- Feedback Remodeling of Cardiac Potassium Current Expression: A Novel Potential Mechanism for Control of Repolarization Reserve
- Fasting Compared With Nonfasting Lipids and Apolipoproteins for Predicting Incident Cardiovascular Events
- Advanced Glycation End Products Accumulate in Vascular Smooth Muscle and Modify Vascular but Not Ventricular Properties in Elderly Hypertensive Canines
- Incidence and Prognostic Implication of Unrecognized Myocardial Scar Characterized by Cardiac Magnetic Resonance in Diabetic Patients Without Clinical Evidence of Myocardial Infarction
- Peroxisome Proliferator–Activated Receptor-δ Agonist Enhances Vasculogenesis by Regulating Endothelial Progenitor Cells Through Genomic and Nongenomic Activations of the Phosphatidylinositol 3-Kinase/Akt Pathway
- Sleep Quality and Elevated Blood Pressure in Adolescents
- Pilot Study to Assess the Influence of β-Blockade on Mitral Regurgitant Volume and Left Ventricular Work in Degenerative Mitral Valve Disease
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Feedback Remodeling of Cardiac Potassium Current Expression: A Novel Potential Mechanism for Control of Repolarization Reserve
Repolarization reserve is an important determinant of the response to contexts involving action potential prolongation, including potassium channel–blocking drugs (both antiarrhythmic agents and compounds with collateral effects on potassium channels), bradycardic drugs, and electrolyte disturbances like hypokalemia and hypomagnesemia. Repolarization reserve is generally attributed to functionally based compensatory increases in potassium currents in response to action potential duration–prolonging tendencies that minimize the resulting action potential prolongation. The possibility that sustained action potential prolongation by potassium channel inhibition may induce remodeling of ion current expression has not been tested. Accordingly, we assessed the effects of sustained rapid delayed-rectifier potassium current (IKr) inhibition with dofetilide on various cardiac ionic currents in isolated paced/cultured dog cardiomyocytes. Sustained dofetilide exposure led to abbreviated action potential duration and increased repolarization reserve (reduced action potential duration–prolonging response to IKr blockade), along with increased slow delayed-rectifier current (IKs) density. A variety of other currents remained unchanged. The mRNA expression of IKs subunits was unchanged, but their protein expression was increased, suggesting posttranscriptional regulation. We quantified the muscle-specific microRNA subtypes miR-133a and miR-133b, which can posttranscriptionally repress protein expression of the IKs α-subunit KvLQT1. Expression levels of miR-133a and miR-133b were decreased in cells cultured in dofetilide, possibly accounting for KvLQT1 protein upregulation. We conclude that chronic action potential prolongation can cause compensatory upregulation of potassium currents, possibly mediated (at least in part) by microRNA changes, adding the regulation of ion channel expression to the potential mechanisms governing repolarization reserve. Function and malfunction of this system could contribute to factors governing the occurrence of cardiac arrhythmias in repolarization dysfunction paradigms like congenital and acquired long-QT syndromes. See p 983.
Fasting Compared With Nonfasting Lipids and Apolipoproteins for Predicting Incident Cardiovascular Events
Current guidelines recommend measurement of a fasting lipid profile for cardiovascular risk assessment. Recent studies suggest that nonfasting triglycerides may better or similarly predict cardiovascular disease (CVD) events than fasting levels. Measurement of nonfasting lipids may have many practical advantages for clinical practice, but it is unknown whether nonfasting status alters the association of nontriglyceride lipids and apolipoproteins with CVD. Using prospectively collected data from the Women’s Health Study with 26 330 healthy women (19 983 fasting; 6347 nonfasting) followed over an 11-year period, we examined the association of CVD with baseline lipids and apolipoproteins according to time from last meal. We found that the concentrations of lipids and apolipoproteins differed minimally when measurements were performed on nonfasting (<8 hours from last meal) compared with fasting blood (≥8 hours from last meal), except for triglycerides, which were higher when nonfasting. However, the associations with CVD were stronger for fasting compared with nonfasting measurements of total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B-100, non–high-density lipoprotein (non-HDL) cholesterol, and the apolipoprotein B-100/A-1 ratio. By contrast, the associations with CVD were similar for fasting and nonfasting HDL cholesterol, apolipoprotein A-1, and the total/HDL cholesterol ratio and stronger for nonfasting triglycerides. These observations suggest that nonfasting blood draws may be highly effective and practical when limited to HDL cholesterol, total/HDL cholesterol ratio, triglycerides, and apolipoprotein A-1. However, these data also suggest that a fasting sample is preferred if risk assessment is based on total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, apolipoprotein B-100, and apolipoprotein B-100/A-1 ratio. See p 993.
