Left Ventricular Remodeling In Dogs Research Articles

Effects of Protective Controlled Coronary Reperfusion on Left Ventricular Remodeling in Dogs With Acute Myocardial Infarction: A Pilot Study

BackgroundCoronary artery obstruction causes ischemia of cardiac tissue, leading to acute myocardial infarction (AMI). The treatment of choice for reducing acute myocardial ischemic injury is early, effective vascular reperfusion using thrombolytic therapy or primary percutaneous coronary intervention. However, reperfusion can cause cardiomyocyte injury. Currently, there is no effective therapy to prevent cardiac reperfusion-related tissue damage. This study evaluated whether Protective Controlled Coronary Reperfusion (PCCR), selectively delivered to ischemic tissue, is associated with decreased myocardial scarring, contractile deterioration and reperfusion-associated myocardial edema. MethodsThree hours of cardiac ischemia was induced in 10 mongrel dogs, and followed by either 30-minute PCCR or sham treatment. Cardiac performance was evaluated 2, 4 and 6 months later. Trichrome staining was used to distinguish collagen from viable myocardial tissue and to evaluate mean scar area. ResultsOne hour following reperfusion, PCCR significantly attenuated the relative increase (edema) in left ventricular end diastolic posterior wall thickness compared with sham treatment. At 6 months follow-up, the PCCR group showed a modest corrected increase in left ventricular ejection fraction (c∆LVEF) in comparison to the sham group where it deteriorated (2.3 ± 10.5% vs. −16.4 ± 10.3%, respectively, p = 0.043). Histomorphometric assessments of the hearts showed the PCCR group had smaller area of scarring, as compared to sham-treated animals (9.0 ± 2.4% vs. 14.0 ± 3.3%, p = 0.047). ConclusionsIn this pilot study, PCCR reduced myocardial edema, modestly increased in c∆LVEF and resulted in a smaller scar area. Further studies are needed to fully ascertain the mechanisms that underlie the potential benefits of PCCR therapy prior to initiating clinical trials in human subjects with AMI.

Abstract 309: Long-Term Therapy with Ivabradine Increases ACE-2 Activity in Left Ventricular Myocardium of Dogs with Chronic Heart Failure

Background: Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE. ACE2 removes the terminal amino-acid from angiotensin-II (Ang II) to form Ang(1-7) which antagonizes the effects of Ang-II by activating the Mas receptor. We showed that ivabradine (IVA), a novel inhibitor of the cardiac pacemaker current I f , improves left ventricular (LV) function and prevents progressive LV remodeling in dogs with microembolization-induced heart failure (HF). Because RAAS system overactivity contributes to the progression of HF, we assessed changes in Ang-II level and ACE and ACE2 activity in LV of dogs treated with IVA. Methods: Studies were performed in LV tissue from 24 HF dogs randomized to 3 months therapy with high dose (HD) IVA (30 mg twice daily, n=8), low dose (LD) IVA (15 mg twice daily, n=8) or to no therapy at all (Control, CON, n=8). LV tissue from 6 normal (NL) dogs was used for comparison. A fluorogenic peptide, captopril (ACE inhibitor) and DX600 (ACE2 inhibitor) were used to quantify the activity of ACE and ACE2 in LV homogenate. Activity was expressed as fluorescence unit (FU)/μ g protein/hour. Ang II level was determined by ELISA. Results: IVA reduced heart rate (HR) and significantly increased LV ejection fraction in a dose-dependent manner. Ang II level and ACE and ACE2 activities were up-regulated in HF CON compared to NL dogs. Compared to CON, treatment with IVA reduced ACE activity and Ang II level but increased ACE2 activity in a dose-dependent manner (Table). Conclusions: In dogs with HF, therapy with IVA reduces activation of ACE and Ang II level but increases activation of ACE2. The latter may contribute to the observed beneficial effects of IVA on LV function and remodeling in HF.

Chronic electrical stimulation of the carotid sinus baroreflex improves left ventricular function and promotes reversal of ventricular remodeling in dogs with advanced heart failure.

Autonomic abnormalities exist in heart failure 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 electric activation of the CSB improves left ventricular (LV) function and attenuates progressive LV remodeling in dogs with advanced chronic heart failure. Studies were performed in 14 dogs with coronary microembolization-induced heart failure (LV ejection fraction ≈25%). Eight dogs were chronically instrumented for bilateral CSB activation using the Rheos System (CVRx Inc, Minneapolis, Minn) 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 ejection fraction 4.0±2.4% compared with 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 with an increase in control dogs of 6.7±2.9 mL (P<0.05). Compared with control, CSB activation significantly decreased LV end-diastolic pressure and circulating plasma norepinephrine, normalized expression of cardiac β(1)-adrenergic receptors, β-adrenergic receptor kinase, and nitric oxide synthase and reduced interstitial fibrosis and cardiomyocyte hypertrophy. In dogs with advanced heart failure, CSB activation improves global LV function and partially reverses LV remodeling both globally and at cellular and molecular levels.

