Human Congestive Heart Failure Research Articles

Calcitriol modulation of cardiac contractile performance via protein kinase C

Vitamin D3 deficiency enhances cardiac contraction in experimental studies, yet paradoxically this deficiency is linked to congestive heart failure in humans. Activated vitamin D3 (1α,25-dihydroxyvitamin D3) or calcitriol, decreases peak force and activates protein kinase C (PKC) in isolated perfused hearts. However, the direct influence of this hormone on adult cardiac myocyte contractile function is not well understood. Our aim is to investigate whether 1α,25-dihydroxyvitamin D3 acutely modulates contractile function via PKC activation in adult rat cardiac myocytes. Sarcomere shortening and re-lengthening were measured in electrically stimulated myocytes isolated from adult rat hearts, and the vitamin D3 response (10−10 to 10−7 M) was compared to shortening observed under basal conditions. Maximum changes in sarcomere shortening and relaxation were observed with 10−9 M 1α,25-dihydroxyvitamin D3. This dose decreased peak shortening, and accelerated contraction and relaxation rates within 5 min of administration, and changes in the Ca2+ transient contributed to the peak shortening and relaxation effects. The PKC inhibitor, bis-indolylmaleimide (500 nM) largely blocked the acute influence of the most potent dose (10−9 M) on contractile function. While peak shortening and shortening rate returned to baseline within 30 min, there was a sustained acceleration of relaxation that continued over 60 min. Phosphorylation of the Ca2+ regulatory proteins, phospholamban, and cardiac troponin I correlated with the accelerated relaxation observed in response to acute application of 1α,25-dihydroxyvitamin D3. Accelerated relaxation continued to be observed after chronic addition of 1α,25-dihydroxyvitamin D3 (e.g. 2 days), yet this sustained increase in relaxation was not associated with increased phosphorylation of phospholamban or troponin I. These results provide evidence that 1α,25-dihydroxyvitamin D3 directly modulates adult myocyte contractile function, and protein kinase C plays an important signaling role in the acute response. Phosphorylation of key Ca2+ regulatory proteins by this kinase contributes to the enhanced relaxation observed in response to acute, but not chronic calcitriol.

Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure

Diuretics are frequently required to treat fluid retention in patients with congestive heart failure (CHF). Unfortunately, they can lead to a decline in renal function, electrolyte depletion, and neurohumoral activation. Arginine vasopressin (AVP) promotes renal water reabsorption via the V2 receptor, and its levels are increased in CHF. This study was designed to assess the effects of a single oral dose of tolvaptan, a selective V2-receptor blocker, in the absence of other medications, on renal function in human CHF and to compare this to the effects of a single oral dose of furosemide. We hypothesized that V2-receptor antagonism would yield a diuresis comparable to furosemide but would not adversely affect renal hemodynamics, plasma electrolyte concentration, or neurohumoral activation in stable human CHF. Renal and neurohumoral effects of tolvaptan and furosemide were assessed in an open-label, randomized, placebo-controlled crossover study in 14 patients with NYHA II-III CHF. Patients received placebo or 30 mg of tolvaptan on day 1 and were crossed over to the other medication on day 3. On day 5, all subjects received 80 mg of furosemide. Tolvaptan and furosemide induced similar diuretic responses. Unlike tolvaptan, furosemide increased urinary sodium and potassium excretion and decreased renal blood flow. Tolvaptan, furosemide, and placebo did not differ with respect to mean arterial pressure, glomerular filtration rate, or serum sodium and potassium. We conclude that tolvaptan is an effective aquaretic with no adverse effects on renal hemodynamics or serum electrolytes in patients with mild to moderate heart failure.

