin II: acute effects in murine heart failure

Corticotropin-releasing factor (CRF) and its paralogues urocortin (Ucn)I, -II, and -III signal by activating their receptors, CRF receptors (CRFR)1 and -2, to maintain homeostasis through endocrine, autonomic, and behavioral responses. CRFR2 is found in cardiomyocytes and in endothelial and smooth muscle cells of the systemic vasculature. Echocardiography and cardiac catheterization were used in mice to assess the physiologic effects of i.v. UcnII and CRFR2 deficiency on left ventricular function and the systemic vasculature. UcnII treatment augmented heart rate, exhibited potent inotropic and lusitropic actions on the left ventricle, and induced a downward shift of the diastolic pressure-volume relation. UcnII also reduced systemic arterial pressure, associated with a lowering of systemic arterial elastance (end-systolic pressure/stroke volume) and systemic vascular resistance. CRFR2-deficient mice showed no alteration in cardiac contractility or blood pressure in response to UcnII administration, suggesting that the effects of UcnII are specific to CRFR2 function. Pretreatment with a beta-adrenergic receptor antagonist, esmalol, had no effect on the inotropic or lusitropic effects of UcnII in vivo, indicating that its actions are independent of beta-adrenergic receptors. Single i.v. bolus administration of UcnII to a heart failure model (muscle-specific LIM protein-deficient mice) produced significant enhancement of inotropic and lusitropic effects on left ventricular function and improved cardiac output. These results demonstrate the potent cardiovascular physiologic actions of UcnII in both wild-type and cardiomyopathic mice and support a potential beneficial use of this peptide in therapy of congestive heart failure.     

A review of phase II acute heart failure syndromes clinical trials

Hospitalization for acute heart failure syndromes (AHFS) is a growing health care burden. Over 1 million hospitalizations occur annually, with a postdischarge mortality and rehospitalization rate of ~45% by 90 days and a financial cost greater than $20 billion. Attempts to improve outcomes through novel therapies have largely failed, suggesting new approaches are needed. We review phase II studies in AHFS to identify opportunities for future development programs.     

Clinical trials in diastolic heart failure

Forty percent to 50% of patients with chronic heart failure have normal or relatively normal left ventricular ejections fractions. These are much more frequently women and tend to be older than those with reduced ejection fractions. In most, left ventricular diastolic dysfunction plays a major role in the genesis of heart failure. Until recently, these patients have been systematically excluded from heart failure trials, so that there are no proven treatments for this group. This article reviews the recent and ongoing trials in patients with diastolic heart failure, which hopefully will lead to improved treatment and outcomes.     

Geographic differences in heart failure trials

Randomized controlled trials (RCTs) are essential to develop advances in heart failure (HF). The need for increasing numbers of patients (without substantial cost increase) and generalization of results led to the disappearance of international boundaries in large RCTs. The significant geographic differences in patients' characteristics, outcomes, and, most importantly, treatment effect observed in HF trials have recently been highlighted. Whether the observed regional discrepancies in HF trials are due to trial‐specific issues, patient heterogeneity, structural differences in countries, or a complex interaction between factors are the questions we propose to debate in this review. To do so, we will analyse and review data from HF trials conducted in different world regions, from heart failure with preserved ejection fraction (HF‐PEF), heart failure with reduced ejection fraction (HF‐REF), and acute heart failure (AHF). Finally, we will suggest objective and actionable measures in order to mitigate regional discrepancies in future trials, particularly in HF‐PEF where prognostic modifying treatments are urgently needed and in which trials are more prone to selection bias, due to a larger patient heterogeneity.     

Anti-inflammatory trials in chronic heart failure

Chronic heart failure (CHF) is accompanied by a dysregulated cytokine network, which is characterized by a rise in inflammatory cytokines and an inadequate elevation of anti-inflammatory mediators. This dysregulation has been implicated in the development and progression of CHF and, in the last decade, attempts have been made to modulate this imbalance in the cytokine network. With the exception of one larger mortality/morbidity study, all studies of immunomodulatory therapy in HF conducted to date have included <100 patients and the overall experience in this therapeutic area is limited compared with studies of neurohormonal antagonists, which have included several thousand patients. While trials of anti-tumor necrosis factor therapies have thus far failed, recent studies of broad-based immunomodulatory agents (e.g. intravenous immunoglobulin, thalidomide, and pentoxifylline) highlight a potential for such therapy in HF patients, in parallel with optimal cardiovascular treatment regimens. In addition to identifying the crucial factors in the immunopathogenesis of CHF in order to develop novel immunomodulatory treatment strategies, there is a clear need to confirm the results of the smaller studies conducted to date with larger placebo-controlled mortality studies that involve a diverse group of patients, with regard to the cause and severity of HF.     

