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1.  Augmentation of Left Ventricular Wall Thickness With Alginate Hydrogel Implants Improves Left Ventricular Function and Prevents Progressive Remodeling in Dogs With Chronic Heart Failure 
JACC. Heart failure  2013;1(3):252-258.
Objectives
The study tested the hypothesis that augmentation of the left ventricular (LV) wall thickness with direct intramyocardial injections of alginate hydrogel implants (AHI) reduces LV cavity size, restores LV shape, and improves LV function in dogs with heart failure (HF).
Background
Progressive LV dysfunction, enlargement, and chamber sphericity are features of HF associated with increased mortality and morbidity.
Methods
Studies were performed in 14 dogs with HF produced by intracoronary microembolizations (LV ejection fraction [EF] <30%). Dogs were randomized to AHI treatment (n = 8) or to sham-operated control (n = 6). During an open-chest procedure, dogs received either intramyocardial injections of 0.25 to 0.35 ml of alginate hydrogel (Algisyl-LVR, LoneStar Heart, Inc., Laguna Hills, California) or saline. Seven injections were made ∼1.0 to 1.5 cm apart (total volume 1.8 to 2.1 ml) along the circumference of the LV free wall halfway between the apex and base starting from the anteroseptal groove and ending at the posteroseptal groove. Hemodynamic and ventriculographic measurements were made before treatment (PRE) and repeated post-surgery for up to 17 weeks (POST).
Results
Compared to control, AHI significantly reduced LV end-diastolic and end-systolic volumes and improved LV sphericity. AHI treatment significantly increased EF (26 ± 0.4% at PRE to 31 ± 0.4% at POST; p < 0.05) compared to the decreased EF seen in control dogs (27 ± 0.3% at PRE to 24 ± 1.3% at POST; p < 0.05). AHI treatment was well tolerated and was not associated with increased LV diastolic stiffness.
Conclusions
In HF dogs, circumferential augmentation of LV wall thickness with AHI improves LV structure and function. The results support continued development of AHI for the treatment of patients with advanced HF.
doi:10.1016/j.jchf.2013.02.006
PMCID: PMC3756288  PMID: 23998003
animal models; congestive heart failure; functional mitral regurgitation; left ventricular function; pressure-volume relationship
2.  Electrical Vagus Nerve Stimulation for the Treatment of Chronic Heart Failure 
Cleveland Clinic journal of medicine  2011;78(0 1):10.3949/ccjm.78.s1.04.
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.
doi:10.3949/ccjm.78.s1.04
PMCID: PMC3817894  PMID: 21972326
Ventricular function; ventricular remodeling; Vagus nerve stimulation; sympathetic activity; parasympathetic activity
3.  Pleiotropic Effects of Long-term Monotherapy with Rosuvastatin in Dogs with Moderate Heart Failure 
Cardiology  2012;123(3):160-167.
Objective
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).
Methods
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.
Results
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.
Conclusion
These pleiotropic effects of RSV may account, in part, for the observed beneficial effect of RSV on LV function and structural remodeling.
doi:10.1159/000342082
PMCID: PMC3544002  PMID: 23128666
Inflammation; Cytokines; Growth factors; Nitric oxide synthase; Hypertrophy; Stem cells
4.  Chronic Therapy with a Partial Adenosine A1 Receptor Agonist, Improves Left Ventricular Function and Remodeling in Dogs with Advanced Heart Failure 
Circulation. Heart failure  2013;6(3):563-571.
Background
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.
Conclusion
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.
doi:10.1161/CIRCHEARTFAILURE.112.000208
PMCID: PMC3790141  PMID: 23564604
Heart failure; Ventricular remodeling; Protein expression; Adenosine receptors
5.  Baroreflex Activation for the Treatment of Heart Failure 
Current cardiology reports  2012;14(3):326-333.
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.
doi:10.1007/s11886-012-0265-y
PMCID: PMC3784338  PMID: 22528555
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
6.  Vagus Nerve Stimulation in Experimental Heart Failure 
Heart failure reviews  2011;16(2):171-178.
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.
doi:10.1007/s10741-010-9209-z
PMCID: PMC3784341  PMID: 21128115
Ventricular function; Ventricular remodeling; Electrical nerve stimulation; Sympathetic activity; Parasympathetic activity; Animal models of disease; Cytokines; Nitric oxide
7.  Chronic Electrical Stimulation of the Carotid Sinus Baroreflex Improves LV Function and Promotes Reversal of Ventricular Remodeling in Dogs with Advanced Heart Failure 
Circulation. Heart failure  2010;4(1):65-70.
Background
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.
Conclusions
In dogs with advanced HF, CSB activation improves global LV function and partially reverses LV remodeling both globally and at cellular and molecular levels.
doi:10.1161/CIRCHEARTFAILURE.110.955013
PMCID: PMC3048958  PMID: 21097604
heart failure; ventricular remodeling; gene expression; baroreflex function
8.  Comparison of Beta Blocker Effectiveness in Heart Failure Patients with Preserved Ejection Fraction vs. those with Reduced Ejection Fraction 
Journal of cardiac failure  2013;19(2):73-79.
