Autonomic dysregulation is a feature of chronic heart failure (HF) and is characterized by a sustained increase of sympathetic drive and by withdrawal of parasympathetic activity. Both sympathetic overdrive and increased heart rate are predictors of poor long-term outcome in patients with HF. Pharmacologic agents that partially inhibit sympathetic activity such as beta-adrenergic receptor blockers are effective in reducing mortality and morbidity in patients with chronic HF. In contrast, modulation of parasympathetic activation as a potential therapy for HF has received only limited attention due to its inherent complex cardiovascular effects. This review examines results of experimental animal studies that provide support for the possible use of electrical Vagus nerve stimulation (VNS) as a long-term therapy for the treatment of chronic HF. The review will also address the effects of VNS on potential modifiers of the HF state including pro-inflammatory cytokines, nitric oxide elaboration, and myocardial expression of gap junction proteins. Finally, we will briefly review the safety, feasibility and efficacy trends of VNS in patients with advanced HF.
Ventricular function; ventricular remodeling; Vagus nerve stimulation; sympathetic activity; parasympathetic activity
The objective of this study was to investigate potential pleiotropic effects of rosuvastatin (RSV) in left ventricular (LV) myocardium of dogs with moderate heart failure (HF).
LV tissue was obtained from HF dogs randomized to 3 months therapy with low dose (LD) RSV (n=7), high dose (HD) RSV (n=7) or to no therapy (Control, n=7), and from 7 normal (NL) dogs. mRNA and protein expression of pro-hypertrophic mediators NGFI-A binding protein 1 (Nab1), phosphatase and tensin homolog (PTEN), phosphoinositide-3 kinase (PI3K) and mammalian target of rapamycin (mTOR); pro-inflammatory cytokine interleukin-6 (IL-6); bone marrow-derived stem cells (BMSCs) markers cKit and Sca1; vascular endothelial (VEGF) and fibroblast (FGF) growth factors and nitric oxide synthase (NOS) isoforms were measured.
Nab1, PTEN, PI3K, mTOR, and IL-6 increased in Controls. HD RSV reduced expression of Nab1, PTEN, PI3K, mTOR, and IL-6 to near normal levels. cKit and Sca1 significantly increased while VEGF and FGF decreased in Controls compared to NL. RSV therapy further increased expression of cKit, Sca1, VEGF and FGF. HD RSV normalized expression of NOS isoforms.
These pleiotropic effects of RSV may account, in part, for the observed beneficial effect of RSV on LV function and structural remodeling.
Inflammation; Cytokines; Growth factors; Nitric oxide synthase; Hypertrophy; Stem cells
Autonomic dysregulation is a feature of heart failure (HF) characterized by sustained increase of sympathetic drive and by withdrawal of parasympathetic activity. Both maladaptations are independent predictors of poor long-term outcome in patients with HF. Considerable evidence exists that supports the use of pharmacologic agents that partially inhibit sympathetic activity as an effective long-term therapy for patients with HF; the classic example being the use of selective and non-selective beta-adrenergic receptor blockers. In contrast, modulation of parasympathetic activation as potential therapy for HF has received only limited attention. This review discusses the results of recent pre-clinical animal studies that provide support for the possible use of baroreflex electrical stimulation, also know as baroreflex activation therapy (BAT), as a long-term therapeutic approach for the treatment of patients with chronic HF. In addition to exploring the effects of chronic BAT on left ventricular (LV) function and chamber remodeling, the review will also address the effects of long-term BAT on ventricular arrhythmias and on potential modifiers of the HF state that include maladaptations of both the nitric oxide and beta-adrenergic receptor signal transduction pathways. The results of the pre-clinical studies conducted to date have shown that in dogs with advanced HF, monotherapy with BAT improves global LV systolic and diastolic function and partially reverses LV remodeling both globally and at cellular and molecular levels. In addition BAT therapy was shown to markedly increase the threshold for lethal ventricular arrhythmias in dogs with chronic HF. These benefits of BAT support the continued exploration of this therapeutic modality for treating patients with chronic HF and those with increased risk of sudden cardiac death.
