Benefit In Heart Failure Research Articles

Cardiac failure: early diagnosis and treatment options

People who have heart failure benefit from prompt diagnosis and evidence-based care, which improves quality of life, reduces mortality and side effects of treatments. In the second article of the series, Linda Nazarko explains diagnosis and treatment

Beneficial effects of bisoprolol on the survival of hypertensive diastolic heart failure model rats

beta-blocker therapy is an established therapeutic strategy for systolic heart failure. However, its benefits in diastolic heart failure (DHF) are controversial. This study was designed to investigate the effects of bisoprolol on DHF. Dahl salt-sensitive rats fed on 8% NaCl diet from age 6 weeks, DHF model rats, were divided into three groups at age 13 weeks. One group was treated with bisoprolol 12.5 mg/kg/day (Low dose group, n=18), one group was treated with bisoprolol 250 mg/kg/day (High dose group, n=18), and there was also an untreated group (Untreated group, n=18). The survival rate was best in the High dose group. Left ventricular hypertrophy and the expression of proinflammatory cytokines in the myocardium were significantly attenuated in the High dose group, but not in the Low dose group, and oxidative stress was most suppressed in the High dose group. Measurement with electron spin resonance revealed that bisoprolol had a potent scavenging ability, and bisoprolol attenuated the down-regulation of peroxisome proliferation-activated receptor coactivator-1alpha, an important element in the mitochondrial reactive oxygen species detoxification system. beta-blocker administration, particularly at high dose, improved the survival rate of the DHF model, at least partly through the attenuation of inflammatory changes and oxidative stress.

Potential Autonomic Nervous System Effects of Statins in Heart Failure

Sympathetic nervous system activation in heart failure, as indexed by elevated norepinephrine levels, higher muscle sympathetic nerve activity and reduced heart rate variability, is associated with pathologic ventricular remodeling, increased arrhythmias, sudden death, and increased mortality. Recent evidence suggests that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy may provide survival benefit in heart failure of both ischemic and nonischemic etiology, and one potential mechanism of benefit of statins in heart failure is modulation of the autonomic nervous system. Animal models of heart failure demonstrate reduced sympathetic activation and improved sympathovagal balance with statin therapy. Initial human studies have reported mixed results. Ongoing translational studies and outcomes trials will help delineate the potentially beneficial effects of statins on the autonomic nervous system in heart failure.

Sleep apnea in chronic heart failure

As heart failure continues to carry significant morbidity and mortality it is crucial to pursue new lines of therapy. Addressing sleep apnea, which is highly prevalent in these patients, offers just such an avenue. We discuss how sleep apnea may contribute to the propagation of heart failure, and how understanding its effects and reversing these effects might benefit heart failure patients. Continuous positive airway pressure ventilation, atrial pacing, and chronic resynchronization therapy have all been studied in sleep apnea. Some of these therapies have shown benefits in heart failure. This offers hope for improved outcomes, particularly with respect to mortality. Delineating how these therapies affect the heart's energetics and metabolism may also provide further understanding of the relationship between sleep apnea and heart failure. As both obstructive and central sleep apnea are highly prevalent in heart failure, treating these patients with continuous positive airway pressure, atrial pacing, or chronic resynchronization therapy may offer morbidity and mortality benefits. Much remains to be understood about the relationship between sleep apnea and heart failure, and understanding the interaction between the two at both the myocardial and clinical level is crucial.

Targeting Na+/H+ exchanger regulation for cardiac protection: a RSKy approach?

Extensive pre-clinical work indicates that inhibition of the Na(+)/H(+) exchanger (NHE) affords significant protection to myocardium subjected to ischaemia and reperfusion. By contrast, clinical studies with the NHE inhibitors cariporide, eniporide and zoniporide, in patients with evolving myocardial infarction and those at risk of myocardial infarction, have provided largely disappointing data. Nevertheless, some of these studies have confirmed that, in certain settings, NHE inhibition does indeed protect human myocardium. Furthermore, pre-clinical work suggests that NHE inhibition may provide therapeutic benefit in heart failure also. As an alternative to direct and global NHE inhibition, which may trigger non-cardiac adverse effects, the molecular mechanisms that stimulate cardiac NHE activity in disease may be targeted to attenuate such activity selectively in jeopardized tissue. Many factors associated with cardiac pathology activate RSK, an established NHE kinase, and several selective RSK inhibitors have been described recently. The role of RSK as a potential therapeutic target for indirectly suppressing cardiac NHE activity warrants further investigation.

