Therapy For Congestive Heart Failure Research Articles

Stem Cell Therapy for Congestive Heart Failure

Heart failure is a major cardiovascular health problem. Coronary artery disease is the leading cause of congestive heart failure (CHF) [1]. Cardiac transplantation remains the most effective long-term treatment option, however is limited primarily by donor availability, rejection and infections. Mechanical circulatory support has its own indications and limitations [2]. Therefore, there is a need to develop more effective therapeutic strategies. Recently, regenerative medicine has received considerable scientific attention in the cardiovascular arena. We report here our experience demonstrating the beneficial effects of cardiac stem cell therapy on left ventricular functions in a patient with Hodgkin’s lymphoma (HL) who developed CHF due to ischemic heart disease during the course of lymphoma treatment.

Natriuretic peptides in therapy for decompensated heart failure

Congestive heart failure (CHF) is the most frequent cause of hospitalization for patients >65years of age and continues to be a major public health burden among the ageing population. Unlike therapy for chronic CHF, there has been only modest progress in medical treatment for acutely decompensated CHF over the past several decades. Moreover, current treatment-consisting generally of diuretic, inotropic, and vasodilatory agents-is associated with many limitations in clinical practice. Natriuretic peptides provide a promising mechanism of action in the pathophysiologic background for CHF treatment based on their vasodilatory and diuretic properties and effective inhibition of the renin-angiotensin-aldosterone system, which is activated early in the course of CHF. Nesiritide (Natrecor® or Noratak®) is a recombinant natriuretic peptide that has the same 32 amino-acid sequence as human B-type natriuretic peptide. Nesiritide has been shown to improve dyspnea and hemodynamic parameters in patients with decompensated heart failure. Ularitide is a synthetic form of urodilatin, a natriuretic peptide hormone secreted by the kidney. Recent clinical studies suggest that ularitide may play a role in managing decompensated heart failure. This review provides an update on natriuretic peptides and their therapeutic potential in advanced CHF.

Akut dekompensierte Herzinsuffizienz: klinischer Stellenwert einer Therapie mit natriuretischen Peptiden

Heart failure is the most frequent cause of hospitalization in elderly population. Unlike the therapy of congestive heart failure, there was only a modest progress in the medical treatment for acutely decompensated heart failure over the past several decades. Moreover, current treatment is associated with many limitations in clinical practice. The family of natriuretic peptides consists of several structurally similar polypeptides (ANP, BNP, CNP, urodilatin, DNP). ANP and BNP are the most characterized substances and represent an important compensatory mechanisms in heart failure because of their vasodilatory, natriuretic and antiproliferative effects. Nesiritide is a recombinant human BNP which has been shown to be effective in treating heart failure in several clinical trials. However, a recent meta-analysis revealed a nesiritide-associated increased 30-day-mortality rate. The results of initial small-sized trials suggest beneficial hemodynamic effects of urodilatin in decompensated heart failure. Despite of being approved for the treatment of decompensated heart failure in some countries, the clinical relevance of nesiritide is currently unclear. Urodilatin might represent a potential alternative.

Recombinant tissue plasminogen activator reduces incidence of catheter malfunction and bacteremia

Recombinant tissue plasminogen activator reduces incidence of catheter malfunction and bacteremia

Recruitment and blocking properties of the CardioFit stimulation lead

The CardioFit vagal stimulation system has been developed as a proposed therapy for congestive heart failure (CHF). CardioFit is to be implanted in several hundred CHF patients enrolled in the INOVATE-HF clinical trial, an FDA approved study. The CardioFit stimulation lead (CSL), which is a cuff electrode that delivers stimulation pulses to the right cervical vagus, was designed to recruit efferent cardiac vagal fibers while minimizing unwanted recruitment of other fibers. This paper presents the CSL and measurements of its recruiting and blocking properties when placed on isolated porcine vagus nerves maintained at an elevated temperature in oxygenated artificial cerebrospinal fluid. Using charge balanced quasi-trapezoidal pulses driven through the CSL, we show in eight out of nine nerves a 63% ± 13% (mean ± SD) unidirectional attenuation of the A-fiber compound action potential attained at a current of 3.0 ± 0.8 mA. The threshold for the activation of A- and B-fibers was found to be 0.3 ± 0.17 mA and 2.5 ± 1.1 mA, respectively. The results presented here should help to guide the optimal parameters used in the upcoming deployment of the CardioFit system.

