- Conditional FKBP12.6 Overexpression in Mouse Cardiac Myocytes Prevents Triggered Ventricular Tachycardia Through Specific Alterations in Excitation-Contraction Coupling
- Impact of Ethnicity and Gender Differences on Angiographic Coronary Artery Disease Prevalence and In-Hospital Mortality in the American College of Cardiology–National Cardiovascular Data Registry
- Cardiac Autonomic Dysfunction: Effects From Particulate Air Pollution and Protection by Dietary Methyl Nutrients and Metabolic Polymorphisms
- High-Dose Folic Acid Pretreatment Blunts Cardiac Dysfunction During Ischemia Coupled to Maintenance of High-Energy Phosphates and Reduces Postreperfusion Injury
- Severe Heart Failure and Early Mortality in a Double-Mutation Mouse Model of Familial Hypertrophic Cardiomyopathy
- Effects of Left Bundle-Branch Block on Cardiac Structure, Function, Perfusion, and Perfusion Reserve: Implications for Myocardial Contrast Echocardiography Versus Radionuclide Perfusion Imaging for the Detection of Coronary Artery Disease
- Matrix-Array 3-Dimensional Echocardiographic Assessment of Volumes, Mass, and Ejection Fraction in Young Pediatric Patients With a Functional Single Ventricle: A Comparison Study With Cardiac Magnetic Resonance
- Phospholemman-Mediated Activation of Na/K-ATPase Limits [Na]i and Inotropic State During β-Adrenergic Stimulation in Mouse Ventricular Myocytes
- Rapid Endothelial Turnover in Atherosclerosis-Prone Areas Coincides With Stem Cell Repair in Apolipoprotein E–Deficient Mice
- Left Ventricular Systolic Function and Outcome After In-Hospital Cardiac Arrest
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Conditional FKBP12.6 Overexpression in Mouse Cardiac Myocytes Prevents Triggered Ventricular Tachycardia Through Specific Alterations in Excitation-Contraction Coupling
Ventricular arrhythmias are a frequent fatal outcome during chronic heart failure. As is the case in catecholaminergic ventricular tachycardia, they seem to result from a leak out of the sarcoplasmic reticulum (SR) during diastole, itself favored by stress. The ryanodine receptor (RyR2) is the SR channel through which calcium normally comes out of the SR during systole to trigger contraction and leaks out of the SR during diastole. It has been suggested that RyR2 leakage may be favored by the unbinding from RyR2 of the small regulatory protein FKBP12.6, also known as calstabin 2. In the present study, we show in a mouse model that increasing the expression level of FKBP12.6 in cardiac myocytes results in increased FKBP12.6 binding to RyR2, even when the latter is hyperphosphorylated, a feature associated with a decreased rate of ventricular tachycardia triggered by burst pacing in stress conditions, and a reduced SR calcium leak in isolated myocytes. Our results firmly support the hypothesis that the FKBP12.6-RyR2 complex is an important candidate target for pharmacological prevention of ventricular tachycardia. Other studies are now needed to determine precisely how FKBP12.6 binding to a hyperphosphorylated RyR2 exerts this beneficial effect and to identify new molecules that may favor this binding. See p 1778.
Impact of Ethnicity and Gender Differences on Angiographic Coronary Artery Disease Prevalence and In-Hospital Mortality in the American College of Cardiology–National Cardiovascular Data Registry
Dramatic population shifts have made the United States ever more ethnically diverse. Its healthcare centers reflect this ethnic “melting pot,” yet our understanding of diverse healthcare needs and differences in disease prevalence and outcomes between male and female ethnic subsets remains poor. The American College of Cardiology’s National Cardiovascular Data Registry (NCDR) for cardiac catheterization, with data collection in >600 US hospitals, is well suited to track national patterns of disease prevalence and clinical outcomes. The present report focused on patients referred for diagnostic coronary angiography and revealed significant gender and ethnic differences in coronary disease prevalence and in-hospital mortality rates. Our results reveal higher risk-adjusted in-hospital mortality for white, non-Hispanic women referred for evaluation of stable and unstable chest pain syndromes. One driver for higher in-hospital mortality for white, non-Hispanic women was their advanced age at presentation. An additional risk driver could relate to lower use of elective coronary revascularization procedures and lower glycoprotein IIb/IIIa inhibitor use. Moreover, in this registry, black women had a consistently lower prevalence of obstructive coronary disease than other patient subsets. A key finding was higher disease prevalence, similar to that of men, in higher-risk black women, including those who were older, diabetic, or hyperlipidemic or who had lung disease. We believe the NCDR data can be invaluable as an aid in the development of clinical practice guidelines tailored to gender subsets of the population to improve the efficient use of angiographic laboratories and to target at-risk populations of women and men. See p 1787.