Abstract 3295: De-induction of the Maladaptive Fetal Gene Program During Chronic Monotherapy with Metoprolol Succinate is Retained Following Withdrawal of Therapy in Dogs with Chronic Heart Failure

Background: Chronic therapy with extended release metoprolol succinate (MET), a selective β1 adrenergic receptor blocker, improves left ventricular (LV) function and attenuates global LV remodeling in dogs with chronic heart failure (HF). We previously showed that chronic therapy with β-blockade results in de-induction of the fetal gene program (FGP) in LV myocardium of dogs with HF. In this study, we tested the hypothesis that in dogs with HF withdrawal of chronic MET does not lead to re-induction of FGP. Methods: Studies were performed in 17 intracoronary microembolization-induced HF dogs randomized to 3 months oral therapy with MET (100 mg, once daily, n=11) or no therapy at all (Controls, n=6). In dogs randomized to MET, 6 were sacrificed after 3 months of therapy and in the remaining 5, MET was withdrawn after 3 months of therapy and dogs were observed for 6 weeks after withdrawal of MET (MET-W) and then sacrificed. LV tissue was also obtained from 6 normal (NL) dogs for comparison. mRNA expression of the FGP genes namely, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), sarcoplasmic reticulum calcium ATPase (CAA), cardiac β-1 adren-ergic receptor (AR) and α-myosin heavy chain isoform (α-MHC) was measured using reverse transcriptase polymerase chain reaction (RT-PCR) and bands were quantified in densitometric units (du). Results: In Controls, mRNA expression of ANP and BNP increased and expression of CAA, β 1-AR and α-MHC decreased. Treatment with MET decreased expression of ANP and BNP and increased expression of CAA, β 1-AR and α-MHC. Except for α-MHC, the improvement in FGP seen during MET treatment was preserved in MET-W dogs. Conclusions: Withdrawal of MET is associated with sustained de-induction of the FGP in LV myocardium of dogs with HF. This observation supports the concept that chronic β-blockade therapy in HF confers lasting reversal of LV remodeling and molecular recovery of the failing myocardium.

Left Atrial Reverse Remodeling in Dogs With Moderate and Advanced Heart Failure Treated With a Passive Mechanical Containment Device: An Echocardiographic Study

Assessment of global left ventricular (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, although 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 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. 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 < or = 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 before CSD implantation and at the end of the treatment period. Treatment effect (delta) comparisons between CSD-treated dogs and controls showed that CSD therapy significantly decreased LA volumes (deltaLAVmax: 3.33 +/- 0.70 vs. -2.87 +/- 1.31 mL, P = .002; 7.77 +/- 1.76 versus -0.37 +/- 0.87 mL, P = .002) and improved LA function (deltaLAAEF: -6.00 +/- 1.53 versus 1.85 +/- 1.32%, P = .003; -2.39 +/- 1.10 versus 3.13 +/- 1.66%, P = .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 or reversal of adverse LA remodeling.

Long-term Pharmacological Activation of PPARγDoes not Prevent Left Ventricular Remodeling in Dogs with Advanced Heart Failure

Peroxisome proliferator-activated receptor gamma (PPARgamma) activators affect the myocardium through inhibition of inflammatory cytokines and metabolic modulation but their effect in the progression of heart failure is unclear. In the present study, we examined the effects of the PPARgamma activator, GW347845 (GW), on the progression of heart failure. Heart failure was produced in 21 dogs by intracoronary microembolizations to LV ejection fraction (EF) less than 30% and randomized to 3 months of therapy with high-dose GW (10 mg/Kg daily, n = 7), low-dose GW (3 mg/Kg daily, n = 7), or no therapy (control, n = 7). In control dogs, EF significantly decreased (28 +/- 1 vs. 22 +/- 1%, p < 0.001) and end-diastolic volume (EDV) and end-systolic volume (ESV) increased during the 3 months of the follow-up period (64 +/- 4 vs. 76 +/- 5; p = 0.003, 46 +/- 3 vs. 59 +/- 4 ml, p = 0.002, respectively). In dogs treated with low-dose GW, EDV increased significantly (69 +/- 4 vs.81 +/- 5 ml, p = 0.01), whereas ESV remained statistically unchanged (50 +/- 3 vs. 54 +/- 3 ml, p = 0.10) resulting in modestly increased ejection fraction (27 +/- 1 vs. 32 +/- 3%, p = 0.05). In dogs treated with high-dose GW, both EDV and ESV increased (72 +/- 4 vs. 79 +/- 5 ml, p = 0.04; 53 +/- 3 vs. 62 +/- 5 ml, p = 0.04) and EF decreased (26 +/- 1 vs. 23 +/- 1%, p = 0.04) as with control dogs. There was significantly increased myocardial hypertrophy as evidenced by increased LV weight to body weight ratio and myocyte cross-section area in the GW treated animals compared to controls. Compared to control, treatment with GW had no effect on mRNA expression of PPARgamma, inflammatory cytokines, stretch response proteins, or transcription factors that may induce hypertrophy. Long-term PPARgamma activation with GW did not prevent progressive LV remodeling in dogs with advanced heart failure.