Controlling the Gap

See related article, pages 558–566 Effective myocardial contraction depends in part on the efficient propagation of electrical signals through the tissue. The principal structure allowing for such rapid myocardial depolarization is the gap junction plaque, a collection of intercellular pores located primarily at intercalated discs. There, at myocyte poles, gap junctions function in close proximity to the complexes responsible for cell–cell tethering—desmosomes and fascia adherens junctions. Thus, the intercalated disc is the site of both intercellular coupling and adhesion. Gap junctions are formed by clusters of paired hexamers, one from each cell, which bridge to form a low-resistance intercellular channel facilitating the transmission of ions and small molecules (<1000 kD). Each hexamer (or connexon) is comprised of six individual connexins, a diverse protein family found in vascular, neural, and cardiac tissue. In humans, ventricular gap junctions are formed primarily from connexin43 (Cx43), a 43-kD protein encoded by chromosome 6.1 Cx43 is a dynamic molecule, with rapid turnover (t1/2 roughly 1 hour)2 and responsiveness to a variety of mechanical and chemical stimuli. Myocyte connectivity, as mediated by gap junctions, depends not only on net expression of Cx43, but on effective translocation of Cx43 to the cell surface, the phosphorylation state of both Cx43 and associated proteins,3 and intracellular pH.4 Ventricular Cx43 net protein expression is downregulated in various cardiac disease conditions such as end-stage ischemic,5 idiopathic,5 hypertrophic,1,6 and tachycardia-induced induced cardiomyopathies,7 myocardial ischemia and hibernation,8 and allograft rejection.9 …

Myocardial Energy Transport and Heart Failure

Abnormalities in myocardial energy metabolism occur in association with progression to congestive heart failure. Conceivably, alterations in cardiac energy metabolism may initiate trophic responses or remodeling noted in myocardium during various disease processes. This review will explore the relationship between myocardial remodeling, contractile dysfunction, and myocardial bioenergetics. Attention will be given to data obtained from studies performed using intact animal models, which emulate congestive heart failure in humans. These data will be considered in relation to studies performed in vitro or in transgenic models. Focus will also be directed towards mechanisms of mitochondrial oxidative phosphorylation regulation (OXPHOS) and high energy phosphate transport.

Transmural expression of transient outward potassium current subunits in normal and failing canine and human hearts

The transient outward current (I(to)), an important contributor to transmural electrophysiological heterogeneity, is significantly remodelled in congestive heart failure (CHF). The molecular bases of transmural I(to) gradients and CHF-dependent ionic remodelling are incompletely understood. To elucidate these issues, we studied mRNA and protein expression of Kv4.3 and KChIP2, the principal alpha and beta subunits believed to form I(to), in epicardial and endocardial tissues and in isolated cardiomyocytes from control dogs and dogs with CHF induced by 240 beats min(-1) ventricular tachypacing. CHF decreased I(to) density in both epicardium and endocardium (by 73 and 55% at +60 mV, respectively), without a significant change in relative current density (endocardium/epicardium 0.11 control, 0.17 CHF). There were transmural gradients in mRNA expression of both Kv4.3 (endocardium/epicardium ratio 0.3 under control conditions) and KChIP2 (endocardium/epicardium ratio 0.2 control), which remained in the presence of CHF (Kv4.3 endocardium/epicardium ratio 0.4; KChIP2 0.4). There were qualitatively similar protein expression gradients in human and canine cardiac tissues and isolated canine cardiomyocytes; however, the KChIP2 gradient was only detectable with a highly selective monoclonal antibody and closely approximated the I(to) density gradient. Kv4.3 mRNA expression was reduced by CHF, but KChIP2 mRNA was not significantly changed. CHF decreased Kv4.3 protein expression in canine cardiac tissues and cardiomyocytes, as well as in terminally failing human heart tissue samples, but KChIP2 protein was not down-regulated in any of the corresponding sample sets. We conclude that both Kv4.3 and KChIP2 may contribute to epicardial-endocardial gradients in I(to), and that I(to) down-regulation in human and canine CHF appears due primarily to changes in Kv4.3.

A cardiovascular-respiratory control system model including state delay with application to congestive heart failure in humans.

