Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Secondary Prevention and Mortality in Peripheral Artery Disease: National Health and Nutrition Examination Study, 1999 to 2004
- Cardiac Dysfunction and Noncardiac Dysfunction as Precursors of Heart Failure With Reduced and Preserved Ejection Fraction in the Community
- Puma Deletion Delays Cardiac Dysfunction in Murine Heart Failure Models Through Attenuation of Apoptosis
- Mitral Valve Abnormalities Identified by Cardiovascular Magnetic Resonance Represent a Primary Phenotypic Expression of Hypertrophic Cardiomyopathy
- Nonmuscle Myosin Light-Chain Kinase Deficiency Attenuates Atherosclerosis in Apolipoprotein E–Deficient Mice via Reduced Endothelial Barrier Dysfunction and Monocyte Migration
- Perishock Pause: An Independent Predictor of Survival From Out-of-Hospital Shockable Cardiac Arrest
- Increased Adipose Tissue Oxygen Tension in Obese Compared With Lean Men Is Accompanied by Insulin Resistance, Impaired Adipose Tissue Capillarization, and Inflammation
- Rhesus Macaques Develop Metabolic Syndrome With Reversible Vascular Dysfunction Responsive to Pioglitazone
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Secondary Prevention and Mortality in Peripheral Artery Disease: National Health and Nutrition Examination Study, 1999 to 2004
Cardiovascular disease remains a major cause of morbidity and mortality in the United States. Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis that confers a significantly increased risk of myocardial infarction, stroke, and death. Whether cardiovascular risk can be reduced by implementation of secondary prevention therapies (such as antiplatelet therapy, statins, or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) in individuals with PAD identified by a screening ankle-brachial index measurement is unknown. Using data from the National Health and Nutrition Examination Survey (NHANES), we demonstrate that millions of high-risk US adults with PAD (ankle-brachial index ≤0.90) were not receiving guideline-recommended secondary prevention therapies. All-cause mortality was significantly higher in individuals with PAD, including those without previously recognized cardiovascular disease. Furthermore, treatment with multiple secondary prevention therapies was associated with significantly reduced risk of all-cause mortality in this population. Given the conflicting literature about the use of secondary prevention therapies, aspirin in particular, in patients with PAD, these observational findings underscore the importance of a large-scale clinical trial to determine whether implementation of multiple secondary prevention therapies specifically in high-risk individuals identified by ankle-brachial index screening as having PAD can indeed reduce cardiovascular morbidity and mortality. See p 17.
Cardiac Dysfunction and Noncardiac Dysfunction as Precursors of Heart Failure With Reduced and Preserved Ejection Fraction in the Community
In our prospective study of a large, community-based sample, antecedent subclinical cardiac and noncardiac major organ system dysfunction was associated with risk of future heart failure. The presence of asymptomatic left ventricular systolic and diastolic dysfunction preceded and increased the risk of incident heart failure by >2-fold and >30%, respectively. With adjustment for cardiac dysfunction, the presence of subclinical renal impairment, airflow limitation, or anemia was each associated with 30% increased risk of incident heart failure. Notably, the significant risk factors differed according to the type of incident heart failure (preserved versus reduced ejection fraction). Antecedent left ventricular systolic dysfunction, subclinical renal impairment, and lower hemoglobin concentrations were associated with a higher incidence of heart failure with reduced ejection fraction, whereas antecedent diastolic dysfunction and baseline airflow obstruction were related positively to the risk of future heart failure with preserved ejection fraction. This study provides longitudinal evidence for the progressive nature of heart failure as emphasized in current heart failure guidelines and underscores the potential importance of noncardiac risk factors in predisposing to the manifestation of overt heart failure. The implications for the early identification of individuals at risk of heart failure and potential strategies to prevent progression to overt heart failure deserve further study. See p 24.
Puma Deletion Delays Cardiac Dysfunction in Murine Heart Failure Models Through Attenuation of Apoptosis
p53 is a tumor suppressor gene that exerts its effect through transcriptional activation. Puma (p53-upregulated modulator of apoptosis) and Mdm4 represent 2 critical p53 targets; although Puma serves as the major downstream proapoptotic effector of p53, Mdm4 inhibits p53-mediated apoptosis by direct binding. Puma is a unique member of the Bcl-2 family because it integrates and implements most signals mediated by different apoptosis inducers. In the present study, we used Puma knockout mice in 2 heart failure models, triggered by pressure overload and heart-specific Mdm4-ablation, and found that Puma-induced apoptosis may play a role in the progression of heart failure. Interestingly, Puma can be activated not only by pressure overload but also by myocardial ischemia. Our results thus provide insight into the function of the Mdm4-p53-Puma axis in cardiomyocytes, which could ultimately aid in the development of antiapoptotic drug candidates to treat various cardiac diseases. Moreover, lack of Puma does not recapitulate the tumor-prone phenotype observed in p53-negative mice. Because the Mdm4-p53-Puma interface has also been the focus of recent drug discovery efforts in cancer, additional functional analysis of this system in the heart could contribute to the development of safer anticancer therapies with minimal cardiotoxic side effects. Of note, Puma is not the only contributor to cardiac signaling during heart failure, and further studies are required to elucidate its connection with other apoptotic pathways. In conclusion, Puma antagonists might be developed in the future to provide cardiac protection without increasing susceptibility to tumors, an adverse effect of therapies based on p53 inactivation. See p 31.
