Circulation. 2008;117:2425-2427
doi: 10.1161/CIRCULATIONAHA.107.189727
doi: 10.1161/CIRCULATIONAHA.107.189727
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(Circulation. 2008;117:2425-2427.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Selective Vacuolar Degeneration in Dystrophin-Deficient Canine Purkinje Fibers Despite Preservation of Dystrophin-Associated Proteins With Overexpression of Dp71 |
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Selective Vacuolar Degeneration...
Acacetin, a Natural Flavone,...In Duchenne muscular dystrophy, a devastating skeletal and cardiac muscle disorder caused by mutations in the dystrophin gene, cardiac failure such as dilated cardiomyopathy and arrhythmia needs to be overcome, although the respiratory management has significantly improved the life span of the patients. Among cardiac involvements, ECG findings such as distinctive deep Q waves have been noted and are ascribed to fibrosis in the posterobasal region of the left ventricle. When Urasawa et al (National Institute of Neuroscience, Tokyo, Japan) examined the hearts of dogs with canine X-linked muscular dystrophy in Japan (CXMDJ), an appropriate dystrophin-deficient model of Duchenne muscular dystrophy, the Purkinje fibers showed remarkable vacuolar degeneration as early as 4 months of age despite no detectable fibrotic lesions in ventricular myocardium. The degeneration of CXMDJ Purkinje fibers was coincident with overexpression of Dp71, a C-terminal truncated form of dystrophin, at the sarcolemma and translocation of calcium-dependent protease µ-calpain to the cell periphery near the sarcolemma or in the vacuoles. Utrophin, a homologue of dystrophin, was highly upregulated in the earlier stage of CXMDJ Purkinje fibers, but the expression was dislocated when vacuolar degeneration was recognized at 4 months of age, despite preservation of dystrophin-associated proteins at the sarcolemma. The selective degeneration of Purkinje fibers can be associated with distinct deep Q waves on ECG and the fatal arrhythmia seen in dystrophin deficiency. Further clarification of the molecular mechanism of selective degeneration of Purkinje fibers may shed light on the development of new therapy for cardiac involvement in dystrophin-deficient muscular dystrophy. See p 2437.
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Acacetin, a Natural Flavone, Selectively Inhibits Human Atrial Repolarization Potassium Currents and Prevents Atrial Fibrillation in Dogs |
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The present study demonstrated that the natural flavone acacetin from the Chinese medicine Xuelianhua selectively inhibited the human atrial ultrarapid delayed rectifier K+ current (IKur) and the transient outward K+ current (Ito) and prolonged action potential duration in human atrial myocytes. The compound blocked the acetylcholine-activated K+ current; however, it had no effect on the Na+ current, L-type Ca2+ current, or inward-rectifier K+ current in guinea pig ventricular myocytes. Although acacetin had a weak reduction in the hERG and hKCNQ1/hKCNE1 channels stably expressed in HEK 293 cells, it did not prolong the corrected QT interval in rabbit hearts. In anesthetized dogs, acacetin prolonged the atrial effective refractory period 1 to 4 hours after intraduodenal administration without prolongation of the corrected QT interval, whereas sotalol prolonged both. In addition, acacetin prevented atrial fibrillation induction in anesthetized dogs. The present study shows that acacetin is an atrium-selective agent and effectively prevents atrial fibrillation in anesthetized dogs after intraduodenal administration, which indicates that oral acacetin is a promising agent for the treatment of atrial fibrillation in humans. See p 2449.
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Effect of Rosuvastatin Therapy on Coronary Artery Stenoses Assessed by Quantitative Coronary Angiography: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden |
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Previous angiographic studies of statin therapy have shown reduced progression of coronary stenoses in proportion to average low-density lipoprotein cholesterol levels during therapy. However, no major statin monotherapy study has demonstrated either halted progression or regression of angiographic disease. A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) tested whether intensive treatment by rosuvastatin for 24 months could modify the course of coronary atherosclerosis measured by either intravascular ultrasound of the artery wall (reported previously) or by quantitative coronary angiography of the artery lumen (the present report). Therapy reduced mean low-density lipoprotein cholesterol to 61 mg/dL and increased mean high-density lipoprotein cholesterol by 13.8% to 48 mg/dL in these patients. Quantitative coronary angiography showed significant net improvement in the 2 measures of stenosis: percent diameter stenosis and minimum lumen diameter of the stenoses. These improvements complement the intravascular ultrasound results from ASTEROID of the decrease in atheroma volume that was previously reported. This indicates that 2 imaging methods that measured different parameters and focused on different segments of the coronary arteries demonstrated concordant improvements consistent with regression of atherosclerosis with intensive statin therapy. In particular, rosuvastatin treatment for 24 months, resulting in mean low-density lipoprotein cholesterol levels well below 70 mg/dL and significant increases in high-density lipoprotein cholesterol, decreased coronary artery percent stenosis and improved minimum lumen diameter in patients with coronary artery disease. Both imaging and outcome studies suggest that intensive statin treatment seems warranted in high-risk coronary artery disease patients. The relative importance of low-density lipoprotein cholesterol reduction and high-density lipoprotein cholesterol elevation with statin therapy in producing these results on atherosclerosis requires further investigation. See p 2458.
