Long-term therapy with elamipretide normalizes activation of the mitochondrial signal transducer and activator of transcription 3 (mstat3) in of left ventricular myocardium of dogs with chronic heart failure

Introduction: The signal transducer and activator of transcription 3 (STAT3) has been identified in mitochondria (MITO) of cardiomyocytes (mSTAT3). In STAT3 -/- cells, the activities of MITO complexes I and II of the electron transport chain (ETC) were reduced suggesting that mSTAT3 is required for optimal ETC function. Deactivation of STAT3, equated with dephosphorylation of tyrosine residues, has been shown to adversely impacted MITO respiration and, consequently, oxidative phosphorylation. We previously showed that long-term (3 months) therapy with elamipretide (ELAM, previously referred to as Bendavia TM, MTP131 or SS31), a novel MITO-targeting peptide, improves LV function and normalizes MITO respiration and rate of ATP synthesis in MITO of LV myocardium of dogs with heart failure (HF). Hypothesis: This study tested the hypothesis that phosphorylation of mSTAT3 (mpSTAT3) is reduced in MITO of LV myocardium of HF dogs and is restored after long-term therapy with ELAM. Methods: LV tissue was obtained from 14 dogs with microembolization-induced HF (LV ejection fraction ∼30%) randomized to 3 months therapy with subcutaneous injections of ELA (0.5 mg/kg once daily, n=7) or saline (Control, n=7). LV tissue from 6 normal (NL) dogs was used for comparison. Protein levels of mSTAT3 and mpSTAT3 were determined in MITO fraction by Western blotting coupled with chemiluminiscence and band intensity was quantified in densitometric units (du). Results: Protein level of mSTAT3 was 0.82±0.05 du in NL, decreased to 0.29±0.03 du in Controls (p Conclusions: mpSTAT3 level is reduced in MITO from LV of HF dogs and restored after chronic therapy with ELAM. Normalization of mpSTAT3 by ELAM likely contributed to be observed improvement in MITO function following therapy with ELAM in HF dogs

Evaluation of the influence of leaflet stiffening on leaflet stresses of porcine bioprosthetic valves using a finite element model

AbstractThe magnitude and distribution of mechanical stresses acting on the closed cusps of porcine bioprosthetic valves were estimated using a finite element model. Leaflet stresses were calculated using reported stress-strain properties of glutaraldehyde processed normal porcine valves and stress-strain properties of porcine valve leaflets stiffened by fatigue cycling (658 x 10 cycles). In the normal leaflet, at a pressure of 80 mm Hg, stresses were highest near the commissures (140 kPa), decreased near the center of the leaflet (110 kPa) and were lowest near the base of the leaflet (30 kPa). With increased leaflet stiffening, stresses near the commissures remained relatively unchanged (140 kPa). Stresses near the center of the leaflet, however, increased markedly (170 kPa). With increased leaflet stiffening, stresses near the base of the leaflet remained the lowest (60 kPa). The development of a site of stress concentration near the center of the leaflet following leaflet stiffening, may offer a clue to the etiology of leaflet perforations reported to occur in the central region of leaflets of degenerated porcine bioprosthetic valves

The Pulmonary Component of the Second Sound in Right Ventricular Failure

Sound within the pulmonary artery was measured in 24 patients to determine if right ventricular failure modifies the amplitude of the pulmonary component of the second sound (P2). The amplitude of P2 in eight patients with right ventricular failure secondary to pulmonary hypertension (2610 ± 370 dynes/cm2) did not differ from P2 in eight patients with pulmonary hypertension not accompanied by right ventricular failure (3120 ± 710 dynes/cm2). In both groups, the amplitude of P2 exceeded control subjects (520 ± 70 dynes/cm2) (P \u3c .001 and P \u3c .01, respectively). The maximal rate of development of the pressure gradient across the closed pulmonary valve was higher in patients with right ventricular failure (580 ± 100 mm Hg/sec) than in control subjects (150 ± 30 mm Hg/sec) (P \u3c .001) and maximal negative dp/dt was also higher in patients with failure (750 ± 70 mm Hg/sec vs 190 ± 20 mm Hg/sec) (P \u3c .001). The maximal rate of change of the diastolic pressure gradient correlated linearly with maximal negative dp/dt (r=.89). These observations indicate that P2 is accentuated in patients with right ventricular failure secondary to pulmonary hypertension. The accentuation results from the augmented rate of development of the diastolic pressure gradient, which reflects an augmented right ventricular negative dp/dt. Therefore, an accentuated P2 remains valid as a clinical sign of pulmonary hypertension whether or not right ventricular failure occurs

Effects of Elamipretide on Skeletal Muscle in Dogs with Experimentally Induced Heart Failure