Mitral Valve Abnormalities Identified by Cardiovascular Magnetic Resonance Represent a Primary Phenotypic Expression of Hypertrophic Cardiomyopathy
Mutations in genes encoding proteins of the cardiac sarcomere are responsible for left ventricular hypertrophy, the diagnostic sine qua non of hypertrophic cardiomyopathy (HCM). However, whether other morphological features of HCM, seemingly unrelated to sarcomere mutations, are part of the disease phenotype is uncertain. We used cardiovascular magnetic resonance to characterize mitral valve abnormalities in a cohort of patients with HCM. Both anterior and posterior mitral valve leaflet lengths were greater among HCM patients compared with an age- and sex-matched control population (26±5 versus 19±5 mm, P<0.001; and 14±4 versus 10±3 mm, P<0.001, respectively), including more than one third of HCM patients in whom one or both of the mitral leaflets were substantially increased in length. In HCM patients, there was no relationship between mitral valve leaflet length and a number of clinical and demographic variables, including age, maximal left ventricular wall thickness, or left ventricular mass. In addition, elongated mitral valve leaflets were often the only clinical manifestation present in HCM family members carrying a sarcomere mutation without left ventricular hypertrophy and can represent the sole clinical marker of genotype-positive status. Elongated mitral valve leaflets were an important determinant of left ventricular outflow obstruction, particularly in patients in whom anterior mitral leaflet length exceeded 2-fold the transverse dimension of the outflow tract. These cardiovascular magnetic resonance–based observations show that structural abnormalities of the mitral valve represent a primary expression of the HCM phenotype and a morphological marker that may aid in diagnostic and management strategies, including optimal planning for septal reduction therapy. See p 40.
Nonmuscle Myosin Light-Chain Kinase Deficiency Attenuates Atherosclerosis in Apolipoprotein E–Deficient Mice via Reduced Endothelial Barrier Dysfunction and Monocyte Migration
Endothelial dysfunction and monocyte migration have been implicated in the pathogenesis of atherosclerosis. Nonmuscle myosin light chain kinase (nmMLCK) is known to contribute to inflammation-associated endothelial barrier dysfunction by activating the cytoskeletal contractile response via its kinase activity on myosin light chain phosphorylation. The specific contribution of nmMLCK to atherosclerotic injury and its mechanism of action have not been evaluated. In this study, we tested the hypothesis that nmMLCK promoted atherosclerotic lesion development by altering endothelial barrier properties. In the aorta of apolipoprotein E–deficient mice fed an atherogenic diet, nmMLCK deficiency significantly reduced lesion size, intimal hyperplasia, and macrophage deposition in the vascular wall, indicating a pathogenic role of nmMLCK in atherosclerosis. Consistent with the in vivo observations, nmMLCK expression was detected in both AECs and peripheral monocytes, and nmMLCK deficiency attenuated endothelial hyperpermeability and monocyte transendothelial migration caused by atherosclerosis-relevant inflammatory stimuli, including thrombin, oxidized low-density lipoprotein, tumor necrosis factor α, and monocyte chemoattractant protein-1. Further mechanistic studies demonstrated that, in addition to myosin light chain phosphorylation, Src signaling contributed to nmMLCK-induced cellular responses. Pharmacological blockade or genetic manipulation of Src inhibited nmMLCK-mediated hyperpermeability and monocyte transmigration. Taken together, the data suggest a novel function of nmMLCK in atherosclerosis that involves a nonconventional signaling pathway independent of myosin light chain phosphorylation. Further characterization of specific cellular responses to isoform-specific MLCK kinase activity and kinase-independent mechanisms would contribute to the development of new therapeutic targets for treating atherosclerosis. See p 48.