Advanced Glycation End Products Accumulate in Vascular Smooth Muscle and Modify Vascular but Not Ventricular Properties in Elderly Hypertensive Canines
Advanced glycation end products (AGEs) are believed to increase left ventricular and vascular stiffness, in part via cross-linking proteins. We determined whether and where AGEs were increased in elderly hypertensive nondiabetic dogs and whether an AGE cross-link breaker (ALT-711) improved vascular or ventricular function. Nε-(Carboxymethyl)lysine, a marker of AGE accumulation, was markedly increased in aortic and aortic vasa vasorum smooth muscle but was not localized to areas of collagen or elastin and was not present in left ventricular myocardium of old hypertensive dogs. ALT-711 therapy was associated with lower blood pressure and pulse pressure, decreased systemic vascular resistance, increased aortic distensibility and arterial compliance, and, notably, significant aortic dilatation. Neither left ventricular systolic nor diastolic function was different in ALT-711–treated dogs. AGE-modifying therapies have been and continue to be tested in patients with heart failure and hypertension. These data in a nondiabetic model with clinical relevance to human hypertension and heart failure suggest that this therapeutic strategy may favorably modify arterial properties but also that such therapies may be associated with aortic dilatation, at least in the setting of persistent hypertension. Thus, aortic size should be monitored carefully in clinical trials of these agents. Furthermore, at least in this nondiabetic model, we did not find evidence of a favorable effect on diastolic function. Whether more prolonged therapy or therapy in diabetics with heart failure or hypertension would be associated with benefit on diastolic function remains to be established. See p 1002.
Incidence and Prognostic Implication of Unrecognized Myocardial Scar Characterized by Cardiac Magnetic Resonance in Diabetic Patients Without Clinical Evidence of Myocardial Infarction
With a high prevalence of atypical cardiac symptoms and ECG findings nonspecific for acute coronary syndrome, a noninvasive technique that improves the detection of occult myocardial infarction (MI) in diabetic patients may serve to advance the management of the cardiovascular complications of this current global epidemic. In this study, we report the clinical utility and prognostic implication of late gadolinium enhancement (LGE) by cardiac magnetic resonance imaging in detecting myocardial scar from MI in a diabetic cohort without any history or ECG evidence of MI. With excellent tissue contrast and spatial resolution, LGE imaging offers a novel method of myocardial characterization not otherwise captured by regional contractile function and nuclear scintigraphy. A high prevalence of LGE at 28% was present among diabetics without a history of MI. This finding was associated with a >3-fold increase in cardiac events and death. Among patients who were detected by LGE imaging to have an unrecognized MI, the reduced median event-free survival was not different from that of a diabetic control cohort who presented with a clinical MI. Furthermore, this study demonstrated that LGE findings provide incremental prognostic value compared with patient age, sex, ST-T changes on ECG, left ventricular systolic function, and the validated United Kingdom Prospective Diabetes Study 5-year risk engine. In summary, LGE by cardiac magnetic resonance imaging can detect subclinical MI and characterize a group of diabetic patients at high risk of cardiac events and death. See p 1011.