AIMS: Elamipretide (ELAM), an aromatic-cationic tetrapeptide, interacts with cardiolipin and normalizes dysfunctional mitochondria of cardiomyocytes. This study examined the effects of ELAM on skeletal muscle mitochondria function in dogs with chronic heart failure (HF). METHODS AND RESULTS: Studies were performed in skeletal muscle biopsy specimens obtained from normal dogs (n = 7) and dogs with chronic intracoronary microembolization-induced HF (n = 14) treated with subcutaneous ELAM 0.5 mg/kg (HF + ELAM, n = 7) or vehicle (normal saline control, HF-CON, n = 7). After 3 months of therapy, triceps skeletal muscle samples were obtained from all dogs, and the proportion of type 1 and type 2 fibres was assessed. Mitochondria isolated from myofibrils of the vastus lateralis skeletal muscle exposed in vitro to ELAM for 1 h were used to assess mitochondrial function. The proportion of skeletal muscle type 1 fibres was lower in HF-CON dogs compared with normal dogs (23 ± 4 vs. 32 ± 5%, P \u3c 0.05). Treatment with ELAM restored a near-normal fibre-type composition (31 ± 7%, P \u3c 0.05 vs. HF-CON). Skeletal muscle mitochondria showed significantly lower levels of adenosine diphosphate-dependent mitochondrial respiration (100 ± 9 vs. 164 ± 15 natom O/min/mg protein, P \u3c 0.05), mitochondrial membrane potential (0.17 ± 0.03 vs. 0.53 ± 0.03 red/green fluorescence ratio, P \u3c 0.05), mitochondrial permeability transition pore (38 ± 3 vs. 62 ± 2 relative light units, P \u3c 0.05), maximum rate of adenosine triphosphate synthesis (3284 ± 418 vs. 8835 ± 423 RLU/μg protein, P \u3c 0.05), and cytochrome c oxidase activity (1390 ± 108 vs. 2459 ± 210 natom O/min/mg protein, P \u3c 0.05) compared with normal dogs. Exposure of skeletal muscle myofibrillar mitochondria from HF dogs to ELAM showed a dose-dependent improvement/normalization of all measures of mitochondrial function. In mitochondria from skeletal muscle of HF dogs exposed to 0.10 μM ELAM, adenosine diphosphate-dependent mitochondrial respiration increased to 183 ± 18 natom O/min/mg protein, membrane potential increased to 0.30 ± 0.03 red/green fluorescence ratio, mitochondrial permeability transition pore increased to 54 ± 4 RLU, maximum rate of adenosine triphosphate synthesis increased to 4423 ± 414, and cytochrome c oxidase activity increased to 2033 ± 191 natom O/min/mg protein. Exposure of skeletal muscle myofibrillar mitochondria from normal dogs to ELAM had no effect on mitochondrial function parameters. CONCLUSIONS: The results indicate that ELAM, previously shown to positively influence mitochondrial function of the failing heart, can also positively impact mitochondrial function of skeletal muscle and potentially help restore skeletal muscle function and improve exercise tolerance

Left ventricular shape is the primary determinant of functional mitral regurgitation in heart failure

AbstractObjectives. The aim of this study was to examine the temporal association between the onset of functional mitral regurgitation and the development of changes in left ventricular shape, chamber enlargement, mitral anulus dilation and regional wall motion abnormalities during the course of evolving heart failure.Background. Despite extensive characterization, the exact etiology of functional mitral regurgitation in patients with chronic heart failure remains unknown.Methods. Heart failure was produced in seven dogs by multiple sequential intracoronary microembolizations. Serial changes in left ventricular chamber volume and shape were evaluated from ventriculograms. Changes in mitral anulus diameter and ventricular regional wall motion abnormalities were evaluated echocardiographically. The presence and severity of mitral regurgitation were determined with Doppler color flow mapping. Measurements were obtained at baseline and then biweekly until mitral regurgitation was first observed.Results. No dag had mitral regurgitation at baseline but all developed mild to moderate regurgitation 12 ± 1 weeks after the first embolization. The onset of mitral regurgitation was not associated with an increase in left ventricular end-diastolic volume relative to baseline (58 ± 3 vs. 62 ± 3 ml), mitral anulus diameter (2.4 ± O.1 vs. 2.4 ± 0.1 cm) or wall motion abnormalities of left ventricular wall segments overlying the papillary muscles. In contrast, the onset of mitral regurgitation was accompanied by significant changes in global left ventricular shape evidenced by increased end-systolic chamber sphericity index (0.22 ± 0.02 vs. 0.30 ± 0.01) (p < 0.01) and decreased end-systolic major axis/ minor axis ratio (1.71 ± 0.05 vs. 1.43 ± 0.04) (p < 0.001).Conclusions. These data indicate that transformation of left ventricular shape (increased chamber sphericity) is the most likely substrate for the development of functional mitral regurgitation

Intracardiac Phonocardiography in Subaortic Stenosis

The purpose of this study is to explore the value of intracardiac sound recordings for the verification of subaortic stenosis. Intracardiac sound was measured in ten patients with subaortic obstructions. Seven had idiopathic hypertrophic subaortic stenosis, two had a subvalvular membrane, and one had a subvalvular tunnel. In each patient, a systolic murmur was recorded within the left ventricle distal to the obstruction. The murmur was of lower amplitude distal to the aortic valve, and it was of even lower amplitude or absent proximal to the obstruction. In the presence of entrapment, no intraventricular murmur occurred although an apparent subvalvular pressure gradient was observed. The identification and localization of the maximal intensity of a systolic murmur in the ventricular outflow tract may assist in the verification of a subvalvular obstruction and help distinguish between artifactual pressure gradients and gradients indicative of subvalvular stenosis