Background
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).
Conclusion
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.
doi:10.1016/j.cardfail.2012.11.011
PMCID: PMC3678365  PMID: 23384631
beta adrenergic receptor blocker; hospitalization; diastolic dysfunction; heart failure with preserved ejection fraction
9.  Venous Congestion and Endothelial Cell Activation in Acute Decompensated Heart Failure 
Current heart failure reports  2010;7(2):10.1007/s11897-010-0009-5.
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.
doi:10.1007/s11897-010-0009-5
PMCID: PMC3874714  PMID: 20424989
Endothelium; Heart failure; Inflammation; Congestion
10.  Atenolol Is Inferior to Metoprolol in Improving Left Ventricular Function and Preventing Ventricular Remodeling in Dogs with Heart Failure 
Cardiology  2008;112(4):294-302.
Objectives
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%].
Methods
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.
Results
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).
Conclusions
In HF dogs, chronic therapy with atenolol does not elicit the same LV function and remodeling benefits as those achieved with metoprolol succinate.
doi:10.1159/000159123
PMCID: PMC2917737  PMID: 18832825
Heart failure; Myocyte hypertrophy; Ventricular remodeling; Gene expression
11.  Cyclosporine A Attenuates Mitochondrial Permeability Transition and Improves Mitochondrial Respiratory Function in Cardiomyocytes Isolated from Dogs With Heart Failure 
Objective
We used isolated cardiomyocytes to investigate a possible role of mitochondrial permeability transition pore in mitochondrial abnormalities associated with heart failure.
Methods
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.
Results
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%.
Conclusions
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.
doi:10.1016/j.yjmcc.2006.09.013
PMCID: PMC2700715  PMID: 17070837
Permeability transition; Heart failure; Mitochondria
12.  Left Atrial Reverse Remodeling in Dogs with Moderate and Advanced Heart Failure Treated with A Passive Mechanical Containment Device: An Echocardiographic Study 
Journal of cardiac failure  2007;13(4):312-317.
Background
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.
Conclusions
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.
doi:10.1016/j.cardfail.2007.01.006
PMCID: PMC1939806  PMID: 17517352
Atrium; Echocardiography; Heart failure; Heart-assist device
13.  Association of Arginine Vasopressin Levels with Outcomes and the Effect of V2 Blockade in Patients Hospitalized for Heart Failure with Reduced Ejection Fraction: Insights from the EVEREST Trial 
Circulation. Heart failure  2012;6(1):47-52.
Background
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).
Conclusions
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.
doi:10.1161/CIRCHEARTFAILURE.112.970012
PMCID: PMC3790140  PMID: 23239836
heart failure; drugs; hormones; outcomes
14.  Beneficial Effects of the CorCap Cardiac Support Device: 5 Year results from the Acorn Trial 
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.jtcvs.2011.06.014
PMCID: PMC3790142  PMID: 21762937
15.  Genome-wide Approach to Identify Novel Candidate Genes for Beta Blocker Response in Heart Failure Using an Experimental Model 
Discovery medicine  2011;11(59):359-366.
Background
We explored use of a canine model of heart failure (HF) for pharmacogenomic discovery, specifically analyzing response to beta blockers (BB)
Methods
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.
Results
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.
Conclusion
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.
PMCID: PMC3725612  PMID: 21524389
16.  Calpain Inhibition Reduces Amplitude and Accelerates Decay of the Late Sodium Current in Ventricular Myocytes from Dogs with Chronic Heart Failure 
PLoS ONE  2013;8(4):e54436.
Calpain is an intracellular Ca2+ -activated protease that is involved in numerous Ca2+ dependent regulation of protein function in many cell types. This paper tests a hypothesis that calpains are involved in Ca2+ -dependent increase of the late sodium current (INaL) in failing heart. Chronic heart failure (HF) was induced in 2 dogs by multiple coronary artery embolization. Using a conventional patch-clamp technique, the whole-cell INaL was recorded in enzymatically isolated ventricular cardiomyocytes (VCMs) in which INaL was activated by the presence of a higher (1μM) intracellular [Ca2+] in the patch pipette. Cell suspensions were exposed to a cell- permeant calpain inhibitor MDL-28170 for 1–2 h before INaL recordings. The numerical excitation-contraction coupling (ECC) model was used to evaluate electrophysiological effects of calpain inhibition in silico. MDL caused acceleration of INaL decay evaluated by the two-exponential fit (τ1 = 42±3.0 ms τ2 = 435±27 ms, n = 6, in MDL vs. τ1 = 52±2.1 ms τ2 = 605±26 control no vehicle, n = 11, and vs. τ1 = 52±2.8 ms τ2 = 583±37 ms n = 7, control with vehicle, P<0.05 ANOVA). MDL significantly reduced INaL density recorded at –30 mV (0.488±0.03, n = 12, in control no vehicle, 0.4502±0.0210, n = 9 in vehicle vs. 0.166±0.05pA/pF, n = 5, in MDL). Our measurements of current-voltage relationships demonstrated that the INaL density was decreased by MDL in a wide range of potentials, including that for the action potential plateau. At the same time the membrane potential dependency of the steady-state activation and inactivation remained unchanged in the MDL-treated VCMs. Our ECC model predicted that calpain inhibition greatly improves myocyte function by reducing the action potential duration and intracellular diastolic Ca2+ accumulation in the pulse train.