Peroxisome Proliferator–Activated Receptor-δ Agonist Enhances Vasculogenesis by Regulating Endothelial Progenitor Cells Through Genomic and Nongenomic Activations of the Phosphatidylinositol 3-Kinase/Akt Pathway
Since the early 2000s, peroxisome proliferator–activated receptors (PPARs), especially PPAR-γ, have been under intense study in various areas, including vascular biology. Although PPAR-γ agonist was found to exert several adverse effects such as weight gain and low-density lipoprotein elevation, it was also known to have many beneficial effects on conditions such as atherosclerosis and postangioplasty restenosis, and the commercial ligands have been prescribed widely as an antidiabetic drug. However, recent studies raised important questions about the cardiovascular safety of PPAR-γ agonist. Naturally, other PPARs have awakened researchers’ interest as an alternative choice. The function of PPAR-δ remained mainly unexplored until recently. In our study, PPAR-δ activation was revealed to regulate endothelial progenitor cells through the dual activation mechanism of the phosphatidylinositol 3-kinase/Akt pathway, leading to vasculogenesis. Metabolically, PPAR-δ is a key regulator with the potential to therapeutically target multiple aspects of the metabolic syndrome. PPAR-δ activation was known to elevate high-density lipoprotein cholesterol robustly and lower low-density lipoprotein cholesterol and triglycerides. It was also reported to be involved in adipose tissue metabolism and to prevent obesity. In liver, PPAR-δ activation was shown to suppress hepatic glucose output, contributing to improved glucose homeostasis. Metabolic syndrome has been strongly linked with cardiovascular disease. Considering the beneficial effects of PPAR-δ agonist in metabolic syndrome, we can expect that its therapeutic potential may be enormous in cardiovascular disease on the basis of our new findings that PPAR-δ activation modulates endothelial progenitor cell biology in a positive direction and augments vasculogenesis. See p 1021.
Sleep Quality and Elevated Blood Pressure in Adolescents
Childhood hypertension is a risk factor for adult hypertension and for target-organ damage. Early recognition and intervention of childhood hypertension are believed to be important in reducing the risk of cardiovascular morbidity in adulthood. Traditional approaches for intervention focus on the role of overweight as a contributing cause of hypertension and include weight reduction, increased physical activity, and nutritional changes. The present report identifies a significant association between increased blood pressure and poor sleep quality (ie, increased wake time during the sleep period), found in 26% of a community sample of adolescents. Independent of obesity, sex, and socioeconomic status and unrelated to sleep apnea, adolescents with poor sleep had a 3.5-fold increased risk of prehypertension or hypertension. This finding suggests that approaches for optimizing sleep quality and duration in children may complement other behavioral approaches for preventing or treating pediatric hypertension. Monitoring sleep quality and duration in children as part of their health supervision may help to identify children who are at risk for both sleep problems and hypertension and who would benefit from behavioral interventions aimed at improving sleep. See p 1034.
Pilot Study to Assess the Influence of β-Blockade on Mitral Regurgitant Volume and Left Ventricular Work in Degenerative Mitral Valve Disease
Mitral valve regurgitation increases left ventricular (LV) stroke volume. Over time, the resulting increase in LV work may cause progressive LV dysfunction, which may be difficult to detect clinically. A medical treatment that decreased this risk would be beneficial. This pilot study determined the short-term effects of a β1-adrenergic receptor blocker on mitral regurgitant volume and LV work in 25 patients with moderate to severe mitral regurgitation caused by primary degenerative disease of the mitral valve. Participants were randomized to both metoprolol and placebo for ≈14 days using a double-blind crossover study design. At the end of each treatment period, forward stroke volume and LV stroke volume were measured by cardiac magnetic resonance imaging, and mitral regurgitant volume and LV work were calculated. On β-blocker compared with placebo, no change was observed in mitral regurgitant volume but a small increase was found in forward stroke volume. Because the β-blocker decreased heart rate, cardiac output was lower. However, the decrease in LV volume pumped per minute was about twice as large as the decrease in forward cardiac output, and LV work was ≈20% lower on metoprolol. These observations suggest that in patients with degenerative mitral regurgitation, long-term treatment with a β-blocker may, by decreasing LV work, reduce the risk of progressive LV dysfunction. A large clinical trial is needed to confirm this hypothesis. See p 1041.
- Sleep Quality and Elevated Blood Pressure in Adolescents
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