Congestive heart failure; Animal models of human disease; Heart failure - basic studies; Baroreflex function; Ventricular Function; Ventricular dilation; mRNA expression; Ventricular arrhythmias; Electrophysiological testing; Plasma biomarkers; Sympathetic stimulation; Parasympathetic stimulation; Beta-adrenergic signaling; Nitric oxide; Inflammatory cytokines
Chronic heart failure (HF) is associated with autonomic dysregulation characterized by a sustained increase of sympathetic drive and by withdrawal of parasympathetic activity. Sympathetic overdrive and increased heart rate are predictors of poor long-term outcome in patients with HF. Considerable evidence exists that supports the use of pharmacologic agents that partially inhibit sympathetic activity as effective long-term therapy for patients with HF; the classic example is the wide use of selective and non-selective beta-adrenergic receptor blockers. In contrast, modulation of parasympathetic activation as potential therapy for HF has received only limited attention over the years given its complex cardiovascular effects. In this article, we review results of recent experimental animal studies that provide support for the possible use of electrical Vagus nerve stimulation (VNS) as a long-term therapy for the treatment of chronic HF. In addition to exploring the effects of chronic VNS on left ventricular (LV) function, the review will also address the effects of VNS on potential modifiers of the HF state that include cytokine production and nitric oxide elaboration. Finally, we will briefly review other nerve stimulation approaches also currently under investigation as potential therapeutic modalities for treating chronic HF.
Ventricular function; Ventricular remodeling; Electrical nerve stimulation; Sympathetic activity; Parasympathetic activity; Animal models of disease; Cytokines; Nitric oxide
To compare the benefit of Beta Blockers (BB) in heart failure (HF) with preserved vs. reduced ejection fraction (EF).
Methods and Results
Retrospective study of insured patients who were hospitalized for HF between January 2000 and June 2008. Pharmacy claims were used to estimate BB exposure over six-month rolling windows. The association between BB exposure and all-cause hospitalization or death was tested using time-updated proportional hazards regression, with adjustment for baseline covariates and other HF medication exposure. The groups were compared by stratification (EF <50% vs. ≥50%) and using an EF-group*BB exposure interaction term. 1835 patients met inclusion criteria; 741 (40%) with a preserved EF. Median follow up was 2.1 years. In a fully-adjusted multivariable model, BB exposure was associated with a decreased risk of death or hospitalization in both groups (EF<50% hazard ratio [HR] 0.53, p<0.0001; EF≥50% HR 0.68, p=0.009). There was no significant difference in this protective association between groups (interaction p=0.32).
BB exposure was associated with a similar protective effect in terms of time to death or hospitalization in HF patients regardless of whether EF was preserved or reduced. An adequately powered randomized trial of BB in HF with preserved EF is warranted.
beta adrenergic receptor blocker; hospitalization; diastolic dysfunction; heart failure with preserved ejection fraction
β-Blockers are standard therapy for patients with heart failure (HF). This study compared the effects of chronic monotherapy with 2 different β1-selective adrenoceptor blockers, namely atenolol and metoprolol succinate, on left ventricular (LV) function and remodeling in dogs with coronary microembolization-induced HF [LV ejection fraction (EF) 30–40%].
Twenty HF dogs were randomized to 3 months of therapy with atenolol (50 mg once daily, n = 6), metoprolol succinate (100 mg, once daily, n = 7) or to no therapy (control, n = 7). LV EF and volumes were measured before initiating therapy and after 3 months of therapy. The change (Δ) in EF and volumes between measurements before and after therapy was calculated and compared among study groups.
In controls, EF decreased and end-systolic volume increased. Atenolol prevented the decrease in EF and the increase in ESV. In contrast, metoprolol succinate significantly increased EF and decreased end-systolic volume. ΔEF was significantly higher and Δend-systolic volume significantly lower in metoprolol succinate-treated dogs compared to atenolol-treated dogs (EF: 6.0 ± 0.86% vs. 0.8 ± 0.85%, p < 0.05; end-systolic volume: −4.3 ± 0.81 ml vs. −1 ± 0.52 ml, p <0.05).
In HF dogs, chronic therapy with atenolol does not elicit the same LV function and remodeling benefits as those achieved with metoprolol succinate.
Heart failure; Myocyte hypertrophy; Ventricular remodeling; Gene expression
We used isolated cardiomyocytes to investigate a possible role of mitochondrial permeability transition pore in mitochondrial abnormalities associated with heart failure.
Cardiomyocytes were isolated from LV myocardium of normal control dogs and dogs with heart failure produced by intracoronary microembolizations. Mitochondrial permeability transition was measured in isolated cardiomyocytes with intact sarcolemma with and without 0.2 μM Cyclosporin A using calcein AM and the fluorometer. State-3 mitochondrial respiration was also measured with the Clark electrode. Mitochondrial membrane potential was measured with JC-1 probe using the fluorometer. Propidium iodide was used to ensure sarcolemma integrity.
200 minutes after loading with calcein AM, mitochondria of failing cardiomyocytes showed only 50% of maximal level of calcein fluorescence while it remained unchanged in normal cells. The mitochondrial membrane potential in failing cardiomyocytes was significantly decreased by 38% compared to normal cardiomyocytes. Cyclosporine A significantly slowed the exit of calcein from mitochondria of failing cardiomyocytes and increased mitochondrial membrane potential by 29%. State-3 respiration was not affected with Cyclosporine A in normal cardiomyocytes while it was significantly increased in failing cardiomyocytes by 20%.