Left Ventricular Inflow Tract Obstruction Secondary to a Myxoma in a Dog

This is the first description of a left ventricular inflow tract obstruction secondary to a myxoma in a dog. A 4 yr old, male fox terrier presented with a 1 mo history of cough and exercise intolerance. Expiratory dyspnea, pulmonary crackles, irregular cardiac rhythm, and a grade 4/6 pansystolic cardiac murmur over the left cardiac apex were the most important features on physical examination. The electrocardiogram revealed atrial fibrillation. Thoracic radiographs showed left-sided cardiac enlargement and mild pulmonary edema, especially in the hilar area. Two-dimensional transthoracic echocardiography showed severe left atrial dilation and a homogenous, echodense mass involving both leaflets of the mitral valve and the posteromedial papillary muscle, inducing mitral stenosis. Spectral Doppler echocardiography was consistent with severe left ventricular inflow tract obstruction secondary to a mass. Therapy for congestive heart failure was prescribed. Follow-up examinations of the dog 1 mo, 2 mo, and 6 mo after diagnosis showed an improvement in clinical signs, but similar echocardiographic features. Eleven months after diagnosis, the dog was euthanized at the owner's request because of recurrent congestive heart failure. The postmortem examination showed the cardiac tumor was consistent with a myxoma.

Treatment and Outcomes for Congestive Heart Failure by Race/Ethnicity in TRICARE

Equitable access to health insurance coverage may improve outcomes of care for chronic health conditions and mitigate racial/ethnic health disparities. This study examines racial/ethnic disparities in the treatment and outcomes of care for TRICARE beneficiaries with congestive heart failure (CHF). Using a retrospective cohort analysis, we examined demographic characteristics, sources of care, and comorbid conditions for 2183 beneficiaries of the Military Health System's TRICARE program (representing 115,584 beneficiaries after adjusting for survey weights) with CHF. Treatments included use of CHF-related medications, while the outcome of interest was any CHF-related potentially avoidable hospitalizations (PAHs). While African Americans were less likely than whites to have received beta blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers following a CHF diagnosis (P<0.0001). Hispanics were, in some cases, equally likely as whites to receive pharmacological treatments for CHF. In multivariate models, there were no significant racial/ethnic differences in the odds of a PAH; age greater than 65 was the most significant predictor of a PAH. This study suggests that although there are some racial and ethnic disparities in the receipt of pharmacological therapy for CHF among TRICARE beneficiaries, these differences do not translate into disparities in the likelihood of a PAH. The findings support previous research suggesting that equal access to care may mitigate racial/ethnic health disparities.

β-Adrenergic receptor blockade reduces endoplasmic reticulum stress and normalizes calcium handling in a coronary embolization model of heart failure in canines

Alterations in calcium homeostasis in the endoplasmic/sarcoplasmic reticulum (ER) cause ER stress that ultimately may affect ventricular function. However, the role of ER stress in β-blocker therapy for congestive heart failure (CHF) has not been studied. This study examined ER stress in CHF and evaluated its role in β-blocker therapy in a canine model of ischaemic CHF. CHF was created by daily coronary embolization in chronically instrumented dogs. After oral administration of β-blocker metoprolol or vehicle for 12 weeks, Ca(2+) transport proteins including sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), ryanodine receptor (RyR2), Na(+)-Ca(2+) exchanger (NCX1), Ca(2+) storage protein calreticulin (CRT), and phospholamban were evaluated by Western blot analysis. Cellular levels of ER stress marker, phosphorylated eukaryotic initiation factor 2α (eIF2α-P), were also examined. Compared with the vehicle-treated group, metoprolol caused significantly improved cardiac function, restored the proteins of SERCA2a, NCX1, and CRT, increased phosphorylated phospholamban, reversed protein kinase A hyperphosphorylation of RyR2, and resulted in normalized ER stress marker eIF2α-P and reduced DNA damage. Our results suggest that ER stress could be induced by abnormal Ca(2+) homeostasis in CHF. The restoration of calcium-handling protein function and resultant decrease in ER stress might, in part, explain the beneficial effects of β-blockade observed in CHF. Whether this mechanism occurs in other animal CHF models or human CHF warrants further study.