This paper considers a model of the human cardiovascular-respiratory control system with one and two transport delays in the state equations describing the respiratory system. The effectiveness of the control of the ventilation rate is influenced by such transport delays because blood gases must be transported a physical distance from the lungs to the sensory sites where these gases are measured. The short term cardiovascular control system does not involve such transport delays although delays do arise in other contexts such as the baroreflex loop (see [46]) for example. This baroreflex delay is not considered here. The interaction between heart rate, blood pressure, cardiac output, and blood vessel resistance is quite complex and given the limited knowledge available of this interaction, we will model the cardiovascular control mechanism via an optimal control derived from control theory. This control will be stabilizing and is a reasonable approach based on mathematical considerations as well as being further motivated by the observation that many physiologists cite optimization as a potential influence in the evolution of biological systems (see, e.g., Kenner [29] or Swan [62]). In this paper we adapt a model, previously considered (Timischl [63] and Timischl et al. [64]), to include the effects of one and two transport delays. We will first implement an optimal control for the combined cardiovascular-respiratory model with one state space delay. We will then consider the effects of a second delay in the state space by modeling the respiratory control via an empirical formula with delay while the the complex relationships in the cardiovascular control will still be modeled by optimal control. This second transport delay associated with the sensory system of the respiratory control plays an important role in respiratory stability. As an application of this model we will consider congestive heart failure where this transport delay is larger than normal and the transition from the quiet awake state to stage 4 (NREM) sleep. The model can be used to study the interaction between cardiovascular and respiratory function in various situations as well as to consider the influence of optimal function in physiological control system performance.

Increased F 2 isoprostane plasma levels in patients with congestive heart failure are correlated with antioxidant status and disease severity

Background A growing body of evidence supports the pathophysiologic role of oxidative stress and the protective role of naturally occurring antioxidants in congestive heart failure (CHF). Circulating levels of a sensitive and specific marker of lipid peroxidation and levels and activities of a broad spectrum of essential antioxidant micronutrients, vitamins, and enzymes, however, have been never simultaneously evaluated in well-characterized CHF patients. Methods and results Plasma levels of 8,12-isoprostane F 2α-VI; vitamins A, C, and E; uric acid; and five carotenoids as well as activities of plasma superoxide dismutase and glutathione peroxidase were measured in 30 patients with class II and III New York Heart Association (NYHA) CHF and in 30 controls. Ejection fraction was measured in all patients. Significantly higher 8,12-isoprostane F 2α-VI levels and lower antioxidant levels and activities were found in CHF patients in comparison to controls. Levels of 8,12-isoprostane F 2α-VI were higher in class III than in class II NYHA CHF patients ( P = .0012), and inversely correlated with ejection fraction; vitamins A, C, and E; uric acid; carotenoid levels; and superoxide dismutase activity. Conclusion There is an association between increased lipid peroxidation and both antioxidant status and disease severity in CHF in humans. These findings support the rationale for intervention trials aiming at exploring beneficial effects of antioxidant micronutrients in this disease.

Renal actions of the cancion® Cardiac Recovery System in severe experimental heart failure

Background: Congestive heart failure (CHF) is a complex disease in which cardiorenal dysfunction reflects clinical status and prognosis. Evidence suggests mechanical unloading of the heart leads to molecular and functional myocardial recovery. The Cancion® Cardiac Recovery System (CRS), a novel percutaneously inserted extracorporeal mechanical device, superimposes continuous aortic flow on existing pulsatile flow. Previous studies in experimental CHF report decreased left ventricular filling pressures with CRS. Early studies in human CHF report decreased pulmonary capillary wedge pressure (PCWP) and plasma creatinine after employment of the CRS. The mechanisms for cardiorenal improvement remain unclear. To further characterize renal resonses to CRS we evaluated renal excretory and hemodynamic function before and after 4 hrs. of CRS therapy in an established model of severe CHF. Methods: Adult male dogs (n = 4) were paced at 240 bpm for 10 days consistent with an established model of CHF characterized by neurohumoral activation, systemic vasoconstriction, impaired cardiac pump function, increased filling pressures, sodium retention and impaired glomerular filtration rate (GFR) and renal blood flow (RBF). Dogs were then anaesthetized and the CRS device inserted percutaneously via the femoral artery into the descending aorta. A baseline clearance for urinary sodium excretion (UNaV) and inulin clearance to measure GFR was obtained. Cardiac filling pressures were measured via a Swan-Ganz catheter, mean arterial pressure (MAP) monitored, and RBF measured with a flow probe. The CRS was activated for 4 hrs., then deactivated and another clearance obtained. Resuts: UNaV (μEq/min) increased (440%±134%, p<0.05 vs baseline) after 4 hours of CRS therapy. GFR (15±5 vs 24±6mL/mim, NS) and RBF (130±12 vs 145±34 mL/min, NS) were maintained and tended to increase despite decreases in MAP (114±10 vs 83±6 mmHg, p<0.05). Consistent with previous studies PCWP decreased (23±2 vs 15±1 mmHg, p<0.05). Conclusion: We report that CRS device activation promotes natriuresis in severe experimental CHF despite decreased MAP. GFR, an important prognostic predictor in CHF is maintained. Consistent with previous studies employment of the CRS results in decreased PCWP in experimental CHF. The time course of these cardiorenal findings suggests neurohumorally mediated mechanisms. Further studies are warranted to elucidate these mechanisms.