Impact of Cardiac Resynchronization Therapy on Exercise Performance, Functional Capacity, and Quality of Life in Systolic Heart Failure With QRS Prolongation: COMPANION Trial Sub-Study

Background A total of 405 participants in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure trial were prospectively enrolled in an exercise sub-study designed to study the influence of cardiac resynchronization therapy (CRT) on measures of exercise capacity, functional capacity, and quality of life (QOL). Methods and Results Substudy eligibility included New York Heart Association (NYHA) functional Class III or IV heart failure, left ventricular ejection fraction ≤0.35, QRS interval of ≥120 ms, normal sinus rhythm, a heart failure hospitalization (or equivalent) within 1 year, a peak VO 2 ≤22 mL ·kg ·min, the ability to walk 150 to 425 meters in 6 minutes, forced expiratory volume in 1 second/forced vital capacity ≥50%, and no clinical indication for a pacemaker or implantable cardioverter-defibrillator. Patients were randomized in a 1:4 ratio to optimal medical therapy (OPT) or to OPT plus CRT. Cardiopulmonary exercise testing (peak VO 2 and 6-minute walk distance [6MWD]) and assessment of NYHA functional class and QOL were assessed at baseline and at 3 and 6 months of assigned therapy. There was no significant improvement in peak VO 2 at 6 months in the CRT group compared with the OPT group (+0.63 mL ·kg ·min) by unadjusted analysis ( P = .05) or by analyses adjusted for missing data. Thus the primary end point of the study was not met. There was significantly greater improvement in the 6MWD in the CRT group compared with the OPT group at both 3 and 6 months by both statistical methods ( P ≤ .045). Likewise, a greater proportion of CRT patients improved by 1 or more NYHA functional classes ( P < .01) at 3 months and had better QOL scores ( P < .01) at 3 and 6 months compared with the OPT patients. Baseline peak VO 2 predicted clinical events (time to death, time to death or first hospitalization, or time to death and first heart failure hospitalization: P < .05) in CRT participants. Conclusion CRT patients with moderate to advanced symptoms of systolic heart failure and prolonged QRS intervals benefit from the addition of CRT to OPT in terms of exercise capacity, functional status, and QOL. CRT should be considered standard therapy in this select group of heart failure patients.

Optimal Anti-ischemic Therapy: Newer Data from the HOPE, EUROPA and PEACE Trials

A B S T R A C T Several trials have proposed ACE-inhibitors as the foundation of anti-ischemic secondary preventive therapy for both short and long-term benefit in systolic heart failure, and an important anti-ischemic therapy in ischemic heart disease, diabetic and renal disease patients. The results of the HOPE trial indicated that ramipril, with “tissue” ACE-inhibition features, would benefit a broad range of patients for both primary and secondary prevention of both ischemic and vascular disease, and was beneficial in all subgroups of atherosclerotic coronary disease, cerebrovascular disease, peripheral vascular disease, or diabetes with one cardiovascular risk factor. Subsequently, the EUROPA trial complemented the findings of the HOPE trial in indicating the unique ability of tissue ACE-inhibition, this time with use of perindopril, in preventing cardiovascular events. On the other hand, the findings of a third trial (PEACE) using trandolapril did not confirm these favorable effects, albeit in a lower risk group of patients with ischemic heart disease. Nevertheless, combined analysis of the results of all three trials indicated that there seems to be a significant reduction of cardiovascular events in all patients with ischemic heart disease treated with an ACE inhibitor even in the absence of systolic left ventricular dysfunction or evidence of heart failure. These unique findings of these landmark trials are herein discussed.