Gene transfer of the sarcoplasmic reticulum pump in the treatment of heart failure

This editorial refers to ‘Augmentation of left ventricularmechanics by recirculation-mediated AAV2/1-SERCA2agene delivery in experimental heart failure’ by JustinMariani et al. published in this issue on page 247–253.Therapy of congestive heart failure was revolutionized more than20 years ago by the introduction of angiotensin-convertingenzyme inhibitors and b-adrenoceptor blocking agents. Bothhave resulted in the improvement of symptoms and prognosis ofpatients with chronic heart failure. In the meantime, device-basedtherapies have been added to the therapeutic armamentarium.However, all attempts to directly address molecular alterations rel-evant to heart failure pathophysiology as treatment strategies havefailed. Because morbidity and mortality of heart failure patients arestill unacceptably high, there is an urgent need for new treatmentstrategies. Alterations of calcium cycling have been identified as asignificant contributor to heart failure pathophysiology, and there-fore, therapeutic strategies addressing calcium homeostasis seemlogical.

A sugar for congestive heart failure patients

The incidence of congestive heart failure (CHF) continues to increase worldwide. Approximately 550,000 patients with CHF are newly diagnosed per year in the USA, which adds to the existing 5 million patients currently afflicted with this disease. Furthermore, there are approximately 3.1 million hospital admissions/year for heart failure, costing over US$23 billion (source: www.americanheartassociation.com). There is no cure for CHF and current therapies try to achieve relief of symptoms, improving a patient’s quality of life, and possibly lessening the progression of disease. Various classes of pharmaceuticals, such as diuretics, beta blockers, and angiotensin-converting enzyme inhibitors, have been the accepted therapy for CHF [Halawa, 1999]. These mainstream pharmaceuticals focus on lowering systolic and diastolic blood pressure, control of ventricular rate for atrial fibrillation, and decrease volume overload [Baliga and Young, 2008]. Acute achievement of these parameters can occur; however, chronic control is usually not maintained due to the progression of disease.

Extracorporeal versus peritoneal ultrafiltration in diuretic-resistant congestive heart failure – a review

SummaryDiuretic-resistant congestive heart failure in the form of type 2 cardiorenal syndrome is a problem of growing significance in everyday clinical practice because of high morbidity and mortality. There has been scant progress in the treatment of overhydration, the main cause of symptoms in this group of patients. The aim of our review is to present recent advances in the ultrafiltration therapy of congestive heart failure, with special attention to the new dedicated device for extracorporeal isolated ultrafiltration, as well as modifications of peritoneal dialysis in the form of peritoneal ultrafiltration with icodextrin solution and incremental peritoneal dialysis. Technical and clinical features, costs and potential risks of available devices for isolated ultrafiltration are presented. This method should be reserved for patients with true diuretic resistance as part of a more complex strategy aiming at the adequate control of fluid retention. Peritoneal ultrafiltration is presented as a viable alternative to extracorporeal ultrafiltration because of medical and psychosocial benefits of home-based therapy, lower costs and more effective daily ultrafiltration. In conclusion, large, properly randomized and controlled clinical trials with long-term follow-up will be essential in assessing the logistics and cost-effectiveness of both methods. Most importantly, however, they should be able to evaluate the impact of both methods on preservation of renal function and delaying the progression of heart failure by interrupting the vicious circle of cardiorenal syndrome. Our review is supplemented with the case report of the use of peritoneal ultrafiltration with a single 12-hour nighttime icodextrin exchange as a life-saving procedure in a patient with congestive heart failure resistant to pharmacological treatment.