Exit of calcein (m.w. 1.0 kDa) from mitochondria of viable failing cardiomyocytes with intact sarcolemma suggests an existence of a reversible transitory permeability transition opening in high conductance mode. Attenuation of calcein exit, ΔΨm and improvement of state-3 respiration achieved with CsA (0.2 μM) show that permeability transition opening could be a cause of mitochondrial dysfunction described in the failing heart.
Permeability transition; Heart failure; Mitochondria
Assessment of global LV remodeling is important in evaluating the efficacy of pharmacologic and device therapies for the treatment of chronic heart failure (HF). The effects of pharmacologic or device therapies on global left atrial (LA) remodeling in HF, while also important, are not often examined. We showed that long-term therapy with the Acorn Cardiac Support Device (CSD), a passive mechanical ventricular containment device, prevents and/or reverses LV remodeling in dogs with HF. This study examined the effects of the CSD on global LA remodeling in dogs with moderate and advanced HF.
Methods and Results
Studies were performed in 24 dogs with coronary microembolization-induced HF. Of these, 12 had moderate HF (ejection fraction, EF 30% to 40%) and 12 advanced HF (EF ≤25%). In each group, the CSD was implanted in 6 dogs and the other 6 served as controls. Dogs were followed for 3 months in the moderate group and 6 months in the advanced HF group. LA maximal volume (LAVmax), LA volume at the onset of the p-wave (LAVp), LA minimal volume (LAVmin), LA active emptying volume (LAAEV) and LA active emptying fraction (LAAEF) were measured from 2-dimensional echocardiograms obtained prior to CSD implantation and at the end of the treatment period. Treatment effect (Δ) comparisons between CSD-treated dogs and controls showed that CSD therapy significantly decreased LA volumes (ΔLAVmax: 3.33 ± 0.70 vs. −2.87±1.31 ml, p=0.002; 7.77 ± 1.76 vs. −0.37 ± 0.87 ml, p=0.002) and improved LA function (ΔLAAEF: −6.00 ± 1.53 vs. 1.85 ± 1.32 %, p=0.003; −2.39 ± 1.10 vs. 3.13 ± 1.66 %, p=0.02) in the moderate HF and advanced HF groups respectively.
Progressive LA enlargement and LA functional deterioration occurs in untreated dogs with HF. Monotherapy with the CSD prevents LA enlargement and improves LA mechanical function in dogs with moderate and advanced HF indicating prevention and/or reversal of adverse LA remodeling.
Atrium; Echocardiography; Heart failure; Heart-assist device
Arginine vasopressin (AVP) levels are elevated in proportion to heart failure (HF) severity and are associated with higher cardiovascular mortality in ambulatory patients. However, the relationship between baseline and trends in AVP with outcomes in patients hospitalized for worsening HF with reduced ejection fraction (EF) is unclear.
Methods and Results
The EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial investigated the effects of tolvaptan in patients with worsening HF and EF≤40%. The present analysis examined baseline and follow-up AVP levels in 3,196 EVEREST patients with valid AVP measurements. Co-primary endpoints included all-cause mortality (ACM), and the composite of cardiovascular mortality or HF hospitalization (CVM/H). Median follow-up was 9.9 months. Times to events were compared with univariate log-rank tests and multivariable Cox regression models, adjusted for baseline risk factors. After adjusting for baseline covariates, elevated AVP levels were associated with increased ACM (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.13 –1.55) and CVM/H (HR 1.23, 95% CI 1.08 –1.39). There was no interaction of baseline AVP with treatment assignment in terms of survival (p=0.515). Tolvaptan therapy increased the proportion of patients with elevated AVP (p<0.001), but this had no effect on mortality (HR 0.95, 95% CI 0.72 – 1.24).
Elevated baseline AVP level was independently predictive of mortality, but did not identify a group of patients who had improved outcomes with tolvaptan treatment. Tolvaptan treatment increased AVP levels during follow-up, but this incremental increase was not associated with worsened outcomes.
heart failure; drugs; hormones; outcomes
Adenosine (AD) elicits cardioprotection through A1-receptor (A1R) activation. Therapy with AD A1R agonists, however, is limited by undesirable actions of full agonism such as bradycardia. This study examined the effects of capadenoson (CAP), a partial AD A1R agonist, on left ventricular (LV) function and remodeling in dogs with heart failure (HF).
