Cardiovascular diseases (CVDs), the major cause of morbidity and mortality for both men and women, occur uncommonly in premenopausal women, but their incidence rises sharply after the menopausal ...transition. Cardiovascular gender differences are apparent long before CVDs appear in men and women, and improved understanding of the biology underlying these differences has the potential to advance the diagnosis and treatment of CVDs in both sexes. This review considers gender differences in the molecular and cellular physiology of the heart and blood vessels in health and disease, highlighting understudied areas that can help resolve the current controversy regarding hormone replacement therapy and improve cardiovascular health in women.
This study sought to assess the efficacy of niacin for reducing cardiovascular disease (CVD) events, as indicated by the aggregate body of clinical trial evidence including data from the recently ...published AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial.
Previously available randomized clinical trial data assessing the clinical efficacy of niacin has been challenged by results from AIM-HIGH, which failed to demonstrate a reduction in CVD event incidence in patients with established CVD treated with niacin as an adjunct to intensive simvastatin therapy.
Clinical trials of niacin, alone or combined with other lipid-altering therapy, were identified via MEDLINE. Odds ratios (ORs) for CVD endpoints were calculated with a random-effects meta-analyses. Meta-regression modeled the relationship of differences in on-treatment high-density lipoprotein cholesterol with the magnitude of effect of niacin on CVD events.
Eleven eligible trials including 9,959 subjects were identified. Niacin use was associated with a significant reduction in the composite endpoints of any CVD event (OR: 0.66; 95% confidence interval CI: 0.49 to 0.89; p = 0.007) and major coronary heart disease event (OR: 0.75; 95% CI: 0.59 to 0.96; p = 0.02). No significant association was observed between niacin therapy and stroke incidence (OR: 0.88; 95% CI: 0.5 to 1.54; p = 0.65). The magnitude of on-treatment high-density lipoprotein cholesterol difference between treatment arms was not significantly associated with the magnitude of the effect of niacin on outcomes.
The consensus perspective derived from available clinical data supports that niacin reduces CVD events and, further, that this may occur through a mechanism not reflected by changes in high-density lipoprotein cholesterol concentration.
Heart failure after an acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. We recently reported that activation of a transvalvular axial-flow pump in the left ...ventricle and delaying myocardial reperfusion, known as primary unloading, limits infarct size after AMI. The mechanisms underlying the cardioprotective benefit of primary unloading and whether the acute decrease in infarct size results in a durable reduction in LV scar and improves cardiac function remain unknown.
This study tested the importance of LV unloading before reperfusion, explored cardioprotective mechanisms, and determined the late-term impact of primary unloading on myocardial function.
Adult male swine were subjected to primary reperfusion or primary unloading after 90 min of percutaneous left anterior descending artery occlusion.
Compared with primary reperfusion, 30 min of LV unloading was necessary and sufficient before reperfusion to limit infarct size 28 days after AMI. Compared with primary reperfusion, primary unloading increased expression of genes associated with cellular respiration and mitochondrial integrity within the infarct zone. Primary unloading for 30 min further reduced activity levels of proteases known to degrade the cardioprotective cytokine, stromal-derived factor (SDF)-1α, thereby increasing SDF-1α signaling via reperfusion injury salvage kinases, which limits apoptosis within the infarct zone. Inhibiting SDF-1α activity attenuated the cardioprotective effect of primary unloading. Twenty-eight days after AMI, primary unloading reduced LV scar size, improved cardiac function, and limited expression of biomarkers associated with heart failure and maladaptive remodeling.
The authors report for the first time that first mechanically reducing LV work before coronary reperfusion with a transvalvular pump is necessary and sufficient to reduce infarct size and to activate a cardioprotective program that includes enhanced SDF-1α activity. Primary unloading further improved LV scar size and cardiac function 28 days after AMI.
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BACKGROUND—Ischemia/reperfusion injury worsens infarct size, a major determinant of morbidity and mortality after acute myocardial infarction (MI). We tested the hypothesis that reducing left ...ventricular wall stress with a percutaneous left atrial-to-femoral artery centrifugal bypass system while delaying coronary reperfusion limits myocardial injury in a model of acute MI.
METHODS AND RESULTS—MI was induced by balloon occlusion of the left anterior descending artery in adult male swine. In the MI group (n=4), 120 minutes of left anterior descending artery occlusion was followed by 120 minutes of reperfusion without mechanical support. In the mechanically supported group (MI+unload; n=4), percutaneous left atrial–to–femoral artery bypass was initiated after 120 minutes of ischemia, and left anterior descending artery occlusion was prolonged for an additional 30 minutes, followed by 120 minutes of reperfusion with device support. All animals were euthanized after reperfusion, and infarct size was quantified by triphenyltetrazolium chloride staining. Compared with baseline, mean left ventricular wall stress and stroke work were not changed at any point in the MI group but were decreased after reperfusion in the MI+unload group (mean left ventricular wall stress, 44 658 versus 22 963 dynes/cm; stroke work, 2823 versus 655 mm Hg·mL, MI versus MI+unload). Phosphorylation of reperfusion injury salvage kinase pathway proteins from noninfarcted left ventricular tissue was unchanged in the MI group but was increased in the MI+unload group. Compared with the MI group, total infarct size was reduced in the MI+unload group (49% versus 28%, MI versus MI+unload).