Gene Therapy in Congestive Heart Failure

Although research and development of gene therapy have encountered several difficulties in recent years, they have also begun to show potential for the treatment of acquired and inherited human diseases. Gene therapy may have wide applicability for the treatment of numerous cardiovascular diseases, including congestive heart failure (CHF), ischemic heart disease, and cardiomyopathy. CHF remains a leading cause of death and morbidity in industrialized nations, and the number of patients with CHF continues to increase as the population ages. Pharmacological therapies control symptoms, reduce left ventricular (LV) dilation, improve function, and reduce mortality. These therapies control the disease but do not cure it. Currently, however, the growing knowledge of molecular mechanisms involved in myocardial dysfunction has allowed the identification of potential therapeutic targets designed with the aim of curing CHF. Several studies in animal models have provided hope that gene therapy may be one of the future strategies for the treatment of clinical CHF. In these studies, myocardial gene transfer has been used to target at least 3 different biological pathways that play a crucial role in the pathophysiology of CHF: Intracellular calcium signaling, β1-adrenergic receptor (β1-AR) signaling, and antiapoptotic signaling. The activity of sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) is decreased in failing myocardium, and this results in abnormal Ca2+ handling.1 In an animal model of heart failure, Miyamoto et al2 showed that in vivo overexpression of SERCA2a, achieved by catheter injection of an adenovirus carrying the SERCA2a gene into the aortic root, restored systolic and diastolic function to normal levels. In another study, Muller et al3 analyzed the chronic overexpression of SERCA2a in both normal and pressure-overloaded hearts (induced by abdominal aortic banding of transgenic rats). Overexpression of SERCA2a resulted in a …

Congestive heart failure after myocardial infarction in the rat: cardiac force and spontaneous sarcomere activity.

The causes of reduced cardiac force development in congestive heart failure (CHF) are still uncertain. We explored the subcellular mechanisms leading to decreased force development in trabeculae from rats with a myocardial infarction. We defined CHF according to clinical and pathological criteria and compared properties of trabeculae from animals with CHF (cMI) to those of animals with a myocardial scar but without evidence of CHF (uMI), and sham-operated animals. The new findings of this study on properties of cMI trabeculae are that (1) maximal twitch force following post-extrasystolic potentiation is unchanged; (2) the sensitivity of cMI trabeculae to [Ca(2+)](o) is increased; (3) spontaneous diastolic sarcomere length (SL) fluctuations (SA) are increased in cMI at all levels of SR Ca(2+) loading; and (4) SA is accompanied by a proportional reduction of F(max). The results suggest that the probability of spontaneous diastolic opening of SR Ca(2+) channels is increased in CHF. These data provide the basis for a novel mechanism underlying systolic and diastolic dysfunction as well as arrhythmias in hearts in CHF. If SA proves to be a component of myocardial dysfunction in human CHF, our thinking about therapy of the patient with CHF may be profoundly changed.

Increased neuronal nitric oxide synthase-derived NO production in the failing human heart

Experimental data suggest that nitric oxide (NO) generated from neuronal NO synthase (nNOS) modulates the myocardial inotropic state. To assess the contribution of NO, derived from endothelial and neuronal isoforms, to the pathophysiology of congestive heart failure in human beings, we compared expression, localisation, and specific activity of NOS isoforms in myocardium from patients with dilated cardiomyopathy with those in controls who had died from head trauma or intracranial bleeds. Diseased hearts had a significant increase in nNOS mRNA and protein expression, and activity associated with the translocation of nNOS to the sarcolemma through interactions with caveolin 3. Enhanced nNOS activity counteracted a decrease in eNOS expression and activity. Our results provide evidence of increased nNOS-derived NO in the failing human heart. Such altered regulation may be important in the pathophysiology of cardiac dysfunction in human congestive heart failure.