Cardiac Autonomic Dysfunction: Effects From Particulate Air Pollution and Protection by Dietary Methyl Nutrients and Metabolic Polymorphisms
Reductions in heart rate variability (HRV), a noninvasive measure of cardiac autonomic dysfunction that independently predicts cardiovascular mortality, have been related to short-term exposure to particulate air pollution (PM), particularly to fine-particulate air pollution of <2.5 μmol/L in aerodynamic diameter (PM2.5). This relation has frequently been investigated to clarify mechanisms underlying the increased risk of cardiovascular disease associated with PM2.5 exposure. In a repeated-measures study of 549 elderly individuals from eastern Massachusetts, we evaluated HRV in relation to genetic polymorphisms (C677T methylenetetrahydrofolate reductase [MTHFR] and C1420T cytoplasmic serine hydroxymethyltransferase [cSHMT]) and dietary intakes of methyl nutrients that participate in the methionine cycle and contribute to biological processes such as methyl group transfers, homocysteine synthesis, and redox states that are potentially affected by PM exposure. Results from this investigation indicate that genetic and nutritional variations conducive to lower methionine cycle function affect HRV either independently or by enhancing the negative effects of PM. In particular, carriers of [CT/TT] MTHFR genotypes exhibited lower HRV, which was decreased further in the presence of higher ambient PM2.5 in the 48 hours before the examination. PM2.5 exposure was associated with lower HRV in individuals with [CC] but not in those with [CT/TT] cSHMT genotypes. In addition, the negative effects of PM2.5 on HRV were abrogated in subjects with higher intakes (above the median) of vitamin B6, vitamin B12, or methionine. These findings provide novel hypotheses to investigate the mechanisms of action of air particles and ultimately to identify measures to reduce the effects of air pollution in human populations. See p 1802.
High-Dose Folic Acid Pretreatment Blunts Cardiac Dysfunction During Ischemia Coupled to Maintenance of High-Energy Phosphates and Reduces Postreperfusion Injury
Cardiac dysfunction/infarction from coronary heart disease is a leading cause of morbidity and mortality. A critical reduction in coronary flow lowers the high-energy supply, and heart function declines as mitochondrial damage and oxidative stress develop. These factors can further amplify damage on coronary reperfusion. Many efforts have been made to ameliorate the consequences of ischemia and reperfusion injury. Here, we report that high-dose folic acid (FA) treatment does both. FA is required for purine biosynthesis and thus formation of high-energy phosphates, is itself an antioxidant, and helps to preserve nitric oxide synthase function. Rats pretreated with FA (10 mg/300 g body weight per day) for 1 week were subjected to 30 minutes of left anterior descending coronary artery occlusion followed by 90 minutes of reperfusion. During the occlusion, FA-treated animals had better global and regional function coupled with enhanced ATP and ADP in the anterior wall. Postreperfusion function was enhanced and myocardial necrosis/apoptosis was reduced by FA treatment, accompanied by reduced oxidant stress (during ischemia and postreperfusion) and preserved nitric oxide synthase function. Reduced necrosis occurred even when FA was administered shortly after the onset of coronary occlusion. FA treatment alone enhanced purine biosynthesis (eg, increased inosine monophosphate and its catabolites), suggesting that by mass action FA may help to maintain high-energy phosphates despite reduced flow and blunt development of irreversible tissue damage coupled to oxidant stress. Clinical translation of these results might pave the way for a novel and inexpensive approach to treat acute coronary syndromes and to potentially reduce postinfarction morbidity and mortality. See p 1810.
