Abnormal mitochondrial respiration in skeletal muscle in patients with peripheral arterial disease

AbstractObjectiveDiscrete morphologic, enzymatic and functional changes in skeletal muscle mitochondria have been demonstrated in patients with peripheral arterial disease (PAD). We examined mitochondrial respiration in the gastrocnemius muscle of nine patients (10 legs) with advanced PAD and in nine control patients (nine legs) without evidence of PAD.MethodsMitochondrial respiratory rates were determined with a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles. Muscle samples were obtained from the anteromedial aspect of the gastrocnemius muscle, at a level 10 cm distal to the tibial tuberosity. Mitochondria respiratory rate, calculated as nanoatoms of oxygen consumed per minute per milligram of noncollagen protein, were measured at baseline (V0), after addition of substrates (malate and glutamate; (VSUB), after addition of adenosine diphosphate (ADP) (VADP), and finally, after adenine nucleotide translocase inhibition with atractyloside (VAT). The acceptor control ratio, a sensitive indicator of overall mitochondrial function, was calculated as the ratio of the respiratory rate after the addition of ADP to the respiratory rate after adenine nucleotide translocase inhibition with atractyloside (VADP/ VAT).ResultsRespiratory rate in muscle mitochondria from patients with PAD were not significantly different from control values at baseline (0.31 ± 0.06 vs 0.55 ± 0.12; P = .09), but Vsub was significantly lower in patients with PAD compared with control subjects (0.43 ± 0.07 vs 0.89 ± 0.20; P < .05), as was VADP (0.69 ± 0.13 vs 1.24 ± 0.20; P < .05). Respiratory rates after atractyloside inhibition in patients with PAD were no different from those in control patients (0.47 ± 0.07 vs 0.45 ± P = .08). Compared with control values, mitochondria from patients with PAD had a significantly lower acceptor control ratio (1.41 ± 0.10 vs 2.90 ± 0.20; P < .001).ConclusionMitochondrial respiratory activity is abnormal in lower extremity skeletal muscle in patients with PAD. When considered in concert with the ultrastructural and enzymatic abnormalities previously documented in mitochondria of chronically ischemic muscle, these data support the concept of defective mitochondrial function as a pathophysiologic component of PAD

965-50 Accumulation of Collagen in the Cardiac Interstitium of Dogs with Chronic Heart Failure is Associated with Decreased Capillary Density and Increased Oxygen Diffusion Distance

Progressive LV dysfunction is a characteristic feature of the failing heart. The mechanism(s) responsible for this functional deterioration are not known. Progressive accumulation of collagen in the cardiac interstitium termed “reactive interstitial fibrosis” (RIF). occurs in the failing heart but its role in the progression of LV dysfunction remains uncertain. We examined the consequences of RIF severity on capillary density (CD) and oxygen diffusion distance (ODD) in LV myocardium of 11 dogs with heart failure produced by intracoronary microembolizations (LV ejection fraction 26±1%). CD was defined as the index capillary to fiber ratio and ODD as half the distance between two adjoining capillaries. Frozen sections were prepared from LV tissue and double stained with a collagen III antibody to quantitate RIF and with GSllectin to visualize capillaries. From each section. 5 infarct free fields manifesting severe RIF (volume fraction 16±2%) and 5 fields with little or no RIF (volume fraction 4±1%) were selected for analyses.No RIFRIFProbabilityCD1.05±0.030.92±0.02P&lt;0.003ODD (μm2.3±0.415.3±0.4P&lt;0.001ConclusionIn the failed canine heart, CD is decreased and ODD is increased in LV regions manifesting severe RIF. These abnormalities may contribute to the progression of LV dysfunction by promoting hypoxia of the collagen encircled cardiocytes

Atenolol Is Inferior to Metoprolol in Improving Left Ventricular Function and Preventing Ventricular Remodeling in Dogs with Heart Failure

OBJECTIVES: β-Blockers are standard therapy for patients with heart failure (HF). This study compared the effects of chronic monotherapy with 2 different β(1)-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

Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure

Acute intravenous infusion of ranolazine (Ran), an anti-ischemic/antiangina drug, was previously shown to improve left ventricular (LV) ejection fraction (EF) without a concomitant increase in myocardial oxygen consumption in dogs with chronic heart failure (HF). This study examined the effects of treatment with Ran alone and in combination with metoprolol (Met) or enalapril (Ena) on LV function and remodeling in dogs with HF. Dogs (n = 28) with microembolization-induced HF were randomized to 3 mo oral treatment with Ran alone [375 mg twice daily (bid); n = 7], Ran (375 mg bid) in combination with Met tartrate (25 mg bid; n = 7), Ran (375 mg bid) in combination with Ena (10 mg bid; n = 7), or placebo (PL; Ran vehicle bid; n = 7). Ventriculographic measurements of LV end-diastolic volume (EDV) and end-systolic volume (ESV) and LV EF were obtained before treatment and after 3 mo of treatment. In PL-treated dogs, EDV and ESV increased significantly. Ran alone prevented the increase in EDV and ESV seen in the PL group and significantly increased EF, albeit modestly, from 35 ± 1% to 37 ± 2%. When combined with either Ena or Met, Ran prevented the increase in EDV, significantly decreased ESV, and markedly increased EF compared with those of PL. EF increased from 35 ± 1% to 40 ± 1% with Ran + Ena and from 34 ± 1% to 41 ± 1% with Ran + Met. Ran alone or in combination with Ena or Met was also associated with beneficial effects at the cellular level on histomorphometric parameters such as hypertrophy, fibrosis, and capillary density as well as the expression for pathological hypertrophy and Ca2+ cycling genes. In conclusion, Ran prevented progressive LV dysfunction and global and cellular myocardial remodeling, and Ran in combination with Ena or Met improved LV function beyond that observed with Ran alone