Methods and Results
12 dogs with microembolization-induced HF were randomized to 12 weeks oral therapy with CAP (7.5 mg Bid, n=6) or to no therapy (Control, n=6). LV end-diastolic (EDV) and end-systolic (ESV) volumes, ejection fraction (EF), plasma norepinephrine (NE) and n-terminal pro-brain natriuretic peptide (nt-pro BNP) were measured before (PRE) and 1 and 12 weeks after therapy (POST). LV tissue obtained at POST was used to assess volume fraction of interstitial fibrosis (VFIF), SERCA-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, EDV and ESV increased and EF decreased significantly from PRE to POST (EF: 30±2 vs. 27±1 %, p<0.05). In CAP-treated dogs, EDV was unchanged; EF increased significantly after one week (36±2 vs. 27±2 %, p<0.05) with a further increase at POST (39±2 %, p<0.05) while ESV decreased. CAP significantly decreased VFIF, normalized SERCA-2a activity and expression of UCP-2 and -3, and GLUT-1 and -2 and significantly decreased NE and nt-pro BNP.
In HF dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial AD A1R agonists for the treatment of chronic HF.
Heart failure; Ventricular remodeling; Protein expression; Adenosine receptors
The CorCap Cardiac Support Device (Acorn Cardiovascular, Inc.) is the first device that specifically addresses ventricular remodeling in heart failure by reducing wall stress. We previously reported outcomes from the Acorn randomized trial to a common closing date (22.9 months of follow up). This report summarizes results of extended follow up to 5 years.
107 patients were enrolled in the No-Mitral Valve Repair/Replacement stratum including 57 in the CorCap treatment group and 50 in the control (optimal medical therapy alone) group. Patients were assessed every year until completing 5 years of follow up, for survival, adverse events, major cardiac procedures, New York Heart Association (NYHA) functional status and echocardiograms, which were read at a core laboratory.
Overall survival rates were similar between the treatment and control groups demonstrating no late adverse effect on mortality. The treatment group had significant reductions in left ventricular end diastolic volume (p = 0.029) as well as a small increase in sphericity index. More patients in the treatment group improved by at least one NYHA functional class (p= 0.0005). There was no difference in rates of adverse events. In a subgroup of patients with an intermediate left ventricular end diastolic dimension, there was a significant reduction in the Kaplan Meier estimate of the freedom from the composite endpoint of death and major cardiac procedures (p= 0.04).
These cumulative data demonstrate the sustained reverse remodeling of the left ventricle and the long term safety and efficacy of the CorCap Cardiac Support Device as an adjunctive therapy for patients with heart failure who remain symptomatic despite optimal medical therapy.
We explored use of a canine model of heart failure (HF) for pharmacogenomic discovery, specifically analyzing response to beta blockers (BB)
Dogs with HF that received BB (n=39) underwent genome-wide genotyping to test the association with changes in left ventricular (LV) volume and ejection fraction after treatment. Resulting candidate genes underwent RNA quantification in cardiac tissue from normal (n=5), placebo-HF (n=5), and BB-HF (n=7) dogs.
Three markers met whole-genome significance for association with improved LV end-systolic volume after BB therapy (each p<5×10−7). RNA quantification of three candidate genes near these markers -- GUCA1B, RRAGD, and MRPS10 --revealed that gene expression levels in BB-HF dogs were between that of placebo-HF dogs and normal dogs.
Genome-wide pharmacogenomic screening in a canine model of HF suggests 3 novel BB response candidate loci. This approach is adaptable to discovering mechanisms of action for other drug therapies, and may be a useful strategy for identifying candidate genes for drug response in the pre-clinical setting.
The incidence and prevalence of heart failure have increased significantly over the past few decades. Available data suggest that patients with heart failure independent of the aetiology have viable but dysfunctional myocardium that is potentially salvageable. Although a great deal of research effort has focused on characterizing the molecular basis of heart failure, cardiac metabolism in this disorder remains an understudied discipline. It is known that many aspects of cardiomyocyte energetics are altered in heart failure. These include a shift from fatty acid to glucose as a preferred substrate and a decline in the levels of ATP. Despite these demonstrated changes, there are currently no approved drugs that target metabolic enzymes or proteins in heart failure. This is partly due to our limited knowledge of the mechanisms and pathways that regulate cardiac metabolism. Better characterization of these pathways may potentially lead to new therapies for heart failure. Targeting myocardial energetics in the viable and potentially salvageable tissue may be particularly effective in the treatment of heart failure. Here, we will review metabolic changes that occur in fatty acid and glucose metabolism and AMP-activated kinase in heart failure. We propose that cardiac energetics should be considered as a potential target for therapy in heart failure and more research should be done in this area.
