Left ventricular (LV) volume overload (VO) results in cardiomyocyte oxidative stress and mitochondrial dysfunction. Because mitochondria are both a source and target of ROS, we hypothesized that the mitochondrially targeted antioxidant mitoubiquinone (MitoQ) will improve cardiomyocyte damage and LV dysfunction in VO. Isolated cardiomyocytes from Sprague-Dawley rats were exposed to stretch in vitro and VO of aortocaval fistula (ACF) in vivo. ACF rats were treated with and without MitoQ. Isolated cardiomyocytes were analyzed after 3 h of cyclical stretch or 8 wk of ACF with MitoSox red or 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate to measure ROS and with tetramethylrhodamine to measure mitochondrial membrane potential. Transmission electron microscopy and immunohistochemistry were used for cardiomyocyte structural assessment. In vitro cyclical stretch and 8-wk ACF resulted in increased cardiomyocyte mitochondrial ROS production and decreased mitochondrial membrane potential, which were significantly improved by MitoQ. ACF had extensive loss of desmin and β₂-tubulin that was paralleled by mitochondrial disorganization, loss of cristae, swelling, and clustering identified by mitochondria complex IV staining and transmission electron microscopy. MitoQ improved mitochondrial structural damage and attenuated desmin loss/degradation evidenced by immunohistochemistry and protein expression. However, LV dilatation and fractional shortening were unaffected by MitoQ treatment in 8-wk ACF. In conclusion, although MitoQ did not affect LV dilatation or function in ACF, these experiments suggest a connection of cardiomyocyte mitochondria-derived ROS production with cytoskeletal disruption and mitochondrial damage in the VO of ACF.
We studied the impact of baseline systolic blood pressure (SBP) on outcomes in mild to moderate chronic systolic and diastolic heart failure (HF) patients in the Digitalis Investigation Group trial using propensity-matched design. Of the 7788 patients, 7785 had baseline SBP data and 3538 had SBP ≤120 mm Hg. Propensity scores for SBP ≤120 mm Hg, calculated for each of the 7785 patients, were used to assemble a matched cohort of 3738 patients with SBP ≤120 and >120 mm Hg who were well-balanced on 32 baseline characteristics. All-cause mortality occurred in 35% and 32% of matched patients with SBP ≤120 and >120 mm Hg respectively during 5 years of follow-up (hazard ratio {HR} when SBP ≤120 was compared with >120 mm Hg, 1.10; 95% confidence interval {CI}, 0.99–1.23; p=0.088). HRs (95% CIs) for cardiovascular and HF mortality associated with SBP ≤120 mm Hg were 1.15 (1.01–1.30; p=0.031) and 1.30 (1.08–1.57; p=0.006). Cardiovascular hospitalization occurred in 53% and 49% of matched patients with SBP ≤120 and >120 mm Hg respectively (HR for SBP ≤120 was compared with >120 mm Hg, 1.13; 95% CI, 1.03–1.24; P=0.008). HRs (95% CIs) for all-cause and HF hospitalization associated with SBP ≤120 mm Hg were 1.10 (1.02–1.194; p=0.017) and 1.21 (1.07–1.36; p=0.002). In conclusion, in patients with mild to moderate chronic systolic and diastolic HF, baseline SBP ≤120 mm Hg was associated with increased cardiovascular and HF mortality and all-cause, cardiovascular and HF hospitalization that was independent of other baseline characteristics.