Subcutaneous administration of the cardiac hormone BNP in symptomatic human heart failure

BackgroundBrain natriuretic peptide (BNP) is a cardiac hormone with vasodilating, natriuretic, renin-angiotensin-aldosterone–inhibiting and lusitropic properties. We have demonstrated that acute subcutaneous (SQ) administration of BNP in experimental congestive heart failure results in elevation of plasma BNP and its second messenger 3′,5′-cyclic guanosine monophosphate (cGMP) with natriuresis and reduction in cardiac filling pressures. Furthermore, chronic subcutaneous BNP in experimental congestive heart failure also resulted in increases in cardiac output and decreases in pulmonary capillary wedge pressure and systemic vascular resistance. MethodsThe objective of the current study was to assess the safety and efficacy of repeated doses of subcutaneous human BNP, nesiritide, a recombinant form of human BNP (Scios Inc, Fremont, CA) in human subjects with New York Heart Association class II-III congestive heart failure. We defined the cardiorenal and humoral responses to subcutaneous BNP (nesiritide) administered every 12 hours with a total of 5 doses over 72 hours in a single-blind placebo-controlled design (n=8). The mean dose of nesiritide was 10 μg/kg every 12 hours. ResultsInitial saline placebo resulted in no change in any measured parameters (P<.05 versus baseline). With the first dose of BNP (nesiritide), cardiac output increased (4.8±0.4 to 6.4±0.5 L/min) and systolic blood pressure decreased (125±5 to 104±3 mm Hg) without a change in heart rate. Plasma BNP (167±115 to 830±470 pg/mL), cGMP (4±2 to 14±4 pmol/mL), and urinary cGMP excretion (3900±930 to 10,600±5000 pmol/min) increased with natriuresis and diuresis. Both plasma renin activity and plasma aldosterone decreased. These favorable biologic responses were observed with the fifth dose 72 hours after the initial dose. All the subjects tolerated the study well without any adverse events except for 1 subject who had a vasovagal episode during micturition after receiving the fifth dose on day 3. ConclusionWe conclude that subcutaneous administration of BNP (nesiritide) represents a novel and efficacious therapeutic strategy in human congestive heart failure to deliver BNP, a cardiac hormone which possesses unique cardiorenal and neurohumoral properties.

Relaxin kinetics during dynamic exercise in patients with chronic heart failure

Background: We investigated circulating relaxin (RLX) and its potential role in human congestive heart failure (CHF) at rest and after physical exercise. Methods: A total of 10 healthy controls and 35 patients with stable CHF were enrolled in the study. Results: RLX plasma concentrations at rest and after exercise were comparable in patients with CHF and in controls. Conclusion: These findings suggest that RLX does not play a major role as a circulating hormone in human CHF.

Circadian and Short-Term Regulation of Blood Pressure and Heart Rate in Transgenic Mice with Cardiac Overexpression of The β1-Adrenoceptor

Congestive heart failure is associated with a loss of circadian and short-term variability in blood pressure and heart rate. In order to assess the contribution of elevated cardiac sympathetic activity to the disturbed cardiovascular regulation, we monitored blood pressure and heart rate in mice with cardiac overexpression of the β1-adrenoceptor prior to the development of overt heart failure. Telemetry transmitters for continuous monitoring of blood pressure and heart rate were implanted in 8 to 9-week-old wildtype and transgenic mice, derived from crosses of heterozygous transgenic (line β1TG4) and wildtype mice. Cardiovascular circadian patterns were analyzed under baseline conditions and during treatment with propranolol (500 mg/L in drinking water). Short-term variability was assessed by spectral analysis of beat-to-beat data sampled for 30 min at four circadian times. Transgenic β1TG4 mice showed an increase in 24 h heart rate, while blood pressure was not different from wildtype controls. Circadian patterns in blood pressure and heart were preserved in β1TG4 mice. Addition of propranolol to the animals’ drinking water led to a reduction in heart rate and its 24 h variation in both strains of mice. Short-term variability in blood pressure was not different between wildtype and β1TG4 mice, but heart rate variability in the transgenic animals showed a rightward shift of the high-frequency component in the nocturnal activity period, suggesting an increase in respiratory frequency. In conclusion, the present study shows that both the circadian and the short-term regulation of blood pressure and heart rate are largely preserved in young, nonfailing β1-transgenic mice. This finding suggests that the loss of blood pressure and heart rate variability observed in human congestive heart failure cannot be attributed solely to sympathetic overactivity but reflects the loss of adrenergic responsiveness to changes in the activity of the autonomic nervous system.