Severe Heart Failure and Early Mortality in a Double-Mutation Mouse Model of Familial Hypertrophic Cardiomyopathy
The well-accepted paradigm in autosomal-dominant monogenic medical diseases is that 1 gene mutation in a single gene is the direct cause of disease. This is seen in a number of medical genetic disorders spanning all subspecialties, including neurological disorders, familial cancer syndromes, and thalassemia. Until recently, cardiac genetic disorders have been thought to involve only single-gene defects; however, several groups have recently reported families with familial hypertrophic cardiomyopathy in which 2 disease-causing gene defects have been identified. These clinically affected patients with 2 mutations develop more severe disease, including earlier age of onset, more severe cardiac hypertrophy, and a greater number of sudden cardiac death events. The present study combined 2 separate animal models of single-mutation familial hypertrophic cardiomyopathy to produce a unique double-mutation model of familial hypertrophic cardiomyopathy, characterized by rapid development of a dilated cardiomyopathy, severe heart failure, and premature death. These mice also demonstrated alterations in both calcium handling and STAT3 signaling. This model provides evidence that the number of disease-causing mutations identified in a patient may explain, at least in part, the clinical heterogeneity observed in human familial hypertrophic cardiomyopathy, particularly in the small subgroup of familial hypertrophic cardiomyopathy patients who develop a burnt-out end-stage heart failure phenotype. Elucidation of how multiple mutations lead to diverse clinical outcomes, using appropriate animal models as presented in this study, will likely affect a range of clinical considerations, including genetic diagnosis and improved risk stratification, and therefore will provide the opportunity to initiate earlier treatment and prevention strategies. See p 1820.
Effects of Left Bundle-Branch Block on Cardiac Structure, Function, Perfusion, and Perfusion Reserve: Implications for Myocardial Contrast Echocardiography Versus Radionuclide Perfusion Imaging for the Detection of Coronary Artery Disease
The present study is the first to simultaneously assess cardiac structure, function, perfusion, and perfusion reserve using quantitative myocardial contrast echocardiography in patients with symptomatic left bundle-branch block who predominantly had left ventricular dysfunction. In these patients, regardless of coronary artery disease (CAD), there were asymmetrical reductions in septal wall thickness and function compared with the posterior wall; however, resting myocardial blood volume and flow were homogeneously preserved. Single-photon emission computed tomography (SPECT) is widely used for the detection and risk stratification of CAD. However, we demonstrated that because of asymmetrical reductions in septal thickness and function, SPECT has a significantly higher incidence of false-positive perfusion defects resulting from partial volume effects as a consequence of its poorer spatial and temporal resolution compared with myocardial contrast echocardiography. Despite no difference in sensitivity between the 2 techniques for the detection of CAD, because of partial volume effects, reversible defects (suggesting myocardial ischemia) occurred in only 57% of CAD patients with SPECT imaging compared with 92% with myocardial contrast echocardiography. This finding has both cost and safety implications in that patients would be inappropriately referred for coronary arteriography after SPECT and a significant proportion of patients undergoing SPECT would inadvertently be denied revascularization. Compared with other imaging techniques such as multislice computed tomography, SPECT, or stress echocardiography, myocardial contrast echocardiography has the advantage of providing an accurate comprehensive assessment of cardiac structure and function and denoting the presence or absence of flow-limiting CAD and the status of myocardial viability in a single examination in patients presenting with symptomatic left bundle-branch block. See p 1832.
Matrix-Array 3-Dimensional Echocardiographic Assessment of Volumes, Mass, and Ejection Fraction in Young Pediatric Patients With a Functional Single Ventricle: A Comparison Study With Cardiac Magnetic Resonance
Quantitative measurement of chamber volumes is a cornerstone of clinical cardiac assessment. Ejection fraction, despite its limitations, is a nearly universal measurement of and surrogate for ventricular contractility. Although ejection fraction can be determined with a wide range of techniques, each method has its own set of advantages and shortcomings. Calculations by 2-dimensional echocardiography require geometric assumptions that cannot be applied to complex-shaped single ventricles or morphological right ventricles. Radionuclide ventriculography can provide accurate right or left ventricular measurements but requires intravenous access and ionizing radiation. Cardiac magnetic resonance avoids radiation exposure for both patient and healthcare worker but requires patient cooperation to the extent that toddlers and infants are imaged reliably only under sedation. Matrix-array 3-dimensional echocardiography imaging is rapid, can be performed at the bedside, and obviates the need for geometric assumptions. With the results of the present study, we are able to introduce the perspective that 3-dimensional echocardiography has the potential to be applied in patients with functional single ventricles. The present study represents the first series that documents matrix-array 3-dimensional echocardiography ventricular volume measurements in patients with single-ventricle physiology. However, challenges remain. Matrix-array 3-dimensional echocardiography requires additional equipment and training and needs further study in unsedated patients. In addition, a significant amount of postprocessing time is needed to manually trace endocardial borders. Despite these limitations, matrix-array 3-dimensional echocardiography is an exciting technique that provides the clinician with an additional tool to help evaluate ventricular volumes and ejection fractions. See p 1842.
