George Suzuki

Reversal of Chronic Molecular and Cellular Abnormalities Due to Heart Failure by Passive Mechanical Ventricular Containment

Abstract— Passive mechanical containment of failing left ventricle (LV) with the Acorn Cardiac Support Device (CSD) was shown to prevent progressive LV dilation in dogs with heart failure (HF) and increase ejection fraction. To examine possible mechanisms for improved LV function with the CSD, we examined the effect of CSD therapy on the expression of cardiac stretch response proteins, myocyte hypertrophy, sarcoplasmic reticulum Ca2+-ATPase activity and uptake, and mRNA gene expression for myosin heavy chain (MHC) isoforms. HF was produced in 12 dogs by intracoronary microembolization. Six dogs were implanted with the CSD and 6 served as concurrent controls. LV tissue from 6 normal dogs was used for comparison. Compared with normal dogs, untreated HF dogs showed reduced cardiomyocyte contraction and relaxation, upregulation of stretch response proteins (p21ras, c-fos, and p38 &agr;/&bgr; mitogen-activated protein kinase), increased myocyte hypertrophy, reduced SERCA2a activity with unchanged affinity for calcium, reduced proportion of mRNA gene expression for &agr;-MHC, and increased proportion of &bgr;-MHC. Therapy with the CSD was associated with improved cardiomyocyte contraction and relaxation, downregulation of stretch response proteins, attenuation of cardiomyocyte hypertrophy, increased affinity of the pump for calcium, and restoration of &agr;- and &bgr;-MHC isoforms ratio. The results suggest that preventing LV dilation and stretch with the CSD promotes downregulation of stretch response proteins, attenuates myocyte hypertrophy and improves SR calcium cycling. These data offer possible mechanisms for improvement of LV function after CSD therapy.

Effects of long-term therapy with bosentan on the progression of Left ventricular dysfunction and remodeling in dogs with heart failure

OBJECTIVES In this study, we examined the effects of long-term therapy with bosentan on the progression of LV dysfunction and remodeling in dogs with moderate HF. BACKGROUND Acute intravenous administration of bosentan, a mixed endothelin-1 type A and type B receptor antagonist, was shown to improve left ventricular (LV) function in patients and dogs with heart failure (HF). METHODS Left ventricular dysfunction was induced by multiple, sequential intracoronary microembolizations in 14 dogs. Embolizations were discontinued when LV ejection fraction (EF) was between 30% and 40%. Dogs were randomized to three months of therapy with bosentan (30 mg/kg twice daily, n = 7) or no therapy at all (control, n = 7). RESULTS In untreated dogs, EF decreased from 35 +/- 1% before initiating therapy to 29 +/- 1% at the end of three months of therapy (p = 0.001), and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 71 +/- 3 vs. 84 +/- 8 ml, p = 0.08; ESV: 46 +/- 2 vs. 60 +/- 6 ml, p = 0.03). By contrast, in dogs treated with bosentan, EF tended to increase from 34 +/- 2% before initiating therapy to 39 +/- 1% at the end of three months of therapy (p = 0.06), and EDV and ESV decreased (EDV: 75 +/- 3 vs. 71 +/- 4 ml, p = 0.05; ESV: 48 +/- 2 vs. 43 +/- 3 ml, p = 0.01). Furthermore, compared with untreated dogs, dogs treated with bosentan showed significantly less LV cardiomyocyte hypertrophy and LV volume fraction of interstitial fibrosis. CONCLUSIONS In dogs with moderate HF, long-term therapy with bosentan prevents the progression of LV dysfunction and attenuates LV chamber remodeling. The findings support the use of mixed endothelin-1 receptor antagonists as adjuncts to the long-term treatment of HF.

Hypoxia, angiotensin-II, and norepinephrine mediated apoptosis is stimulus specific in canine failed cardiomyocytes: a role for p38 MAPK, Fas-L and cyclin D1.

Apoptosis may contribute to the myocardial dysfunction associated with heart failure (HF). Activation of the p38 MAPK cascade can induce apoptosis in non‐cardiac cells through increased expression of Fas‐L, or through decreased expression of cyclin D1.