Carvedilol of no clear benefit for systolic heart failure in children

Among children and adolescents with symptomatic systemic ventricular systolic dysfunction, does carvedilol improve heart failure symptoms compared with placebo? Multi-center, randomized, double-blind, placebo-controlled study. Enrollment began in June 2000, and the last dose was given in May 2005 (each patient received medication for 8 months). 26 centers in the United States. 161 children and adolescents (median age, 3 years) with symptomatic systolic heart failure. Etiologies of heart failure included dilated cardiomyopathy and congenital heart disease with both left and right systemic ventricular morphology. Patients were assigned to receive placebo or carvedilol in addition to treatment with conventional heart failure medications. The primary outcome was a composite measure of heart failure outcomes described as “worsened,” “improved,” or “unchanged.” This composite measure included heart failure class, need for hospitalization, requirement for discontinuation of study treatment, and global assessment score. There was no statistically significant difference in the groups for the composite end point on the basis of the percentage of patients whose outcome improved, worsened, or was unchanged. Of 54 patients assigned to placebo, 30 improved (56%), 16 worsened (30%), and 8 were unchanged (15%). Of 103 patients assigned to carvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates of worsening were lower than expected. The odds ratio for worsened outcome for patients in the combined carvedilol group versus the placebo group was 0.79 (95% CI, 0.36-1.59; P = .47). A pre-specified subgroup analysis noted significant interaction between treatment and ventricular morphology (P = .02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and patients whose systemic ventricle was not a left ventricle (non-beneficial trend). These preliminary results suggest that carvedilol does not significantly improve clinical heart failure outcomes in children and adolescents with symptomatic systolic heart failure. However, because of the lower than expected event rates, the trial may have been under-powered. There may be a differential effect of carvedilol in children and adolescents on the basis of ventricular morphology.

Abstract 2491: Neurohumoral Effects Of A New Oral Direct Renin Inhibitor In Stable Heart Failure: The Aliskiren Observation Of Heart Failure Treatment Study (ALOFT).

Background: Treatments that inhibit the renin-angiotensin-aldosterone system (RAAS) are of established benefit in heart failure (HF). These include ACE-inhibitor, angiotensin receptor blockers (ARB) and aldosterone antagonists (AA). In addition, beta blockers (BB) are also effective inhibitors of renin secretion. In this first placebo-controlled study, we have investigated whether the new orally-active direct renin inhibitor, aliskiren, has additional neurohumoral actions when added to these proven therapies. Methods: Inclusion criteria for the AL iskiren O bservation of Heart F ailure T reatment study (ALOFT) were: age 18 years or older, stable heart failure with NYHA functional class II–IV, prior or current hypertension, plasma B-type natriuretic peptide (BNP) concentration &gt;100 pg/mL and treatment with an ACE-I or ARB and BB, unless contraindicated or not tolerated. Patients were randomized to 3 months double-blind treatment with placebo or aliskiren (150 mg qd), added to standard therapy. Results: Overall, 302 patients (78% male, mean age 68 years, mean LVEF 31%) were randomized. Baseline treatment: 84% ACE-I, 15% ARB, 94% BB and 33% AA. Change in neurohormones versus baseline are shown in the table (expressed as % change using geometric means in an analysis of covariance model). Aliskiren significantly suppressed plasma renin activity (PRA), BNP and urinary aldosterone excretion overall and to a similar extent in patients treated and not treated with an AA. Conclusions: Aliskiren suppresses PRA in patients treated with a beta blocker and has additional and potentially beneficial neurohumoral effects in patients already comprehensively treated with neuroendocrine antagonists.

Effects of levosimendan versus dobutamine on long-term survival of patients with cardiogenic shock after primary coronary angioplasty

Background Cardiogenic shock (CS) after ST elevation myocardial infarction (STEMI) worsens patient's outcome. Levosimendan treatment offers short-term survival benefit in acute heart failure but its effect on long-term outcome remains unclear. We sought to assess the effect on long-term survival of levosimendan compared to dobutamine treatment in patients with STEMI revascularized by primary coronary angioplasty (PCI) who subsequently developed CS. Methods and results Twenty-two consecutive STEMI patients with CS after PCI randomized to receive levosimendan or dobutamine treatment for 24 h were followed-up for twelve months. Complete follow-up was obtained in 100% of them. The endpoint was cardiac death. Baseline clinical and haemodynamic characteristics were similar in both groups. The probability of survival calculated with Kaplan–Meier curves analysis showed no statistically significant differences between both groups ( p = 0.24). Conclusions Levosimendan compared to dobutamine did not improve long-term survival in STEMI patients revascularized by PCI who developed CS.