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Cross-Sectional Relations of Digital Vascular Function to Cardiovascular Risk Factors in the Framingham Heart Study |
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Endothelial dysfunction contributes to atherogenesis and the development of clinical cardiovascular disease. Digital pulse amplitude response to hyperemia is a novel method for noninvasively assessing vascular function in humans. In a large, community-based sample, we measured digital vascular function using a fingertip peripheral arterial tonometry device. Hyperemia produced a time-dependent increase in fingertip pulse amplitude. We related digital vascular response to hyperemia to cardiovascular risk factors. We observed that male sex, body mass index, ratio of total to high-density lipoprotein cholesterol, diabetes mellitus, smoking, and lipid-lowering treatment were associated with lower pulse amplitude hyperemic response. Digital vascular function was related to multiple traditional and metabolic cardiovascular risk factors. Our findings support further studies to define the clinical utility and predictive value of digital pulse amplitude. See p 2467.
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Association of Serum Creatinine With Abnormal Hemodynamics and Mortality in Pulmonary Arterial Hypertension |
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Pulmonary arterial hypertension is a devastating disease of the pulmonary vasculature that ultimately leads to right heart failure and death. Novel risk predictors for mortality in pulmonary arterial hypertension may assist in the identification of high-risk patients and may also lead to a better understanding of disease pathophysiology. Several studies have found serum creatinine (SCr) and SCr-based estimates of glomerular filtration rate to be potent predictors of poor outcome in patients with cardiovascular diseases such as coronary artery disease and heart failure. We sought to determine whether elevated SCr was associated with abnormal hemodynamics and predicted death in 500 patients with World Health Organization group I pulmonary arterial hypertension who were followed up for a median of 3.5 years (maximum follow-up 21 years). We found that SCr was significantly associated with abnormal hemodynamics and poor functional status. Furthermore, a single baseline measurement of SCr predicted death. Compared with patients with SCr <1.0 mg/dL, those with SCr 1.0 to 1.4 mg/dL and SCr >1.4 mg/dL had an increased hazard ratio of death (unadjusted hazard ratio 1.65, 95% confidence interval 1.26 to 2.17, P<0.0001 for SCr 1.0 to 1.4 mg/dL; unadjusted hazard ratio 2.54, 95% confidence interval 1.73 to 3.71, P<0.0001 for SCr >1.4 mg/dL). On multivariable analysis, we found a significant interaction between SCr and right atrial pressures, whereby increased SCr best predicted death in patients with right atrial pressure <10 mm Hg. Our results show that measurement of SCr is practical and offers a simple way to noninvasively predict abnormal hemodynamics and death. See p 2475.
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Asymptomatic Peripheral Arterial Disease Is Associated With More Adverse Lower Extremity Characteristics Than Intermittent Claudication |
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Eight million men and women in the United States have lower extremity peripheral arterial disease (PAD). Fully 20% to 50% of persons with PAD have no exertional leg symptoms (ie, are asymptomatic). Asymptomatic individuals with PAD who develop leg symptoms during a 6-minute walk test presumably have restricted their physical activity to avoid exertional leg symptoms during daily life. The clinical significance of asymptomatic PAD among those who do not develop leg symptoms during the 6-minute walk test is unclear. In this study, asymptomatic PAD participants who did not develop leg symptoms during the 6-minute walk test were classified as always asymptomatic. Among 429 men and women with PAD identified by the noninvasive vascular laboratory, we found that persons with PAD who are always asymptomatic have significantly smaller calf muscle area, higher calf muscle percent fat, lower calf muscle density, poorer lower extremity peripheral nerve function, and poorer lower extremity functional performance compared with PAD participants with classic symptoms of intermittent claudication. Our results indicate that clinicians should not equate lack of exertional leg symptoms with a "benign" form of PAD. Our results also underscore the importance of ankle brachial index screening to identify persons with PAD who are asymptomatic. Further study is needed to identify therapies that improve walking performance in asymptomatic individuals with PAD. See p 2484.
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Mitochondrial Haplogroups: Ischemic Cardiovascular Disease, Other Diseases, Mortality, and Longevity in the General Population |
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More than 75 human diseases have been associated with rare mutations in the mitochondrial genome; these mutations either impair mitochondrial protein synthesis or impair proteins encoded by the mitochondrial genome. Recently, numerous reports have suggested a role for mitochondrial haplogroups, defined by the presence or absence of common polymorphisms, in the pathogenesis of ischemic cardiovascular disease and other diseases, as well as in longevity. However, other reports could not confirm such associations, emphasizing the need for large prospective population-based studies to clarify this. In the present study, we tested the hypothesis that common haplogroups predict risk of ischemic cardiovascular disease, morbidity from other causes, mortality, and longevity in a general population of European descent. A total of 9254 individuals from the Danish general population, in the Copenhagen City Heart Study, were followed prospectively for risk of ischemic cardiovascular disease, morbidity, and mortality during 25 and 11 years, respectively. Hazard ratios for hospitalization due to all cardiovascular disorders and ischemic cerebrovascular disease did not differ from 1.0 for any haplogroup versus the most common haplogroup H. Results were similar for hospitalization due to infectious diseases, respiratory disorders, malignant neoplasms, digestive disorders, musculoskeletal disorders, and miscarriages. Likewise, hazard ratios for death from all causes were not different from 1.0 for any haplogroup. Finally, after stratification by major causes of death, hazard ratios remained insignificant. Our results do not support an association of mitochondrial haplogroups with risk of ischemic cardiovascular disease, morbidity from other causes, mortality, or longevity in a large general population of European descent. See p 2492.