Clinical trials on heart failure

n 1987 the results of the Consensus study were published, and showed that enalapril, an angiotensin convertor enzyme inhibitor (ACEI), was able to modify the clinical course of the heart failure syndrome thereby reducing mortality. Other ACEI later demonstrated the same effect on the different degrees of symptomatic heart failure, left ventricular dysfunction, myocardial infarction and more recently in diabetic patients. In 1996 studies on the betablockers carvedilol, bisoprolol and metoprolol showed their efficacy in reducing deaths due to progressive heart impairment and sudden death in chronic heart failure. The RALES study showed that small doses of spironolactone also improved the prognosis on this disease. Digital improves the quality of life but not the survival rate. Only amiodarone (among the antiarrhythmics) reduces sudden death. Other drugs and groups of drugs can not be considered for chronic outpatient treatment of heart failure. Multicenter trials make it possible to obtain scientific evidence for establishing rational treatments. Many groups of patients such as women, elderly people and the more severe cases of the disease are often not included in these trials. Occasionally, multicenter trials are badly designed (CIBIS and MCD), which in the case of betablockers, led to a substantial delay in their administration. Other times, as in the ELITE study, the results were badly interpreted. The knowledge obtained from these studies is slow in reaching patients, with few patients taking betablockers. It is known that most patients do not take the doses found to be effective in multicenter trials.     

Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials

OBJECTIVE: To summarise the current evidence from randomised controlled trials for diuretics in patients with congestive heart failure (CHF). DATA SOURCES: English-language randomised controlled trials and review papers referenced in Medline, Embase between 1966 and 1999. General literature review of pertinent journals was carried out and reference lists of papers were inspected. REVIEW METHOD: STUDY DESIGN: Meta-analysis of randomised controlled trials of diuretic therapy in patients with CHF. STUDY SELECTION: Studies were included if they were randomised comparisons of loop or thiazide diuretics and control, or one diuretic and another active agent (e.g. ACE inhibitors, ibopamine and digoxin). DATA ABSTRACTION: Using a standardised protocol, two reviewers independently abstracted the data and assessed the methodological quality of each paper. DATA SYNTHESIS: The odds ratio (OR) of treated group compared with control was estimated for each end-point outcome and plotted against each other using the fixed-effects model. THE MAIN OUTCOME MEASURES: The primary outcomes of our analysis were effects of diuretics on mortality and morbidity. RESULTS: Eighteen trials met our criteria and were eligible for analysis, involving 928 patients. Eight trials were placebo-controlled. We analysed the data for mortality and for worsening heart failure. A further ten trials compared diuretics against other agents such as ACE inhibitors, ibopamine, and digoxin. Mortality data were available in three of the placebo-controlled trials (n=221); the mortality rate was lower for patients treated with diuretics than for control [the odds ratio for death, 0.25; 95% confidence intervals (CI), 0.07-0.84; P=0.03]. Admissions for worsening heart failure in the four small trials (n=448) showed an odds ratio of 0.31 (95% CI 0.15-0.62; P=0.001). In six studies of diuretics compared to active control, diuretics significantly improved exercise capacity in patients with CHF [OR: 0.37; CI: 0.10-0.64, P=0.007]. CONCLUSION: Compared to active control, diuretics appear to reduce the risk of worsening disease and improve exercise capacity. The available data from small studies show that in CHF conventional diuretics reduce the risk of death and worsening heart failure compared to placebo.     

Pharmacotherapy in congestive heart failure: reflections on diabetes,clinical trials,and cardiovascular morbidity and mortality

Hypertension and diabetes are commonly found conditions, which predispose to premature cardiovascular morbidity and mortality. A strong consensus has emerged in support of aggressive blood pressure reduction in order to forestall the almost inevitable complications that follow from being a hypertensive diabetic. As of yet though it is not clearly determined as to what represents the best class(es) of antihypertensive medications to effect such blood pressure reduction. In this regard, considerable debate has arisen as to the cost/benefit ratio of dihydropyridine calcium channel blockers in the hypertensive diabetic. Although studies such as the Fosinopril vs. Amlodipine Cardiovascular Events Trial and the Appropriate Blood Pressure Control in Diabetes study would seem to argue against the use of dihydropyridine calcium channel blockers in the diabetic hypertensive, other studies such as the subset analyses of the Syst-Eur and the Syst-China and the Hypertension Optimal Treatment study provide almost compelling evidence for the safety of low to moderate doses of a dihydropyridine calcium channel blockers in this population. Safety issues of dihydropyridine calcium channel blockers will remain unresolved until the release of the Antihypertensive and Lipid Lowering Study to Prevent Heart Attack results at which time a resolution to this question should be forthcoming. (c)2000 by CHF, Inc.