CONCLUSIONS—These data support that first unloading the left ventricle despite delaying coronary reperfusion during an acute MI reduces myocardial injury.
BACKGROUND—Heart failure is a growing cause of morbidity and mortality worldwide. Transforming growth factor beta (TGF-β1) promotes cardiac fibrosis, but also activates counter-regulatory pathways ...that serve to regulate TGF-β1 activity in heart failure. Bone morphogenetic protein 9 (BMP9) is a member of the TGFβ family of cytokines and signals via the downstream effector protein Smad1. Endoglin is a TGFβ co-receptor that promotes TGF-β1 signaling via Smad3 and binds BMP9 with high affinity. We hypothesized that BMP9 limits cardiac fibrosis by activating Smad1 and attenuating Smad3 and further that neutralizing endoglin activity promotes BMP9 activity.
METHODS—We examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. We utilized the thoracic aortic constriction (TAC) induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling.
RESULTS—BMP9 expression is increased in the circulation and left ventricle (LV) of human subjects with heart failure and is expressed by cardiac fibroblasts. Next, we observed that BMP9 attenuates Type I collagen synthesis in human cardiac fibroblasts using recombinant human BMP9 and an siRNA approach. In BMP9 mice subjected to TAC, loss of BMP9 activity promotes cardiac fibrosis, impairs LV function, and increases LV levels of phosphorylated Smad3 (pSmad3), not pSmad1. In contrast, treatment of wild-type mice subjected to TAC with recombinant BMP9 limits progression of cardiac fibrosis, improves LV function, enhances myocardial capillary density, and increases LV levels of pSmad1, not pSmad3 compared to vehicle treated controls. Since endoglin binds BMP9 with high affinity, we explored the effect of reduced endoglin activity on BMP9 activity. Neutralizing endoglin activity in human cardiac fibroblasts or in wild-type mice subjected to TAC induced heart failure limits collagen production, increases BMP9 protein levels, and increases levels of pSmad1, not pSmad3.
CONCLUSIONS—Our results identify a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis due to LV pressure overload and further show that treatment with either recombinant BMP9 or disruption of endoglin activity promotes BMP9 activity and limits cardiac fibrosis in heart failure, thereby providing potentially novel therapeutic approaches for patients with heart failure.
Objectives We sought to examine the relationship between high-density lipoprotein cholesterol (HDL-C) levels and the risk of the development of cancer in large randomized controlled trials (RCTs) of ...lipid-altering interventions. Background Epidemiologic data demonstrate an inverse relationship between serum total cholesterol levels and incident cancer. We recently reported that lower levels of low-density lipoprotein cholesterol are associated with a significantly higher risk of incident cancer in a meta-analysis of large RCTs of statin therapy. However, little is known about the relationship between HDL-C levels and cancer risk. Methods A systematic MEDLINE search identified lipid intervention RCTs with ≥1,000 person-years of follow-up, providing baseline HDL-C levels and rates of incident cancer. Using random-effects meta-regressions, we evaluated the relationship between baseline HDL-C and incident cancer in each RCT arm. Results A total of 24 eligible RCTs were identified (28 pharmacologic intervention arms and 23 control arms), with 625,477 person-years of follow-up and 8,185 incident cancers. There was a significant inverse association between baseline HDL-C levels and the rate of incident cancer (p = 0.018). The inverse association persisted after adjusting for baseline low-density lipoprotein cholesterol, age, body mass index (BMI), diabetes, sex, and smoking status, such that for every 10-mg/dl increment in HDL-C, there was a 36% (95% confidence interval: 24% to 47%) relatively lower rate of the development of cancer (p < 0.001). Conclusions There is a significant inverse association between HDL-C and the risk of incident cancer that is independent of LDL-C, age, BMI, diabetes, sex, and smoking.