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Impact of Time of Presentation on the Care and Outcomes of Acute Myocardial Infarction |
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Previous studies showed an inconsistent association between patients’ arrival time for acute myocardial infarction (AMI) and their subsequent medical care and outcomes. Using a contemporary national clinical registry, we examined differences in medical care and in-hospital mortality among AMI patients admitted during regular hours (weekdays 7 AM to 7 PM) versus off-hours (weekends, holidays, and 7 PM to 7 AM weeknights). In the current large cohort study of 62 814 patients with AMI from the multicenter Get With the Guidelines–Coronary Artery Disease database, we found that AMI patients arriving during off-hours were slightly less likely to undergo revascularization or primary percutaneous coronary intervention, more likely to receive fibrinolytic therapy, and had no differences in the use of overall reperfusion therapy compared with those arriving during regular hours. ST-elevation MI patients, in particular, were less likely to receive timely mechanical reperfusion. Despite the slight disparities in revascularization rates and especially the larger differences in timely mechanical reperfusion, no measurable differences were found in in-hospital mortality in the overall AMI cohort and in the ST-elevation MI and non–ST-elevation MI subpopulations. Similar observations were made across most age and sex subgroups and using an alternative definition for arrival time (weekends/holidays versus weekdays). Healthcare providers should continue to work to enhance the healthcare system during regular hours and off-hours and to reduce existing disparities in cardiac care through multifaceted initiatives aiming to improve the timely delivery of evidence-based therapies. See p 2502.
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Hands-On Defibrillation: An Analysis of Electrical Current Flow Through Rescuers in Direct Contact With Patients During Biphasic External Defibrillation |
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During resuscitation from cardiac arrest due to ventricular fibrillation or ventricular tachycardia, "all-clear" or "hands-off" periods are mandated to avoid potential electrocution of rescuers. These hands-off periods interfere with resuscitation, especially given that current strategies emphasize the importance of avoiding any interruption of chest compressions. There have been substantial changes to external defibrillation technology since hands-off precautions were developed. We addressed the feasibility and safety of direct rescuer-patient contact during defibrillation by measuring the voltage and current through mock rescuers simulating chest compressions on patients receiving external biphasic countershocks with adhesive shock electrodes. The main finding of this work was that the leakage current, the key determinant of potential harm to a rescuer, was very low. Within the constraints of our model, uninterrupted manual chest compressions in a patient being defibrillated are associated with exposure to safe, imperceptible levels of electrical current. In many cases of cardiac arrest, these observations would allow for elimination of routine harmful delays during resuscitation and simplify the resuscitation protocol. See p 2510.
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Torcetrapib Does Not Reduce Atherosclerosis Beyond Atorvastatin and Induces More Proinflammatory Lesions Than Atorvastatin |
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Inhibition of cholesteryl ester transfer protein (CETP) activity is regarded as a promising strategy to increase high-density lipoprotein cholesterol and to reduce atherosclerosis. Torcetrapib was the first CETP inhibitor tested in large human trials and was shown to increase high-density lipoprotein cholesterol by
60%. However, the Rating Atherosclerosis Disease Change by Imaging With a New CETP Inhibitor (RADIANCE) and the Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE) trials revealed no therapeutic benefit of combining torcetrapib with atorvastatin with respect to atherosclerosis progression. Moreover, the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial was stopped prematurely because of an excess of (cardiovascular) deaths in patients receiving torcetrapib. By using hyperlipidemic APOE*3-Leiden.CETP transgenic mice, which respond in a human-like manner to the lipid-lowering effect of atorvastatin and the high-density lipoprotein cholesterol–raising effect of torcetrapib, we demonstrated that torcetrapib did not increase the antiatherogenic potency of atorvastatin, but torcetrapib alone did reduce atherosclerosis progression to a higher extent than expected on the basis of the cholesterol reduction. On the other hand, torcetrapib resulted in lesions of a more proinflammatory phenotype than atorvastatin. Although plaque rupture is a rare phenomenon in mice, such lesions with a high ratio of macrophage to collagen are more unstable and may well have caused an increased incidence of plaque rupture in humans, thereby partially explaining the increased cardiovascular death in the of trial. Whether the effects of torcetrapib on cardiovascular events and death are compound specific or related to CETP inhibition remains to be evaluated. Taken together, these results suggest that CETP inhibition per se is still a valid strategy for reducing cardiovascular risk, given that (novel) CETP inhibitors (eg, JTT-705 and anacetrapib) do not adversely affect plaque composition. See p 2515.
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