PPARs of the Heart

The peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors within the broad nuclear receptor superfamily. The PPAR family includes three members encoded by distinct genes: α, β/δ, and γ (see reviews1,2). PPARα was originally identified as the intracellular receptor for a class of nongenotoxic rodent hepatocarcinogens, which includes the hypolipidemic drug clofibrate, a potent inducer of hepatic peroxisomal proliferation and hypolipidemic agent. The three PPARs are now distinguished by tissue- and developmental-specific patterns of expression and by the distinct, albeit overlapping, nature of ligands capable of activating each receptor. PPARα, which is abundant in tissues with high rates of mitochondrial fatty acid oxidation, such as heart, liver, and kidney, regulates a wide variety of target genes involved in cellular lipid catabolism. In contrast, PPARγ, an adipose-enriched nuclear receptor, directs the expression of genes involved in adipocyte differentiation and fat storage. The function of the ubiquitously expressed PPARβ/δ, is not well understood although some evidence suggests that it exerts actions on the epidermis and activates antiinflammatory programs. Ligand activation of PPARs leads to obligate heterodimerization with the 9- cis retinoic acid-activated receptor, RXR, promoting binding of the complex to cognate DNA response elements within PPAR target gene promoter regions (Figure). A variety of natural and synthetic compounds including fatty acids, eicosanoids, and arachidonic acid derivatives can serve as activators of the PPARs, some in a receptor-specific manner. However, the true endogenous ligands have not been identified. PPAR transcriptional regulatory complex. PPARs bind to sequence-specific target elements (PPREs) as a liganded heterodimer with the retinoid X receptor (RXR). Major functions based on known target genes and examples of relevant tissues (in parentheses) for each member of the PPAR family are shown. The question mark indicates that target genes for PPARβ/δ are largely unidentified. PPARα has been shown to …

Effects of chronic neutral endopeptidase inhibition on the progression of left ventricular dysfunction and remodeling in dogs with moderate heart failure.

The diuretic actions of endogenously produced atrial natriuretic factor (ANF) may be beneficial in the treatment of chronic heart failure (CHF). Neutral endopeptidase (NEP) is the primary enzyme responsible for the degradation of ANF. The present study investigates the effects of long-term NEP inhibition on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure. LV dysfunction was produced in 12 dogs by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LV ejection fraction (EF) was between 30-40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with the NEP inhibitor ecadotril (100 mg, once daily, n = 6) or to no therapy at all (control, n = 6). During the 3 months of follow-up, LV EF in control dogs decreased from 37 +/- 1% to 28 +/- 1% (P < 0.01) and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 72 +/- 3 vs. 84 +/- 5 ml, P < 0.01); ESV: 45 +/- 1 vs. 60 +/- 4 ml, P < 0.01). In dogs treated with ecadotril, LV EF (34 +/- 1% vs. 37 +/- 2%), EDV (79+/- 5 vs. 78+/- 6 ml) and ESV (52 +/- 3 vs. 49 +/- 4) remained essentially unchanged after 3 months of therapy. Histomorphometric measurements at the termination of the study showed that ecadotril was associated with significantly reduced cardiomyocyte hypertrophy compared to control. Early, long-term NEP inhibition with ecadotril prevents the progression of LV dysfunction and attenuates progressive LV remodeling in dogs with moderate heart failure.

Ventricular remodeling: insights from pharmacologic interventions with angiotensin-converting enzyme inhibitors.

Structural remodeling of the left ventricular (LV) myocardium develops in a time-dependent fashion following acute myocardial infarction and may be an integral component in the transition toward overt heart failure. Globally, the remodeling process is characterized by progressive LV enlargement and increased chamber sphericity. At the cellular level, the remodeling process is associated with myocyte slippage, hypertrophy, and accumulation of collagen in the interstitial compartment. In the present study, we examined the effects of early, long-term monotherapy with the angiotensin converting enzyme (ACE) inhibitor, enalapril, on the progression of LV remodeling in dogs with LV dysfunction (ejection fractions 30-40%) produced by multiple sequential intracoronary microembolizations. Dogs were randomized to 3 months oral therapy with enalapril (n = 7) or to no treatment (n = 7). In untreated dogs, LV end-systolic volume index (ESVI), end-diastolic volume index (EDVI) and chamber sphericity increased significantly during the 3 months follow-up period. In contrast, in dogs treated with enalapril ESVI, EDVI and chamber sphericity remained essentially unchanged. Treatment with enalapril attenuated myocyte hypertrophy and the accumulation of interstitial collagen in comparison to untreated dogs. These data indicate that early treatment with ACE inhibitors can prevent the progression of LV remodeling in dogs with LV dysfunction. Afterload reduction, inhibition of direct action of angiotensin-II and possibly the decrease in bradykinin degradation elicited by ACE inhibition may act in concert in preventing the progression LV chamber remodeling.