Effects of Long-Term Monotherapy with Metoprolol CR/XL on the Progression of Left Ventricular Dysfunction and Remodeling in Dogs with Chronic Heart Failure

We examined the effects of long-term monotherapy with the beta-blocker, metoprolol controlled release/extended release (CR/XL), on the progression of LV dysfunction as well as on global and cellular remodeling in dogs with heart failure (HF). Chronic HF was produced by intracoronary microembolizations that were discontinued when LV ejection fraction (EF) was between 30% and 40%. Dogs were randomized to 3 months oral monotherapy with metoprolol CR/XL (100 mg once daily, n = 7) or no therapy at all (control, n = 7). In control dogs, EF decreased from 38 ± 1% to 31 ± 2% (p = 0.002), and LV end-systolic volume (ESV) and LV end-diastolic volume (EDV) increased (37 ± 2 vs 45 ± 2 ml, p = 0.001; 59 ± 3 vs 65 ± 3 ml, p = 0.001; respectively) during the 3 month follow-up period. In dogs treated with metoprolol CR/XL, EF increased after 3 months from 36 ± 1% to 43 ± 1% (p = 0.001), and ESV decreased (42 ± 2 vs 38 ± 2 ml, p = 0.003), whereas EDV remained unchanged. Compared to controls, treatment with metoprolol CR/XL showed 46% reduction in replacement fibrosis, 54% reduction in interstitial fibrosis and 20% reduction in myocyte cross-sectional area, a measure of myocyte hypertrophy. These findings indicate that metoprolol CR/XL improves LV function and attenuates progressive global and cellular LV remodeling in dogs with HF. The benefits are fully attributable to β-blockade alone as no other adjunctive therapy was used.

Hemodynamic unloading of the failing left ventricle using an arterial-to-arterial extracorporeal flow circuit

We tested the hypothesis that creation of a constant-flow extracorporeal circuit between the proximal and distal aorta will unload the failing left ventricle. Studies were performed in 14 heart failure dogs produced by intracoronary microembolizations. An extracorporeal circuit incorporating a diagonal pump was placed between a femoral and a carotid artery, with flow directed to the carotid. Hemodynamic measurements were made with the pump delivering 0.25 L/min through the circuit for 4 hours (active group). Measurements obtained from 8 sham-operated heart failure dogs were used for comparison (control group). Heart rate, peak left ventricular systolic pressure, left ventricular end-diastolic pressure, end-diastolic volume, end-systolic volume, and ejection fraction were measured at baseline and at 30, 60, 120, and 240 minutes. There were no differences in any of the hemodynamic values during the 4 hours of follow-up in the control group. In the active group, there was no effect on heart rate or peak systolic pressure, but reductions between baseline and 240 minutes were observed in left ventricular end-diastolic pressure (15 +/- 1 vs 6 +/- 1 mm Hg, p < 0.05), end-diastolic volume (61 +/- 3 vs 50 +/- 3 mL, p < 0.05), and end-systolic volume (44 +/- 2 vs 32 +/- 2 mL, p < 0.05), and an increase in ejection fraction (28 +/- 2 vs 37% +/- 2%, p < 0.05). Acute use of this artery-to-artery extracorporeal system effectively unloads the failing left ventricle. The potential benefits of this approach on long-term myocardial recovery in heart failure require further investigation.

Effects of the AT1-receptor antagonist eprosartan on the progression of left ventricular dysfunction in dogs with heart failure.

We examined the effects of eprosartan, an AT1 receptor antagonist, on the progression of left ventricular (LV) dysfunction and remodelling in dogs with heart failure (HF) produced by intracoronary microembolizations (LV ejection fraction, EF 30 to 40%). Dogs were randomized to 3 months of oral therapy with low‐dose eprosartan (600 mg once daily, n=8), high‐dose eprosartan (1200 mg once daily, n=8), or placebo (n=8). In the placebo group, LV end‐diastolic (EDV) and end‐systolic (ESV) volumes increased after 3 months (68±7 vs 82±9 ml, P<0.004, 43±1 vs 58±7 ml, P<0.003, respectively), and EF decreased (37±1 vs 29±1%, P<0.001). In dogs treated with low‐dose eprosartan, EF, EDV, and ESV remained unchanged over the course of therapy, whereas in dogs treated with high‐dose eprosartan, EF increased (38±1 vs 42±1%, P<0.004) and ESV decreased (41±1 vs 37±1 ml, P<0.006), Eprosartan also decreased interstitial fibrosis and cardiomyocyte hypertrophy. We conclude that eprosartan prevents progressive LV dysfunction and attenuates progressive LV remodelling in dogs with moderate HF and may be useful in treating patients with chronic HF.

Effects of Chronic Neutral Endopeptidase Inhibition on the Progression of Left Ventricular Dysfunction and Remodeling in Dogs with Moderate Heart Failure

AbstractBackground. 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. Methods. 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). Results. 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. Conclusion. Early, long-term NEP inhibition with ecadotril prevents the progression of LV dysfunction and attenuates progressive LV remodeling in dogs with moderate heart failure.