Cardiac resynchronization therapy: left or left-and-right for optimal symptomatic effect the LOLA ROSE study

Biventricular (BiV) pacing and left univentricular (LUV) pacing can each produce clinical benefits in heart failure. The impact of modern refinements in pacing optimization on the relative benefits of these two modes is unknown. We aimed to compare these two modes in patients with heart failure, using Echo-based optimization of each pacing mode. Paired data were collected on 18 patients (age 72 +/- 8 years; 16 male) with refractory heart failure symptoms, sinus rhythm, and LBBB with QRS duration>120 ms. Patients were randomized to an initial 8 weeks of either BiV or LUV pacing, followed by 8 weeks of the other mode, in a blinded cross-over design. Echocardiography was used to optimize atrioventricular delay for both modes and right ventricular-left ventricular offset for BiV mode. Peak oxygen consumption (baseline 13.6 +/- 2.7; BiV 15.8 +/- 3.0; LUV 15.2 +/- 3.1 mL/kg/min), 6 min walk distance (baseline 258 +/- 47; BiV 290 +/- 63; LUV 287 +/- 69 m), and scores on SF36 health questionnaire (baseline 41.5 +/- 16.8; BiV 58.6 +/- 19.6; LUV 51.8 +/- 21.3) did not differ between BiV and LUV modes. New York Heart Association class was significantly better in BiV than in LUV mode (P < 0.01). In this pilot study, we found no differences in major clinical outcome measures between the two modes of resynchronization.

Role of the V1 vasopressin receptor in pressure overload-induced cardiac hypertrophy

Arginine vasopressin (AVP) is a peptide hormone critical to cardiovascular homeostasis. AVP binds the vascular V1 and the renal V2 receptor subtypes, and blockade of the V2 receptor produces a profound aquaresis indicative of a potential benefit in heart failure. The V1 receptor has been identified in cardiac myocytes, but its role in cardiac hypertrophy is unknown. Cardiac adaptations to pressure overload-induced hypertrophy were determined in wild-type (WT) and V1 receptor knockout mice (VKO) mice. Pressure overload was surgically induced by transaortic constriction (TAC), and mice were killed 14 days later. TAC resulted in cardiac hypertrophy, as heart weight/body weight (HW/BW in mg/g) and heart weight/tibia length (HW/TL in mg/mm) ratios were significantly (p<0.05) greater for WT and VKO mice compared to their respective sham group (n=6). Interestingly, VKO mice exhibited an enhanced hypertrophic response for HW/BW (5.46±0.08 vs. 4.98±0.08) and HW/TL (6.39±0.10 vs. 5.81±0.08) compared to WT (p<0.05). Genes associated with cardiac hypertrophy were also differentially regulated, as expression of ANF, β-MHC, and α-skeletal actin (p<0.01) were upregulated in VKO compared to WT TAC. These studies are the first to identify a role for the V1 receptor in pressure overload-induced cardiac hypertrophy, suggesting that AVP signalling through the V1 receptor may be involved in the pathophysiologic adaptations that occur in heart failure.

St Christopher’s hospice clinical guidelines: oxygen therapy

To ensure that patients in need of oxygen therapy are provided with the correct measures for treatment and comfort. Dyspnoea (breathlessness) and other symptoms of hypoxia can be managed through pharmacological and other measures. Some, but not all, patients may additionally benefit from oxygen. Hypoxaemia (insufficient oxygen in the blood) and dyspnoea are only weakly correlated. However, oxygen may be helpful in selected patients with advanced cancer or chronic obstructive pulmonary disease (COPD), but there is currently no evidence for benefit in heart failure (Booth et al, 2004). Oxygen therapy requirements vary depending on the nature of the problem. Some patients need carefully monitored concentrations of oxygen (high or low), while for others …

Cardiac Resynchronization Treatment of Heart Failure

Cardiac resynchronization therapy (CRT) is well established as a treatment for patients with moderate to severe heart failure on optimal medical therapy. Early studies demonstrated improved functional capacity and evidence of reverse remodeling; more recently, CRT has been associated with a survival benefit in advanced heart failure both with and without a defibrillator. We review the eight landmark trials in CRT. To date, criteria have focused on electrical delay, but echocardiographic parameters emphasize the importance of mechanical delay or ventricular dyssynchrony. With the exponential rise in implants, new issues have emerged, such as optimal device programming, identifying appropriate candidates, and accounting for cases without clinical benefit from CRT.