CC, Wright GL. O2-sensing signal cascade: clamping of O2 respiration, reduced ATP utilization, and inducible fumarate respiration. Am J Physiol Cell Physiol 295: C29 -C37, 2008. First published May 7, 2008 doi:10.1152/ajpcell.00466.2007.-These studies explore the consequences of activating the prolyl hydroxylase (PHD) O2-sensing pathway in spontaneously twitching neonatal cardiomyocytes. Full activation of the PHD pathway was achieved using the broadspectrum PHD inhibitor (PHI) dimethyloxaloylglycine (DMOG). PHI treatment of cardiomyocytes caused an 85% decrease in O 2 consumption and a 300% increase in lactic acid production under basal conditions. This indicates a ϳ75% decrease in ATP turnover rate, inasmuch as the increased ATP generation by glycolysis is inadequate to compensate for the lower respiration. To determine the extent to which decreased ATP turnover underlies the suppressed O2 consumption, mitochondria were uncoupled with 2,4-dinitrophenol. We were surprised to find that 2,4-dinitrophenol failed to increase O 2 consumption by PHI-treated cells, indicating that electron transport chain activity, rather than ATP turnover rate, limits respiration in PHItreated cardiomyocytes. Silencing of hypoxia-inducible factor-1␣ (HIF-1␣) expression restored the ability of uncoupled PHI-treated myocytes to increase O 2 consumption; however, basal O2 uptake rates remained low because of the unabated suppression of cellular ATP consumption. Thus it appears that respiration is actively "clamped" through an HIF-dependent mechanism, whereas HIF-independent mechanisms are responsible for downregulation of ATP consumption. In addition, we find that PHD pathway activation enables mitochondria to utilize fumarate as a terminal electron acceptor when cytochrome c oxidase is inactive. The source of fumarate for this unusual respiration is derived from aspartate via the purine nucleotide cycle. In sum, these studies show that the O 2-sensing pathway is sufficient to actively "clamp" O 2 consumption and independently suppress cellular ATP consumption. The PHD pathway also enables the mitochondria to utilize fumarate for respiration. mitochondrial membrane potential; hibernation; cardioprotection ALTHOUGH OXYGENATION of lower eukaryotes is accomplished by simple diffusion, an extensive cardiovascular and respiratory system has evolved in higher animals to enable tissue and organ oxygenation. In turn, cells, and the tissue they comprise, closely monitor O 2 levels and initiate a complex response to restore homeostasis when lower O 2 concentrations are detected. These responses include release of vasodilator agents, expression of angiogenic factors, and upregulation of anaerobic glycolytic metabolism, among others. Many of the cellular responses to lower O 2 occur at concentrations higher than those limiting aerobic mitochondrial ATP production (38), an observation that first suggested the presence of a cellular O 2 -sensing mechanism distinct from the electron transport chain (ETC) or ATP depletion. More recently, a cellular O ...
Aging is often associated with increased systolic blood pressure and decreased diastolic blood pressure. Isolated systolic hypertension or an elevated systolic blood pressure without an elevated diastolic blood pressure is a known risk factor for incident heart failure in older adults. In the current study, we examined whether isolated diastolic hypotension, defined as a diastolic blood pressure <60 mm Hg and a systolic blood pressure ≥100 mm Hg, is associated with incident heart failure. Of the 5795 Medicare-eligible community-dwelling adults age ≥65 years in the Cardiovascular Health Study, 5521 were free of prevalent heart failure at baseline. After excluding 145 individuals with baseline systolic blood pressure <100 mm Hg, the final sample included 5376 participants, of whom 751 (14%) had isolated diastolic hypotension. Propensity scores for isolated diastolic hypotension were calculated for each of the 5376 participants and used to match 545 and 2348 participants with and without isolated diastolic hypotension, respectively who were balanced on 58 baseline characteristics. During over 12 years of median follow-up, centrally-adjudicated incident heart failure developed in 25% and 20% of matched participants with and without isolated diastolic hypotension respectively (hazard ratio associated with isolated diastolic hypotension, 1.33; 95% confidence interval, 1.10–1.61; p=0.004). Among the 5376 pre-match individuals, multivariable-adjusted hazard ratio for incident heart failure associated with isolated diastolic hypotension was 1.29 (95% confidence interval, 1.09–1.53; p=0.003). As in isolated systolic hypertension, among community-dwelling older adults without prevalent heart failure, isolated diastolic hypotension is also a significant independent risk factor for incident heart failure.
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