The development of a whole-cell based medium throughput screening system for the discovery of human aldosterone synthase (CYP11B2) inhibitors: Old drugs disclose new applications for the therapy of congestive heart failure, myocardial fibrosis and hypertension

Cytochrome P450 enzymes play an important role in steroid hormone biosynthesis of the human adrenal gland, e.g., the production of cortisol and aldosterone. Aldosterone, the most important human mineralocorticoid, is involved in the regulation of the salt and water homeostasis of the body and thus in the regulation of blood pressure, whereas cortisol is the most important glucocorticoid of the human body. CYP11B-dependent steroid hydroxylases are drug development targets, and since they are very closely related enzymes, the discovery of selective inhibitors has been subject to intense investigations for several years. Here we report the development of a whole-cell medium throughput screening technology for the discovery of CYP11B2 inhibitors. The new screening system displayed high reproducibility and was applied to investigate a library of pharmacologically active compounds. 1268 compounds were investigated during this study which revealed 5 selective inhibitors of CYP11B2 (after validation against CYP11B1). The new inhibitors of CYP11B2 are already existing drugs that could be used either in the treatment of hyperaldosteronism-related diseases or as lead compounds that could further be optimised to achieve safer and selective inhibitors of aldosterone synthase. Article from the Special issue on ‘Targeted Inhibitors’

Mechanical Support and Medical Therapy Reverse Heart Failure in Infants and Children

Most infants and children implanted with ventricular assist devices (VADs) go on to cardiac transplantation. Recovery of dilated cardiomyopathies with the combination left ventricular decompression with a VAD and treatment with maximal medical therapy has been possible in some adults, and may be more feasible in infants and children. We used pulsatile and continuous flow VADs and the total artificial heart (TAH) as bridges to transplantation or to recovery. Candidates for native heart recovery were treated with maximal medical therapy for congestive heart failure and short-term dobutamine prior to weaning off device support. Since 1997, 28 infants and children, ages 1 month to 16 years, were implanted for durations of 3-107 days (mean 27). Eighteen received left VADs (LVAD), seven biventricular assist devices (BiVADs), and three TAHs. Device-related mortality was 7/28 (25%), leaving 21/28 (75%) surviving to transplantation or weaning from device support and 20/28 (71%) discharged from the hospital and currently surviving for 2 months to 9 years. Ten of 11 transplant recipients (90%) have survived 2 to 9 years. All 10 with recovered hearts are alive and well for 2 months to 5 years. Eight of 12 (67%) LVAD patients with dilated hearts recovered. None of the recovery patients were over 6 years old. Infants and children who have failed inotropic therapy may be treated with an LVAD and medical therapy for congestive heart failure anticipating native heart recovery. A variety of devices have been tried. All small LVADs yielded comparable results. Larger and older children also have a chance of recovery, but our experience with them is too small except to note that they do well with larger devices and transplantation.

Lack of Improvement in Outpatient Management of Congestive Heart Failure in the United States

Congestive heart failure (CHF) continues to account for 3% of admissions to hospitals in the United States, and the diagnosis carries a mortality rate of 20% at one year and 80% at eight years.1,2 There have been numerous advances in the chronic medical management of CHF, including angiotensin antagonists, beta blockers, and aldosterone antagonists, all of which have shown significant mortality reductions in clinical trial populations with varying degrees of CHF severity.2–4 Evidence from clinical trials, however, does not always readily translate to community practice.5,6 Previous studies in outpatient populations in the late 1990s and the early 2000s observed suboptimal use of evidence-based therapy for CHF. Using nationally representative data, we evaluated whether patterns of medication use have improved over time.