Potential Mechanisms of Benefit with Thalidomide in Chronic Heart Failure

This review considers the recent clinical and relevant preclinical evidence that thalidomide may have therapeutic benefit in chronic heart failure (HF), and considers some of the mechanisms by which thalidomide may elicit potentially beneficial effects. Persistent inflammation, involving increased levels of inflammatory cytokines, seems to play a pathogenic role in chronic HF by influencing heart contractility, inducing matrix degradation and fibrosis, and promoting apoptosis, contributing to myocardial remodeling. On the basis of these issues, immunomodulating therapy has emerged as an option in the management of chronic HF. Failure of anti-tumor necrosis factor (TNF) therapy has lead to further interest in a more general immunomodulatory approach, directed against the imbalanced cytokine network rather than at one particular cytokine.Some recent studies suggest that thalidomide, a glutamic acid derivative with proposed antiangiogenic, anti-inflammatory, and immunomodulatory properties, should be added to the list of potential immunomodulating agents in chronic HF. Thus, in a recent double-blind, placebo-controlled study in patients with chronic HF, thalidomide was found to significantly improve left ventricular ejection fraction. Although thalidomide has been regarded as an anti-TNF drug, it was found to increase plasma levels of TNFalpha in a placebo-controlled study in patients with HF, suggesting that other mechanisms may contribute to its beneficial effects. Such mechanisms could involve inhibition of neutrophils, matrix stabilizing, and antifibrotic effects, as well as a thalidomide-mediated decrease in the heart rate. However, our knowledge of the mechanisms of action of this drug is still scarce and will have to be further examined in forthcoming studies. Such studies should include experiments in animal models of HF as well as further preclinical trials, attempting to identify the potential mechanisms by which thalidomide may be beneficial in human HF.

Prediction and Prevention of Chemotherapy-Induced Cardiomyopathy

Although anthracyclines are highly effective at treating certain cancers, their use is limited by the potential for cardiotoxicity. Studies report a wide range of the incidence of cardiotoxicity, related to differences in definitions, chemotherapy regimens, and patient populations. The occurrence of clinical heart failure seems to be in the range of 1% to 5%, and asymptomatic decrease in left ventricular function is in the range of 5% to 20%.1,2 Toxicity can occur early (within 1 year) or late (particularly among children, where late cardiac abnormalities are detectable in two thirds of surviving patients).3 The occurrence of cardiomyopathy is related to cumulative dose of anthracycline (especially doxorubicin doses >550 mg/m2), dosing schedule, age, gender, mediastinal irradiation, and combination with other agents, including trastuzumab.4 Other chemotherapy, including imatinib mesylate,5 can also cause cardiotoxicity, suggesting a broader potential for adverse cardiac effects from novel chemotherapy and, especially, from inhibitors of nonreceptor tyrosine kinases. Anthracycline-induced cardiomyopathy seems to have a similar impact on survival as other forms of heart failure.6 Thus, identification of individuals at risk, prevention, early diagnosis, and effective treatment are all important goals. Most of these needs have been addressed by uncontrolled or small studies, and guidelines have relatively sparse information on which to base recommendations for care, other than careful monitoring of left …

Enoxaparin may offer benefits for chronic heart failure

Enoxaparin may offer benefits for chronic heart failure

Left Ventricular Lead Stabilization Utilizing a Coronary Stent

Cardiac resynchronization therapy has been recently demonstrated to have a mortality and morbidity benefit in heart failure (HF) patients with cardiac dyssynchrony. Currently, the most widely used method of left ventricular (LV) lead placement involves transvenous placement of leads via the coronary sinus (CS) and into a tributary branch. Lead dislodgement is a common cause for reoperation, and continues to be a common problem despite advances in equipment and operator techniques. We describe a case where a coronary stent was placed in a lateral branch of the CS to stabilize the lead against the vessel wall.