Estrogen promotes the proliferation and migration of vascular endothelial cells (ECs), which likely underlies its ability to accelerate re-endothelialization and reduce adverse remodeling after ...vascular injury. In previous studies, we have shown that the protective effects of E2 (the active endogenous form of estrogen) in vascular injury require the estrogen receptor alpha (ERα). ERα transduces the effects of estrogen via a classical DNA binding, "genomic" signaling pathway and via a more recently-described "rapid" signaling pathway that is mediated by a subset of ERα localized to the cell membrane. However, which of these pathways mediates the effects of estrogen on endothelial cells is poorly understood. Here we identify a triple point mutant version of ERα (KRR ERα) that is specifically defective in rapid signaling, but is competent to regulate transcription through the "genomic" pathway. We find that in ECs expressing wild type ERα, E2 regulates many genes involved in cell migration and proliferation, promotes EC migration and proliferation, and also blocks the adhesion of monocytes to ECs. ECs expressing KRR mutant ERα, however, lack all of these responses. These observations establish KRR ERα as a novel tool that could greatly facilitate future studies into the vascular and non-vascular functions of ERα rapid signaling. Further, they support that rapid signaling through ERα is essential for many of the transcriptional and physiological responses of ECs to E2, and that ERα rapid signaling in ECs, in vivo, may be critical for the vasculoprotective and anti-inflammatory effects of estrogen.
Statin-Associated Myopathy Thompson, Paul D; Clarkson, Priscilla; Karas, Richard H
JAMA : the journal of the American Medical Association,
04/2003, Letnik:
289, Številka:
13
Journal Article
Recenzirano
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors)
are associated with skeletal muscle complaints, including clinically important
myositis and rhabdomyolysis, mild serum creatine ...kinase (CK) elevations, myalgia
with and without elevated CK levels, muscle weakness, muscle cramps, and persistent
myalgia and CK elevations after statin withdrawal. We performed a literature
review to provide a clinical summary of statin-associated myopathy and discuss
possible mediating mechanisms. We also update the US Food and Drug Administration
(FDA) reports on statin-associated rhabdomyolysis. Articles on statin myopathy
were identified via a PubMed search through November 2002 and articles on
statin clinical trials, case series, and review articles were identified via
a PubMed search through January 2003. Adverse event reports of statin-associated
rhabdomyolysis were also collected from the FDA MEDWATCH database. The literature
review found that reports of muscle problems during statin clinical trials
are extremely rare. The FDA MEDWATCH Reporting System lists 3339 cases of
statin-associated rhabdomyolysis reported between January 1, 1990, and March
31, 2002. Cerivastatin was the most commonly implicated statin. Few data are
available regarding the frequency of less-serious events such as muscle pain
and weakness, which may affect 1% to 5% of patients. The risk of rhabdomyolysis
and other adverse effects with statin use can be exacerbated by several factors,
including compromised hepatic and renal function, hypothyroidism, diabetes,
and concomitant medications. Medications such as the fibrate gemfibrozil alter
statin metabolism and increase statin plasma concentration. How statins injure
skeletal muscle is not clear, although recent evidence suggests that statins
reduce the production of small regulatory proteins that are important for
myocyte maintenance.
The relationship between biological sex and aldosterone on blood pressure (BP) is unclear. We hypothesized that sex would modify the interaction between aldosterone and vascular responses to salt ...intake and angiotensin II (AngII). To test this hypothesis, in 1592 subjects from the well-controlled Hypertensive Pathotype cohort, we compared responses of women and men to chronic (BP and aldosterone levels in response to dietary salt) and acute (BP, renal plasma flow, and aldosterone responses to AngII infusion) manipulations. Women had a 30% higher salt sensitivity of BP than men (P<0.0005) regardless of age or hypertension status, a greater BP response to AngII, and a 15% greater aldosterone response to AngII on both restricted and liberal salt diets (P<0.005). Furthermore, there was an interaction (P=0.003) between sex and aldosterone on BP response to AngII. Women also had a greater (P<0.01) increment in renal plasma flow in response to AngII than men. To assess potential mechanisms for this sex effect, we compared aldosterone responses to AngII or potassium from rat zona glomerulosa cells and observed greater aldosterone production in female than male zona glomerulosa cells basally and in response to both agonists (P<0.0001). In a rodent model of aldosterone-mediated cardiovascular disease induced by increased AngII and low NO, circulating aldosterone levels (P<0.01), myocardial damage (P<0.001), and proteinuria (P<0.05) were greater in female than male rats despite having similar BP responses. Thus, increased aldosterone production likely contributes to sex differences in cardiovascular disease, suggesting that women may be more responsive to mineralocorticoid receptor blockade than men.
The incidence of cardiovascular disease differs significantly between men and women, in part because of differences in risk factors and hormones.
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The incidence of atherosclerotic diseases is low in ...premenopausal women, rises in postmenopausal women, and is reduced to premenopausal levels in postmenopausal women who receive estrogen therapy.
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Until recently, the atheroprotective effects of estrogen were attributed principally to the hormone's effects on serum lipid concentrations. However, estrogen-induced alterations in serum lipids account for only approximately one third of the observed clinical benefits of estrogen.
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Reviews of the data suggest that the direct actions of estrogen on blood . . .
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