Conclusions
Calpain inhibition reverses INaL changes in failing dog ventricular cardiomyocytes in the presence of high intracellular Ca2+. Specifically it decreases INaL density and accelerates INaL kinetics resulting in improvement of myocyte electrical response and Ca2+ handling as predicted by our in silico simulations.
doi:10.1371/journal.pone.0054436
PMCID: PMC3626653  PMID: 23596505
17.  Targeting myocardial substrate metabolism in heart failure: potential for new therapies 
European Journal of Heart Failure  2012;14(2):120-129.
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.
doi:10.1093/eurjhf/hfr173
PMCID: PMC3260022  PMID: 22253453
Energetics; Cardiac metabolism; AMP-activated kinase; Heart failure
18.  High intake of saturated fat, but not polyunsaturated fat, improves survival in heart failure despite persistent mitochondrial defects 
Cardiovascular Research  2011;93(1):24-32.
Aims
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.
Conclusion
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.
doi:10.1093/cvr/cvr258
PMCID: PMC3243037  PMID: 21960686
Cardiomyopathy; Low-carbohydrate diet; Metabolism; Obesity
19.  Late Sodium Current Contributes to Diastolic Cell Ca2+ Accumulation in Chronic Heart Failure 
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.
doi:10.1007/s12576-010-0092-0
PMCID: PMC2891122  PMID: 20490740
Action potential remodeling; Ca2+ handling; Heart failure; Na+ current; Na+/Ca2+ exchange
20.  Effect of adjustable passive constraint on the failing left ventricle: A finite element model study 
The Annals of thoracic surgery  2010;89(1):132-137.
Background
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.
Methods
“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.”
Results
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).
Conclusion
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.
doi:10.1016/j.athoracsur.2009.08.075
PMCID: PMC2844501  PMID: 20103222
Passive constraint device; wall stress; pump function
21.  Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction 
Cardiovascular Research  2008;81(2):319-327.
Aims
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.
Conclusion
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.
doi:10.1093/cvr/cvn310
PMCID: PMC2721645  PMID: 19015135
α-linolenic acid; Diet; Docosahexaenoic acid; Eicosapentaenoic acid; Heart failure
22.  Agents with inotropic properties for the management of acute heart failure syndromes. Traditional agents and beyond 
Heart Failure Reviews  2009;14(4):243-253.
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.
doi:10.1007/s10741-009-9153-y
PMCID: PMC2772951  PMID: 19876734
Acute heart failure; Advanced chronic heart failure; Inotropic agents; Prognosis; Istaroxime; Omecamtiv mecarbil
23.  Short term effects of milrinone on biomarkers of necrosis, apoptosis, and inflammation in patients with severe heart failure 
Introduction
Inotropes are associated with adverse outcomes in heart failure (HF), raising concern they may accelerate myocardial injury. Whether biomarkers of myocardial necrosis, inflammation and apoptosis change in response to acute milrinone administration is not well established.
Methods
Ten patients with severe HF and reduced cardiac output who were to receive milrinone were studied. Blood samples were taken just before initiation of milrinone and after 24 hours of infusion. Dosing was at the discretion of the patient's attending physician (range 0.25–0.5 mcg/kg/min). Plasma measurements of troponin, myoglobin, N-terminal-pro-BNP, interleukin-6, tumor necrosis factor-α, soluble Fas, and soluble Fas-ligand were performed at both time points.
Results
Troponin was elevated at baseline in all patients (mean 0.1259 ± 0.17 ng/ml), but there was no significant change after 24 hours of milrinone (mean 0.1345 ± 0.16 ng/ml, p = 0.44). There were significant improvements in interleukin-6, tumor necrosis factor-α, soluble Fas, and soluble Fas-ligand (all p < 0.05) indicative of reduced inflammatory and apoptotic signaling compared to baseline.
Conclusion
In conclusion, among patients with severe HF and low cardiac output, ongoing myocardial injury is common, and initiation of milrinone did not result in exacerbation of myocardial injury but instead was associated with salutary effects on other biomarkers.
doi:10.1186/1479-5876-7-67
PMCID: PMC2724498  PMID: 19640280
24.  Modulation of the late sodium current by Ca2+, calmodulin, and CaMKII in normal and failing dog cardiomyocytes: similarities and differences 
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1152/ajpheart.00484.2007
PMCID: PMC2376056  PMID: 18203851
heart failure; late Na+ current; calcium; arrhythmia
25.  Cardiac mitochondria in heart failure: decrease in respirasomes and oxidative phosphorylation 
Cardiovascular Research  2008;80(1):30-39.
Aims
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.
Conclusions
We propose that the mitochondrial defect lies in the supermolecular assembly rather than in the individual components of the ETC.
doi:10.1093/cvr/cvn184
PMCID: PMC2533423  PMID: 18710878
Heart failure; Mitochondria; Oxidative phosphorylation; Respirasomes; Electron transport chain complexes

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