Outpatient Disparities in Recommended Therapy for Congestive Heart Failure

Outpatient Disparities in Recommended Therapy for Congestive Heart Failure

Système pour la stimulation cardiaque du ventricule gauche sur de multiples électrodes reconfigurables avec une électronique encapsulée hermétique et biocompatible

MULTICARDE is a Tecsan ANR exploratory project that was launched in 2007 and ended up in 2009. ELA Medical (SORIN Group) and the CEA-Leti were associated for this development. The project aims at enhancing the therapy for congestive heart failure based on biventricular electrical resynchronization therapy. Several studies proved the efficiency of this therapy, which remains subjected to the good positioning of the left pacing lead. The MULTICARDE project develops a programmable multi-electrodes pacing to improve the hemodynamic status of the patient. Multiple constraints must be taken into account for this kind of project, such as the power consumption, the size and the interoperability towards leads’ standards. To address these requirements an innovative collective packaging process was developed to integrate electronics inside the lead.

Renal and Anti-Aldosterone Actions of Vasopressin-2 Receptor Antagonism and B-Type Natriuretic Peptide in Experimental Heart Failure

Hemodynamic and neurohumoral function can affect the efficacy of diuretic therapy in congestive heart failure. Arginine vasopressin increases water reabsorption through the V(2) receptor in the collecting duct, whereas B-type natriuretic peptide (BNP) decreases sodium reabsorption in the collecting duct. We hypothesized that combining BNP to the V(2)-receptor antagonist tolvaptan (TLV) would enhance renal excretory function by augmenting sodium excretion together with aquaresis without adversely affecting renal hemodynamics in experimental congestive heart failure. Congestive heart failure was induced in 3 groups (n=6 per group) of dogs by tachypacing. A acute experiment was done after 10 days. After baseline measurements, study groups received a 0.1 mg/kg IV bolus of TLV alone (TLV), TLV in combination with BNP (TLV+BNP; 50 ng/[kg . min]), or BNP alone (BNP). Mean arterial pressure increased with TLV, remained unchanged with TLV+BNP, and decreased with BNP (+5+/-1mm Hg versus -1+/-1 mm Hg versus -15+/-1 mm Hg; P<0.05). Renal blood flow and glomerular filtration rate were preserved with all regimens. Urine flow increased in all 3 groups but significantly more so with TLV+BNP (TLV: +0.4+/-0.1 mL/min versus TLV+BNP: +2.4+/-0.5 mL/min versus BNP: +0.8+/-0.3 mL/min; P<0.05). Only TLV+BNP and BNP were natriuretic (P<0.05), whereas only TLV and TLV+BNP increased electrolyte-free water excretion (P<0.05). Compared with TLV alone, TLV+BNP prevented an increase in aldosterone (P<0.05). Coadministration of TLV and BNP in experimental HF resulted in a beneficial profile of renal, neurohumoral, and hemodynamic actions, specifically potent diuresis with natriuresis, neutral effect on mean arterial pressure, and lack of aldosterone activation.

The new targets of ouabain in retinal interneurons of Sprague-Dawley rats

Ouabain is both a cardiac glycoside used in therapy of congestive heart failure and an endogenous steroid hormone. It specifically binds to Na +, K +-ATPase (NKA) and blocks its activity. Overdose of ouabain induces retinal damage. In different species ouabain-induced retinal degeneration affects different cell types. In fish and rabbit ouabain induces retinal cell death preferentially in the ganglion cell layer and outer photoreceptor segments respectively. In rats, the pattern of NKA expression has been studied with most detail among retinal neurons. In addition, ouabain selectively destroyed some types of neurons in rodents. However, ouabain-sensitive retinal neurons remain unclear in rats. We show here that injection of ouabain into the rat vitreous body induced dramatic cell death in the inner nuclear layer (INL). The cell death was time- and dose-dependent. Ouabain-induced dying cells in the INL were TUNEL-positive. Immunohistochemistry analysis revealed that there was a significant decrease in the number of calbindin D-28K- and syntaxin-1-positive horizontal and amacrine cells in the INL of ouabain-treated rat retinas. Thus our results revealed that the horizontal and amacrine cells are the most sensitive cell types to ouabain in the retina of Sprague-Dawley rat.