Energetics; Cardiac metabolism; AMP-activated kinase; Heart failure
The impact of a high-fat diet on the failing heart is unclear, and the differences between polyunsaturated fatty acids (PUFA) and saturated fat have not been assessed. Here, we compared a standard low-fat diet to high-fat diets enriched with either saturated fat (palmitate and stearate) or PUFA (linoleic and α-linolenic acids) in hamsters with genetic cardiomyopathy.
Methods and results
Male δ-sarcoglycan null Bio TO2 hamsters were fed a standard low-fat diet (12% energy from fat), or high-fat diets (45% fat) comprised of either saturated fat or PUFA. The median survival was increased by the high saturated fat diet (P< 0.01; 278 days with standard diet and 361 days with high saturated fat)), but not with high PUFA (260 days) (n = 30–35/group). Body mass was modestly elevated (∼10%) in both high fat groups. Subgroups evaluated after 24 weeks had similar left ventricular chamber size, function, and mass. Mitochondrial oxidative enzyme activity and the yield of interfibrillar mitochondria (IFM) were decreased to a similar extent in all TO2 groups compared with normal F1B hamsters. Ca2+-induced mitochondrial permeability transition pore opening was enhanced in IFM in all TO2 groups compared with F1B hamsters, but to a significantly greater extent in those fed the high PUFA diet compared with the standard or high saturated fat diet.
These results show that a high intake of saturated fat improves survival in heart failure compared with a high PUFA diet or low-fat diet, despite persistent mitochondrial defects.
Cardiomyopathy; Low-carbohydrate diet; Metabolism; Obesity
Autonomic abnormalities exist in heart failure (HF) and contribute to disease progression. Activation of the Carotid sinus baroreflex (CSB) has been shown to reduce sympathetic outflow and augment parasympathetic vagal tone. This study tested the hypothesis that long-term electrical activation of carotid sinus baroreflex improves left ventricular (LV) function and attenuates progressive LV remodeling in dogs with advanced chronic HF.
Methods and Results
Studies were performed in 14 dogs with coronary microembolization-induced HF (LV ejection fraction, EF ~25%). Eight dogs were chronically instrumented for bilateral CSB activation using the Rheos® System (CVRx® Inc., Minneapolis, MN) and 6 were not and served as controls. All dogs were followed for 3 months and none received other background therapy. During follow-up, treatment with CSB increased LV EF 4.0 ± 2.4 % compared to a reduction in control dogs of −2.8 ± 1.0% (p<0.05). Similarly, treatment with CSB decreased LV end-systolic volume −2.5 ± 2.7 ml compared to an increase in control dogs of 6.7 ± 2.9 ml (p<0.05). Compared to control, CSB activation significantly decreased LV end-diastolic pressure and circulating plasma norepinephrine, normalized expression of cardiac β1-adrenergic receptors, β-adrenergic receptor kinase and nitric oxide synthase and reduced interstitial fibrosis and cardiomyocyte hypertrophy.
In dogs with advanced HF, CSB activation improves global LV function and partially reverses LV remodeling both globally and at cellular and molecular levels.
heart failure; ventricular remodeling; gene expression; baroreflex function
We elucidate the role of late Na+ current (INaL) for diastolic intracellular Ca2+ (DCa)accumulation in chronic heart failure (HF). HF was induced in 19 dogs by multiple coronary artery microembolizations; 6 normal dogs served as control. Ca2+ transients were recorded in field-paced (0.25 or 1.5Hz) fluo-4-loaded ventricular myocytes (VM). INaL and action potentials were recorded by patch-clamp. Failing VM, but not normal VM, exhibited 1) prolonged action potentials and Ca2+ transients at 0.25 Hz, 2) substantial DCa accumulation at 1.5Hz, 3) spontaneous Ca2+ releases, which occurred after 1.5 Hz stimulation trains in ~31% cases. Selective INaL blocker ranolazine (10μM) or the prototypical Na+ channel blocker tetrodotoxin (2μM) reversibly improved function of failing VM. The DCa accumulation and the beneficial effect of INaL blockade were reproduced in silico using an excitation-contraction coupling model. We conclude that INaL contributes to diastolic Ca2+ accumulation and spontaneous Ca2+ release in HF.
Action potential remodeling; Ca2+ handling; Heart failure; Na+ current; Na+/Ca2+ exchange
Passive constraint is used to prevent left ventricular (LV) dilation and subsequent remodeling. However, there has been concern about the effect of passive constraint on diastolic LV chamber stiffness and pump function. This study determined the relationship between constraint, diastolic wall stress, chamber stiffness and pump function. We tested the hypothesis that passive constraint at 3 mmHg reduces wall stress with minimal change in pump function.
“A 3-dimensional finite element model of the globally dilated LV based on LV dimensions obtained in dogs that had undergone serial intracoronary microsphere injection was created. The model was adjusted to match experimentally observed end-diastolic LV volume and mid-ventricular wall thickness. The experimental results used to create the model were previously reported.