Perishock Pause: An Independent Predictor of Survival From Out-of-Hospital Shockable Cardiac Arrest
Interruptions in chest compressions during cardiopulmonary resuscitation are commonplace and known to be deleterious to resuscitation success. The 2010 American Heart Association guidelines on cardiopulmonary resuscitation recommend minimizing any interruptions in chest compressions to <10 seconds. Pauses occurring before and after defibrillatory shock, otherwise known as perishock pauses, have been shown to have a significant impact on both termination of ventricular fibrillation and return of spontaneous circulation. In this observational study from the Resuscitation Outcomes Consortium Cardiac Epistry, researchers have been able to demonstrate significant relationships between both preshock and perishock pause and survival to hospital discharge from shockable cardiac arrest. Interestingly, no significant relationship was noted between postshock pause and survival to hospital discharge. Although we recognize the study limitations, the implications of these findings are important for both defibrillator manufacturers and cardiopulmonary resuscitation educators. We suggest multiple methods of decreasing preshock pause, including increased use of manual-mode defibrillation for emergency medical service providers, improved algorithms for detecting ventricular fibrillation while working in automatic defibrillator mode, quicker charging of the defibrillator to allow earlier administration of a defibrillatory shock, and performance of cardiopulmonary resuscitation during the defibrillator charging phase, all with a goal of attaining an optimal preshock pause of <5 seconds. By minimizing the preshock pause interval, we may further improve the likelihood of resuscitation success from shockable cardiac arrest. See p 58.
Increased Adipose Tissue Oxygen Tension in Obese Compared With Lean Men Is Accompanied by Insulin Resistance, Impaired Adipose Tissue Capillarization, and Inflammation
The increase in adipose tissue mass during the development of obesity is accompanied by impaired adipose tissue function, which may underlie type 2 diabetes mellitus and cardiovascular disease. The inciting event causing the metabolic and endocrine derangements in adipose tissue of obese individuals remains to be established. Recent cell culture experiments suggest that a reduced oxygen tension in adipose tissue (adipose tissue hypoxia) may be involved. It has been proposed that the expansion of adipose tissue mass during weight gain may lead to adipose tissue hypoxia because angiogenesis is insufficient to maintain normoxia. Although adipose tissue hypoxia has been demonstrated in rodent models of obesity, evidence for this in humans is scarce. We hypothesized that decreased adipose tissue blood flow in obese humans may lower adipose tissue oxygen tension, thereby affecting adipose tissue inflammation and insulin sensitivity. In the present study, we describe a novel system for the continuous monitoring of adipose tissue oxygen tension in humans using microdialysis. Using both pharmacological and physiological approaches, we demonstrate that adipose tissue blood flow regulates adipose tissue oxygen tension in humans. Nevertheless, obese individuals exhibit adipose tissue hyperoxia (increased oxygen tension) despite lower adipose tissue blood flow, which seems to be explained by lower oxygen consumption in adipose tissue. This was accompanied by insulin resistance, impaired adipose tissue capillarization, and higher adipose tissue gene expression of inflammatory cell markers. Although these findings are preliminary in nature and require confirmation, this work sheds new light on the role of adipose tissue oxygen tension in metabolic disease. See p 67.
Rhesus Macaques Develop Metabolic Syndrome With Reversible Vascular Dysfunction Responsive to Pioglitazone
The metabolic syndrome (MetS) is a constellation of clinical features that include central obesity, hypertension, atherogenic dyslipidemia, and insulin resistance and is clinically important both because of its prevalence and because it increases the risk for cardiovascular disease and type 2 diabetes mellitus (T2D). However, the concept remains controversial, and there is a need for better understanding of how MetS predisposes to cardiovascular disease and T2D. Here, we devised and implemented a strategy to establish a spontaneous nonhuman primates model of MetS, investigated the emergence of MetS in relation to vascular dysfunction, and determined the response to an established pharmacological treatment for diabetes mellitus. By identifying MetS-predisposed animals among 408 rhesus monkeys of 12.7 years age and acclimating them to standardized laboratory conditions for 18 months, we established a nonhuman primates model of spontaneous MetS that faithfully reproduced salient features of human MetS. During the transition from pre-MetS to onset MetS, individual components of MetS emerged together, indicating common shared underlying processes rather than simultaneous occurrence of independent risk factors. Importantly, vascular dysfunction (60% impairment of flow-mediated dilation of brachial artery) tracked with development of MetS. Pioglitazone, a peroxisome proliferator–activated receptor γ agonist, reversibly improved atherogenic dyslipidemia and insulin resistance and fully restored flow-mediated dilation with persistent effect, suggesting the benefit for early treatment of MetS before frank T2D develops. This unique nonhuman primate model of MetS, as demonstrated here, should be highly valuable in mechanistic and translational studies on the pathogenesis of MetS in relation to cardiovascular disease and T2D. See p 77.
- © 2011 American Heart Association, Inc.
- Perishock Pause: An Independent Predictor of Survival From Out-of-Hospital Shockable Cardiac Arrest
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