β-adrenergic blockade attenuates cardiac dysfunction and myofibrillar remodelling in congestive heart failure

Although β-adrenoceptor (β-AR) blockade is an important mode of therapy for congestive heart failure (CHF), subcellular mechanisms associated with its beneficial effects are not clear. Three weeks after inducing myocardial infarction (MI), rats were treated daily with or without 20 and 75 mg/kg atenolol, a selective β1-AR antagonist, or propranolol, a non-selective β-AR antagonist, for 5 weeks. Sham operated rats served as controls. All animals were assessed haemodynamically and echocardiographically and the left ventricle (LV) was processed for the determination of myofibrillar ATPase activity, α- and β-myosin heavy chain (MHC) isoforms and gene expression as well as cardiac troponin I (cTnI) phosphorylation. Both atenolol and propranolol at 20 and 75 mg/kg doses attenuated cardiac hypertrophy and lung congestion in addition to increasing LV ejection fraction and LV systolic pressure as well as decreasing heart rate, LV end-diastolic pressure and LV diameters in the infarcted animals. Treatment of infarcted animals with these agents also attenuated the MI-induced depression in myofibrillar Ca2+-stimulated ATPase activity and phosphorylated cTnI protein content. The MI-induced decrease in α-MHC and increase in β-MHC protein content were attenuated by both atenolol and propranolol at low and high doses; however, only high dose of propranolol was effective in mitigating changes in the gene expression for α-MHC and β-MHC. Our results suggest that improvement of cardiac function by β-AR blockade in CHF may be associated with attenuation of myofibrillar remodelling.

HNO Uncouples PLN from SERCA2a Enhancing Pump Activity

The sarco(endo)plasmic Ca-ATPase (SERCA2a) sequesters Ca2+ ions from the cytosol into the cardiac sarcoplasmic reticulum (CSR) to promote cardiac relaxation. Phospholamban (PLN) is an integral membrane protein that regulates SERCA2a in CSR. Phosphorylation of PLN in response to β-adrenergic stimulation enhances cardiac inotropy by increasing CSR Ca2+ uptake. Nitroxyl (HNO), a new candidate drug therapy for congestive heart failure (CHF), improves overall cardiovascular function by increasing Ca2+ release and Ca2+ re-uptake in CSR through direct effects on RyR2 and SERCA2a, respectively. We propose that HNO, a thiol oxidant, modifies one or more PLN sulfhydryls and thereby decreases the regulatory interaction of PLN with SERCA2a, contributing to SERCA2a activation. To test this model, we have used fluorescence and EPR spectroscopy to determine the effects of HNO on the physical regulation of SERCA2a by PLN. We used expressed SERCA2a ± coexpressed PLN in High Five insect cells microsomes and Angeli's Salt (AS) as our HNO donor. Steady-state fluorescence intensity studies of FITC-labeled SERCA2a coexpressed with PLN showed that AS/HNO increased the amplitude of the Ca2+-dependent E2 to E1Ca2 conformational change by nearly two fold, similar to the effect observed when PLN is uncoupled from SERCA2a by anti-PLN antibody treatment. This matches our previous finding that AS/HNO stimulates SERCA2a activity nearly two fold. Saturation-transfer EPR studies of maleimide spin-labeled SERCA2a coexpressed with PLN showed that AS/HNO decreased the rotational mobility of SERCA2a, but not significantly more than that of control SERCA2a without PLN. Taken together, our results suggest HNO physically uncouples PLN from SERCA2a increasing SERCA2a conformational flexibility and SERCA2a activity. We are investigating the role of individual PLN cysteines in this mechanism by repeating these experiments using SERCA2a coexpressed with PLN cysteine mutants, and direct effects of HNO on SERCA2a are also being investigated.