A pressure of 3, 5, 7, and 9 mmHg was applied to the epicardium. Fiber stress, end-diastolic pressure volume relationship (EDPVR), end-systolic pressure volume relationship (ESPVR) and the stroke volume end-diastolic pressure (Starling) relationship were calculated.”
As epicardial constraint pressure increased, fiber stress decreased, the EDPVR shifted to the left and the Starling relationship shifted down and to the right. The ESPVR did not change. A constraining pressure of 2.3 mm Hg was associated with a 10% reduction in stroke volume and mean end-diastolic fiber stress was reduced by 18.3% (Inner wall), 15.3% (Mid wall), and 14.2% (Outer wall).
Both stress and cardiac output decrease in a linear fashion as the amount of passive constraint is increased. If the reduction in cardiac output is to be less than 10%, passive constraint should not exceed 2.3 mmHg. On the other hand, this amount of constraint may be sufficient to reverse eccentric hypertrophy after myocardial infarction.
Passive constraint device; wall stress; pump function
Clinical studies suggest that intake of ω-3 polyunsaturated fatty acids (ω-3 PUFA) may lower the incidence of heart failure. Dietary supplementation with ω-3 PUFA exerts metabolic and anti-inflammatory effects that could prevent left ventricle (LV) pathology; however, it is unclear whether these effects occur at clinically relevant doses and whether there are differences between ω-3 PUFA from fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and vegetable sources [α-linolenic acid (ALA)].
Methods and results
We assessed the development of LV remodelling and pathology in rats subjected to aortic banding treated with ω-3 PUFA over a dose range that spanned the intake of humans taking ω-3 PUFA supplements. Rats were fed a standard food or diets supplemented with EPA+DHA or ALA at 0.7, 2.3, or 7% of energy intake. Without supplementation, aortic banding increased LV mass and end-systolic and -diastolic volumes. ALA supplementation had little effect on LV remodelling and dysfunction. In contrast, EPA+DHA dose-dependently increased EPA and DHA, decreased arachidonic acid in cardiac membrane phospholipids, and prevented the increase in LV end-diastolic and -systolic volumes. EPA+DHA resulted in a dose-dependent increase in the anti-inflammatory adipokine adiponectin, and there was a strong correlation between the prevention of LV chamber enlargement and plasma levels of adiponectin (r = −0.78). Supplementation with EPA+DHA had anti-aggregatory and anti-inflammatory effects as evidenced by decreases in urinary thromboxane B2 and serum tumour necrosis factor-α.
Dietary supplementation with ω-3 PUFA derived from fish, but not from vegetable sources, increased plasma adiponectin, suppressed inflammation, and prevented cardiac remodelling and dysfunction under pressure overload conditions.
α-linolenic acid; Diet; Docosahexaenoic acid; Eicosapentaenoic acid; Heart failure
Treatment with inotropic agents is one of the most controversial topics in heart failure. Initial enthusiasm, based on strong pathophysiological rationale and apparent empirical efficacy, has been progressively limited by results of controlled trials and registries showing poorer outcomes of the patients on inotropic therapy. The use of these agents remains, however, potentially indicated in a significant proportion of patients with low cardiac output, peripheral hypoperfusion and end-organ dysfunction caused by heart failure. Limitations of inotropic therapy seem to be mainly related to their mechanisms of action entailing arrhythmogenesis, peripheral vasodilation, myocardial ischemia and damage, and possibly due to their use in patients without a clear indication, rather than to the general principle of inotropic therapy itself. This review will discuss the characteristics of the patients with a potential indication for inotropic therapy, the main data from registries and controlled trials, the mechanism of the untoward effects of these agents on outcomes and, lastly, perspectives with new agents with novel mechanisms of action.
Acute heart failure; Advanced chronic heart failure; Inotropic agents; Prognosis; Istaroxime; Omecamtiv mecarbil
Augmented and slowed late Na+ current (INaL) was implicated in action potential duration variability, early afterdepolarizations, and abnormal Ca2+ handling in human and canine failing myocardium Objective was to study INaL modulation by cytosolic Ca2+ ([Ca2+]i) in normal and failing ventricular myocytes.
Chronic heart failure was produced in 10 dogs by multiple sequential coronary artery microembolizations, 6 normal dogs served as a control. INaL fine structure was measured by whole-cell patch-clamp in ventricular myocytes and approximated by a sum of fast and slow exponentials produced by burst and late scattered modes of Na+ channel gating, respectively.