Phospholemman-Mediated Activation of Na/K-ATPase Limits [Na]i and Inotropic State During β-Adrenergic Stimulation in Mouse Ventricular Myocytes
During activation of the sympathetic nervous system, cardiac performance is increased as part of the fight-or-flight stress response. The increase in contractility with sympathetic stimulation is an orchestrated combination of intrinsic inotropic, lusitropic, and chronotropic effects mediated in part by activation of β-adrenergic receptors and protein kinase A. This activation causes phosphorylation of several Ca cycling proteins in cardiac myocytes (increasing Ca entry via L-type Ca channels, sarcoplasmic reticulum Ca pumping, and the dissociation rate of Ca from the myofilaments). Here, we demonstrate how Na/K-pump stimulation, mediated by phospholemman phosphorylation, is an additional important player in the sympathetic fight-or-flight response. Enhancement of Na/K-ATPase activity limits the rise in intracellular Na caused by the higher level of Na influx and, by doing so, limits the rise in cellular and sarcoplasmic reticulum Ca load. Mutations that would prevent phospholemman phosphorylation and thus make Na/K-ATPase insensitive to sympathetic stimulation could lead to excessive elevation of intracellular Na during stress. Although this could enhance inotropy (like Na/K-ATPase inhibition by cardiac glycosides), it also could contribute to arrhythmogenesis (again, like glycosides) during stress or exercise when sympathetic tone is elevated. See p 1849.
Rapid Endothelial Turnover in Atherosclerosis-Prone Areas Coincides With Stem Cell Repair in Apolipoprotein E–Deficient Mice
It is well established that atherosclerotic lesions in the arteries are localized in some areas where endothelial dysfunction could be crucial in determining lesion development, but less is known about endothelial death and regeneration. In the present study, we provided quantitative data on endothelial turnover in whole aorta and mapped the location of high-turnover areas of endothelial cells, which are colocalized with endothelial dysfunction and lesion location. We also demonstrated that stem cells contribute to the repair of severely damaged endothelial cells in high-turnover areas, which have not been shown to exhibit the full function of mature endothelial cells. Clinically, one of the conventional treatments for vascular diseases involves lowering blood cholesterol levels, which may have a role in endothelial protection of the vessel wall. Our findings in animal models may illustrate a new strategy for therapy, that is, promoting endothelial repair by stem cells that exist in circulating blood. If more detailed mechanisms of stem cell differentiation into endothelial cells are elucidated, we may be able to design new drugs to enhance stem cell differentiation into mature endothelial cells. Thus, atherosclerotic lesions may be retarded or prevented in the early stage of the disease. See p 1856.
Left Ventricular Systolic Function and Outcome After In-Hospital Cardiac Arrest
In-hospital cardiac arrest is a major public health problem. In 2005, >20 000 in-hospital cardiac arrests were reported in the American Heart Association’s National Registry of Cardiopulmonary Resuscitation, representing ≈10% of the hospitals in the United States. Only 18% of these adults with in-hospital arrests survived to hospital discharge. Importantly, postarrest myocardial dysfunction occurs commonly after successful resuscitation and is a major contributor to poor outcome. Although pre-event left ventricular ejection fraction (LVEF) is well established as a major prognostic factor in many cardiac conditions, the effect of prearrest LVEF on outcome after cardiac arrest has not been previously evaluated. In the present study of 613 in-hospital cardiac arrest patients with recent prearrest echocardiograms from the Heart Institute in Sao Paulo, the patients with a prearrest LVEF <45% (ie, moderate or severe dysfunction) were substantially less likely to survive to hospital discharge than patients with prearrest LVEF ≥45% (8% versus 19% survival rate). Among patients who had postarrest echocardiograms within 72 hours, LVEF decreased by 25% in both groups. Therefore, the mean postarrest LVEF was 23% in the patients with prearrest LVEF <45%. This resultant severe postarrest left ventricular dysfunction among patients with prearrest LVEF <45% presumably contributed to the lower rate of survival to discharge in that group. Importantly, 84% of the hospital deaths after initially successful resuscitations were due to postresuscitation refractory shock with or without multiple organ failure. Prearrest LVEF appears to be an important contributor to outcome after in-hospital cardiac arrest. See p 1864.
- Left Ventricular Systolic Function and Outcome After In-Hospital Cardiac Arrest
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