Pharmacological modulations of the renin-angiotensin-aldosterone system in human congestive heart failure: effects on peripheral vascular endothelial function.

Elevated peripheral vascular tone has been proposed as one of the detrimental factors causing increased cardiac after load and reduced exercise capacity in patients with congestive heart failure (CHF). A number of studies have shown impaired endothelium-dependent vasodilation in limb resistance and conduit vessels in CHF, suggesting that this is one of the important etiologies of vascular dysfunction. Several clinical trials have shown that pharmacological inhibition of the renin-angiotensin-aldosterone system by angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, or aldosterone receptor antagonists, significantly improves prognosis in this disorder. However, the relationship between the clinical utility of this type of drug and its pharmacological effects on the peripheral vasculature has not been extensively assessed in patients with CHF. The present review summarizes recent reports including our own observations on the pharmacological effects and mechanisms of this type of drug on vascular endothelial function in the peripheral vasculature in human CHF.

Ventricular cardiotrophin-1 activation precedes BNP in experimental heart failure

Both cardiotrophin-1 (CT-1) and B-type or brain natriuretic peptide (BNP) are activated by cardiomyocyte stretch, and gene expression of CT-1 and BNP are augmented in the heart in experimental and human congestive heart failure (CHF). The goal of this study was to define cardiac gene expression of CT-1 and BNP by Northern blot analysis in normal ( n=5), early left ventricular dysfunction (ELVD, n=5) and overt CHF dogs ( n=5), in which ventricular function is progressively decreased. CT-1 mRNA was detected in both atria and ventricles in normal dogs. Ventricular CT-1 mRNA production increased in ELVD, and it further increased in overt CHF. Ventricular BNP mRNA remained below or at the limit of detection in normal and ELVD models, and it markedly increased in overt CHF. This study reports differential regulation of gene expression of CT-1 and BNP in the heart during the progression of CHF, and demonstrates that ventricular CT-1 gene activation precedes ventricular BNP gene activation.

Gap junction remodeling in heart failure

Gap junctions, clusters of transmembrane channels that link adjoining cells, mediate myocyte-to-myocyte electrical coupling and communication. The component proteins of gap junction channels are termed connexins, and gap-junctional channels composed of different connexin types exhibit different biophysical properties. In common with other tissues, the heart expresses multiple connexin isotypes. Spatially defined patterns of expression of 3 connexin isotypes—connexin43, connexin40, and connexin45—form specific cell-to-cell conduction pathways for the spread of current flow that governs the normal cardiac rhythm. Remodeling of gap junction organization and connexin expression is a conspicuous feature of human congestive heart failure and other cardiac conditions in which there is an arrhythmic tendency. This remodeling may take the form of disturbances in the distribution of gap junctions, in which the normal ordered pathways for cell-to-cell conduction are disrupted, or quantitative alterations in connexin expression, notably reduced connexin43 levels, which may contribute to slowing of conduction. Recent evidence from studies in experimental animals strengthens the case that gap junction remodeling is a key determinant of the proarrhythmic substrate in the diseased heart.