INaL greatly enhanced as [Ca2+]i increased from “Ca2+ free” to 1μM: its maximum density increased, decay of both exponentials slowed, and steady-state-inactivation curve (SSI) shifted towards more positive potentials. Testing inhibition of CaMKII and CaM revealed similarities and differences of INaL modulation in failing vs. normal myocytes. Similarities: 1) CaMKII slows INaL decay and decreases the amplitude of fast exponential; 2) Ca2+shifts SSI rightward. Differences: 1) slowing INaL by CaMKII is greater; 2) CaM shifts SSI leftward; 3) Ca2+ increases the amplitude of slow exponential.
Ca2+/CaM/CaMKII signaling increases INaL and Na+ influx in both normal and failing myocytes by slowing inactivation kinetics and shifting SSI. This Na+ influx provides a novel Ca2+ positive feedback mechanism (via Na+/Ca2+exchanger), enhancing contractions at higher beating rates, but worsening cardiomyocytes contractile and electrical performance in conditions of poor Ca2+ handling in heart failure.
heart failure; late Na+ current; calcium; arrhythmia
Mitochondrial dysfunction is a major factor in heart failure (HF). A pronounced variability of mitochondrial electron transport chain (ETC) defects is reported to occur in severe acquired cardiomyopathies without a consistent trend for depressed activity or expression. The aim of this study was to define the defect in the integrative function of cardiac mitochondria in coronary microembolization-induced HF.
Methods and results
Studies were performed in the canine coronary microembolization-induced HF model of moderate severity. Oxidative phosphorylation was assessed as the integrative function of mitochondria, using a comprehensive variety of substrates in order to investigate mitochondrial membrane transport, dehydrogenase activity and electron-transport coupled to ATP synthesis. The supramolecular organization of the mitochondrial ETC also was investigated by native gel electrophoresis. We found a dramatic decrease in ADP-stimulated respiration that was not relieved by an uncoupler. Moreover, the ADP/O ratio was normal, indicating no defect in the phosphorylation apparatus. The data point to a defect in oxidative phosphorylation within the ETC. However, the individual activities of ETC complexes were normal. The amount of the supercomplex consisting of complex I/complex III dimer/complex IV, the major form of respirasome considered essential for oxidative phosphorylation, was decreased.
We propose that the mitochondrial defect lies in the supermolecular assembly rather than in the individual components of the ETC.
Heart failure; Mitochondria; Oxidative phosphorylation; Respirasomes; Electron transport chain complexes
Clinical and experimental evidence has recently accumulated about the importance of alterations of Na+ channel (NaCh) function and slow myocardial conduction for arrhythmias in infarcted and failing hearts (HF). The present study evaluated the molecular mechanisms of local alterations in the expression of NaCh subunits which underlie Na+ current (INa) density decrease in HF. HF was induced in 5 dogs by sequential coronary microembolization and developed approximately 3 months after the last embolization (left ventricle, LV, ejection fraction = 27±7%). 5 normal dogs served as a control group. Ventricular cardiomyocytes (VCs) were isolated enzymatically from LV mid-myocardium and INa was measured by whole-cell patch-clamp. The mRNA encoding the cardiac-specific sodium channel (NaCh) α-subunit Nav1.5, and one of its auxiliary subunits β1 (NaChβ1), was analyzed by competitive RT-PCR. Protein levels of Nav1.5, NaChβ1 and NaChβ2 were evaluated by Western blotting. The maximum density of INa/Cm was decreased in HF (n=5) compared to control hearts (32.3±2.6 vs. 50.8±6.5 pA/pF, mean±SEM, n=5, P<0.05). The steady-state inactivation and activation of INa remained unchanged in HF compared to control hearts. The levels of mRNA encoding Nav1.5, and NaChβ1 were unaltered in failing hearts. However, Nav1.5 protein expression was reduced about 30% in HF, while NaChβ1 and NaChβ2 protein were unchanged. We conclude that experimental HF in dogs results in post-transcriptional changes in cardiac NaCh α-subunit expression.
heart failure; sodium channel; β-subunits; patch clamp; RT-PCR; Western blot
Ventricular repolarization and contractile function are frequently abnormal in ventricular myocytes from human failing hearts as well as canine hearts with experimentally induced heart failure (HF). These abnormalities have been attributed to dysfunction involving various steps of the excitation-contraction coupling process, leading to impaired intracellular sodium and calcium homeostasis. We previously reported that the slow inactivating component of the Na+ current (late INa) is augmented in myocytes from failing hearts, and this appears to play a significant role in abnormal ventricular myocytes repolarization and function. We tested the effect of ranolazine, a novel drug being developed to treat angina, on 1) action potential duration (APD), 2) peak transient and late INa (INaT and INaL respectively), 3) early afterdepolarizations (EADs), and 4) twitch contraction (TC) including aftercontractions and contracture.