Hypertension treatment and implications of recent cardiovascular outcome trials

Clinical trials have shown that effective control of blood pressure reduces the risk of cardiovascular events in high-risk patients. For example, data from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study show significant reductions in the incidence of cardiac events, stroke and all-cause mortality in patients in whom blood pressure control was achieved compared with those in whom blood pressure remained uncontrolled. Although the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) demonstrated no significant difference in cardiovascular mortality and morbidity between patients receiving diuretics, calcium channel blockers or angiotensin-converting enzyme (ACE) inhibitors, this finding might have been confounded by differences in the blood pressure reductions achieved with the three treatments. Other studies have consistently shown that newer antihypertensive agents, such as ACE inhibitors and calcium channel blockers, reduce cardiovascular events to a similar, or possibly greater, extent as older therapies, such as diuretics and beta-blockers. In particular, ACE inhibitors appear to offer additional benefits beyond blood pressure reduction in terms of reducing cardiovascular events and producing renoprotective effects. Angiotensin II receptor blockers (ARBs) have been less extensively studied, but there is evidence already that they have heart failure, stroke and renoprotective benefits. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) is currently comparing the effects of the ARB telmisartan 80 mg and the ACE inhibitor ramipril 10 mg, alone and in combination, on cardiovascular events in high-risk patients.

Prospective validation of stress echocardiography as an identifier of cardiac resynchronization therapy responders

Cardiac resynchronization therapy (CRT) provides benefit for congestive heart failure (CHF), but predictors of the clinical response are debated. The aim of this prospective study was to assess the predictive role of dobutamine stress echocardiography (DSE) in identifying a suitable candidate for CRT. From March 2001 to December 2003, 71 CHF patients were prospectively enrolled on the basis of four criteria: New York Heart Association (NYHA) class III and IV; QRS > or =150 ms with a left bundle branch block pattern, and left ventricular ejection fraction (LVEF) < or =35% under optimal medical treatment. The combined endpoints were hospital readmission for class IV CHF, heart transplant (HT), and CHF-related death. The 67 patients completing the study presented with the following characteristics: age (70 +/- 10 years; 11 women); etiology (idiopathic in 44, ischemic in 23); NYHA class (40 in class III and 27 in class IV); LVEF 26% (+/-5%); QRS duration (190 +/- 28 ms); 6-minute walk test 330 m (+/-108); peak oxygen uptake 10.7 (+/-3.3 mL/kg/min); mitral insufficiency in 42 (> or =III grade); interventricular (IV) delay (62 +/- 21 ms); and intraventricular dyssynchrony in 30 patients. Over the follow-up period of 12.1 +/- 8.7 months, 20 (29.9%) of 67 patients presented with at least one hemodynamic event: hospitalization for CHF in 19 (28%) of 67, HT in 2 (3%) of 67, and CHF death in 7 (10%) 67. Univariate analysis identified NYHA class (P = .03), LVEF (P = .015), IV dyssynchrony before (P = .038) and after CRT (P = .0035), IV delay after CRT (P = .002), 6-minute walk distance (P = .01), and DSE Res+ (P = .008) as significant predictors of clinical events. A receiver operating curve established a cut-off value of 1.25 for the DSE responders (Res+: 34 patients at 10 microg/kg/min infusion rates), and the improvement at the 10 microg/kg/min level was 41% +/- 7% in Res+ and 29% +/- 8% in nonresponders (P<.0001). With a cut-off value of 1.25-fold the LVEF increase, the DSE test exhibits 70% sensitivity, 61.7% specificity, 43.8% positive predictive value, and 82.9% negative predictive value. Cox analysis identified IV dyssynchrony before CRT (P = .01) and DSE Res+ (P = .003) as independent predictive factors. Independent predictive factors of severe hemodynamic clinical outcome in patients with CRT are IV dyssynchrony and DSE.