Plasma levels and cardiovascular gene expression of urotensin-II in human heart failure

The peptide urotensin-II (U-II) has been described as most potent vasoconstrictor identified so far, but plasma values in humans and its role in cardiovascular pathophysiology are unknown. We investigated circulating urotensin-II and its potential role in human congestive heart failure (CHF). We enrolled control individuals ( n=13; cardiac index [CI], 3.5±0.1 l/min/m 2; pulmonary wedge pressure [PCWP], 10±1 mm Hg), patients with moderate ( n=10; CI, 2.9±0.3 l/min/m 2; PCWP, 14±2 mm Hg) and severe CHF ( n=11; CI, 1.8±0.2 l/min/m 2; PCWP, 33±2 mm Hg). Plasma levels of urotensin-II differed neither between controls, patients with moderate and severe CHF nor between different sites of measurement (pulmonary artery, left ventricle, coronary sinus, antecubital vein) within the single groups. Hemodynamic improvement by vasodilator therapy in severe CHF (CI, +78±3%; PCWP, −55±3%) did not affect circulating U-II over 24 h. Preprourotensin-II mRNA expression in right atria, left ventricles, mammary arteries and saphenous veins did not differ between controls with normal heart function and patients with end-stage CHF. In conclusion, urotensin-II plasma levels and its myocardial and vascular gene expression are unchanged in human CHF. Circulating urotensin-II does not respond to acute hemodynamic improvement. These findings suggest that urotensin-II does not play a major role in human CHF.

Differential effects of the angiotensin-converting enzyme inhibitor lisinopril versus the beta-adrenergic receptor blocker atenolol on hemodynamics and left ventricular contractile function in experimental mitral regurgitation.

The goal of this study was to determine the therapeutic efficacy of angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic receptor blockers in experimental chronic mitral regurgitation (MR), gaining knowledge using methods difficult to apply in humans. Both ACE inhibitors and beta-blockers are cornerstones in the treatment of human congestive heart failure. However, the roles of these treatments for chronic MR is unclear. Mitral regurgitation was created in 11 closed-chest dogs. Three months after the creation, the ACE inhibitor lisinopril 20 mg was given orally daily. After three months of lisinopril therapy, the beta-blocker atenolol was added to lisinopril for another three months. Atenolol was begun at a dose of 12.5 mg daily and increased gradually to 100 mg daily. Hemodynamics and left ventricular (LV) function were assessed throughout the study. Regurgitant fraction was consistently >50% over the course of this study. Pulmonary capillary wedge pressure and LV end-diastolic pressure were significantly increased after three months of MR and decreased during both lisinopril and the combined therapy in which it was not different from baseline. Left ventricular contractility measured by the end-systolic stiffness constant was depressed from 3.66 +/- 0.20 to 2.65 +/- 0.12 (p < 0.05) at three months of MR and rose insignificantly after lisinopril treatment (2.99 +/- 0.17). When atenolol was added, it rose significantly and returned to normal (3.50 +/- 0.22, p < 0.05). Although lisinopril significantly reduced preload, its effect on LV contractility was insignificant in experimental MR. Conversely, atenolol, when added to lisinopril, achieved maximum hemodynamic benefit and also restored LV contractility.

The potential of brain natriuretic peptide as a biomarker for New York Heart Association class during the outpatient treatment of heart failure

Background: Plasma C-terminal atrial natriuretic peptide (C-ANP), N-terminal ANP (N-ANP), and brain natriuretic peptide (BNP) have diagnostic utility in detecting left ventricular dysfunction. Their relative value in monitoring symptom status during the chronic treatment of congestive heart failure (CHF) remains undefined. Methods and Results: Ninety-eight subjects with CHF were evaluated. Baseline natriuretic peptides were measured by radioimmunoassay, left ventricular ejection fraction (LVEF) was estimated with echocardiography, and New York Heart Association (NYHA) class was determined independently by attending heart failure specialists. Forty-one subjects were restudied during a 6- to 12-month follow-up period after optimizing therapy. At baseline, all natriuretic peptides and LVEF correlated positively with NYHA class (P <.005). Plasma BNP, however, correlated best with NYHA class. At follow-up, only changes of BNP correlated to changes of NYHA class (P =.04). BNP decreased (−45% ± 12%, N = 14, P =.002) in subjects whose NYHA class improved whereas BNP remained unchanged (−1% ± 10%, N = 25, P =.95) in those whose NYHA class was stable. Conclusions: This investigation demonstrates the superiority of plasma BNP as compared to ANP and LVEF in objectively assessing NYHA class during the chronic treatment of CHF. Given that clinical assessment of CHF is subjective, plasma BNP is a useful objective biomarker in monitoring human CHF in the outpatient setting.