Myocytes were isolated from the left ventricle of normal dogs and of dogs with chronic HF caused by multiple sequential intracoronary microembolizations. INaT and INaL were recorded using conventional whole-cell patch-clamp techniques. APs were recorded using the β-escin perforated patch-clamp configuration at frequencies of 0.25 and 0.5 Hz. TCs were recorded using an edge movement detector at stimulation frequencies ranging from 0.5 to 2.0 Hz.
Ranolazine significantly (p < 0.05) and reversibly shortened the APD of myocytes stimulated at either 0.5 or 0.25 Hz in a concentration-dependent manner. At a stimulation frequency of 0.5 Hz, 5, 10 and 20 μM ranolazine shortened the APD90 (APD measured at 90% repolarization) from 516 ± 51 to 304 ± 22, 212 ± 34 and 160 ± 11 ms, respectively, and markedly decreased beat-to-beat variability of APD90, EADs and dispersion of APDs. Ranolazine preferentially blocked INaL relative to INaT in a state-dependent manner; with a ~ 38-fold greater potency against INaL to produce tonic block (IC50 = 6.5 μ M) than INaT (IC50 =294 μM). When we evaluated inactivated state blockade of INaL from the steady-state inactivation mid-potential shift using a theoretical model, ranolazine was found to bind more tightly to the inactivated state than the resting state of the sodium channel underlying INaL, with apparent dissociation constants Kdr=7.47μ M and Kdi=1.71μ M, respectively. TCs of myocytes stimulated at 0.5 Hz were characterized by an initial spike followed by a dome-like aftercontraction, which was observed in75% of myocytes from failing hearts and coincided with the long AP plateau and EADs. Ranolazine at 5, and 10 μM reversibly shortened duration of TCs and abolished the aftercontraction. When the rate of myocyte stimulation was increased from 1.0 to 2.0 Hz, there was a progressive increase in diastolic “tension”, i.e., contracture. Ranolazine at 5, and 10 μM reversibly prevented this frequency-dependent contracture.
Heart failure; patch clamp; myocytes; action potential; contraction; late sodium current
Late Na+ current (INaL) in human and dog hearts has been implicated in abnormal repolarization associated with heart failure (HF). HF slows inactivation gating of late Na+ channels, which could contribute to these abnormalities.
To test how altered gating affects INaL time course, Na+ influx, and action potential (AP) repolarization.
INaL and AP were measured by patch clamp in left ventricular cardiomyocytes from normal and failing hearts of humans and dogs. Canine HF was induced by coronary microembolization.
INaL decay was slower and INaL density was greater in failing hearts than in normal hearts at 24°C (human hearts: τ=659±16 vs. 529±21 ms; n=16 and 4 hearts, respectively; mean±SEM; p<0.002; dog hearts: 561±13 vs. 420±17 ms; and 0.307±0.014 vs. 0.235±0.019 pA/pF; n=25 and 14 hearts, respectively; p<0.005) and at 37°C this difference tended to increase. These INaL changes resulted in much greater (53.6%) total Na+ influx in failing cardiomyocytes. INaL was sensitive to cadmium but not to cyanide and exhibited low sensitivity to saxitoxin (IC50=62nM) or tetrodotoxin (IC50=1.2μM) tested in dogs. A 50% INaL inhibition by toxins or passing current opposite to INaL, decreased beat-to-beat AP variability and eliminated early afterdepolarizations in failing cardiomyocytes.
Chronic HF leads to larger and slower INaL generated mainly by the cardiac-type Na+ channel isoform, contributing to larger Na+ influx and AP duration variability. Interventions designed to reduce/normalize INaL represent a potential cardioprotective mechanism in HF via reduction of related Na+ and Ca2+ overload and improvement of repolarization.
heart failure; late Na+ current inactivation; action potential; early afterdepolarizations
Despite accumulating clinical evidence supporting a key role for venous congestion in the development of acute decompensated heart failure (ADHF), there remain several gaps in our knowledge of the pathophysiology of ADHF. Specifically, the biomechanically driven effects of venous congestion on the vascular endothelium (the largest endocrine/paracrine organ of the body), on neurohormonal activation, and on renal and cardiac dysfunction remain largely unexplored. We propose that venous congestion is a fundamental, hemodynamic stimulus for vascular inflammation, which plays a key role in the development and possibly the resolution of ADHF through vascular, humoral, renal, and cardiac mechanisms. A better understanding of the role of venous congestion and endothelial activation in the pathophysiology of ADHF may provide a strong rationale for near-future testing of treatment strategies that target biomechanically driven inflammation. Targeting vascular and systemic inflammation before symptoms arise may prevent progression to overt clinical decompensation in the ADHF syndrome.
Endothelium; Heart failure; Inflammation; Congestion