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Lack of blood flow to the lower extremities in peripheral arterial disease causes oxygen and nutrient deprivation in ischemic skeletal muscles, leading to functional impairment. Treatment options for muscle regeneration in this scenario are lacking. Here, we selectively targeted the Hippo pathway in myofibers, which provide architectural support for muscle stem cell niches, to facilitate functional muscle recovery in ischemic extremities by promoting angiogenesis, neovascularization, and myogenesis. We knocked down the core Hippo pathway component, Salvador (SAV1), by using an adeno‐associated virus 9 (AAV9) vector expressing a miR30‐based triple short‐hairpin RNA (shRNA), controlled by a muscle‐specific promoter. In a mouse hindlimb‐ischemia model, AAV9 SAV1 shRNA administration in ischemic muscles induced nuclear localization of the Hippo effector YAP, accelerated perfusion restoration, and increased exercise endurance. Intravascular lectin labeling of the vasculature revealed enhanced angiogenesis. Using 5‐ethynyl‐2′‐deoxyuridine to label replicating cellular DNA in vivo, we found SAV1 knockdown concurrently increased paired box transcription factor Pax7+ muscle satellite cell and CD31+ endothelial cell proliferation in ischemic muscles. To further study Hippo suppression in skeletal muscle regeneration, we used a cardiotoxin‐induced muscle damage model in adult (12‐15 weeks old) and aged mice (26‐month old). Two weeks after delivery of AAV9 SAV1 shRNA into injured muscles, the distribution of regenerative myofibers shifted toward a larger cross‐sectional area and increased capillary density compared with mice receiving AAV9 control. Together, these findings suggest our approach may have clinical promise in regenerative therapy for leg ischemia and muscle injury. Our AAV9 Salvador shRNA strategy recreates a myofiber‐guided regenerative stem cell niche and promotes simultaneous myogenesis and angiogenesis‐neovascularization for the functional recovery of skeletal muscles in ischemic extremities. These myofibers release paracrine elements to activate (a) satellite cells to proliferate and self‐renew for myogenesis and (b) endothelial cells to stimulate angiogenesis and neovascularization.

Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls. Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.

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In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and maximal oxygen consumption (VO2max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2max during the 6-month course of the FOCUS-CCTRN study (group 1, n= 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n= 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n= 11). Group 1 had higher frequencies of B-cell and CXCR4+BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy—even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials.

This review presents the findings from a select group of clinical trials of stem cell therapy for both acute and chronic heart disease. These studies are used to highlight the insight gained through such investigations and the remaining challenges.

The accumulation of macrophages in inflamed atherosclerotic plaques has long been recognized. In an attempt to develop an imaging agent for detection of vulnerable plaques, we evaluated the feasibility of a liposomal-iodine nanoparticle contrast agent for computed tomography imaging of macrophage-rich atherosclerotic plaques in a mouse model.

Mesenchymal stem cells (MSCs) can differentiate into endothelial cells in vivo. However, it is unknown if the differentiated MSCs persist in vivo and if this potential persistence contributes to functional improvement after experimental myocardial infarction.

Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are classic forms of systolic and diastolic heart failure, respectively. Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of HCM and DCM. MURC, encoding muscle-restricted coiled-coil, a Z-line protein, regulates cardiac function in mice. We investigated potential causal role of MURCin human cardiomyopathies.

Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2 366 858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2 478 304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

Introduction: Although current guidelines recommend withholding statins in perioperative patients, little information is available on whether perioperative statin use increases risk for postoperative renal failure. Aims: We examined the relation between preoperative statin therapy and postoperative risk for renal insufficiency in patients undergoing cardiac surgery. Methods: Retrospective cohort review from the Texas Heart Institute research database was performed. Patients were divided into two groups: those who received preoperative statins and those who did not. Primary outcome was the development of postoperative renal insufficiency (requiring dialysis or not). Outcomes were assessed in the entire cohort and in subgroups undergoing isolated coronary artery bypass grafting (CABG), isolated valve surgery, or combined CABG and valve surgery. Results: Of 3001 patients, 56% received preoperative statins. In multivariate logistic regression analysis, preoperative statins were associated with significant reductions in risk for postoperative renal insufficiency in the entire cohort (odds ratio [OR]= 0.60, 95% confidence interval [CI] 0.38–0.95) and in patients undergoing isolated CABG (OR = 0.34, 95% CI 0.17–0.68). In patients undergoing isolated valve surgery (OR = 1.35, 95% CI 0.61–2.96) or combined CABG and valve surgery (OR = 1.39, 95% CI 0.48–3.99), preoperative statins were not associated with decreased incidence of postoperative renal insufficiency. Age >65 years, preoperative renal insufficiency, history of congestive heart failure, preoperative intra‐aortic balloon pump insertion, and total cardiopulmonary bypass time >80 min were also independent predictors associated with increased risk for postoperative renal insufficiency. Conclusions: Preoperative statin therapy was associated with decreased incidence of postoperative renal insufficiency in patients undergoing cardiac surgeries, particularly in patients undergoing isolated CABG.

Introduction: Although current guidelines recommend withholding statins in perioperative patients, little information is available on whether perioperative statin use increases risk for postoperative renal failure. Aims: We examined the relation between preoperative statin therapy and postoperative risk for renal insufficiency in patients undergoing cardiac surgery. Methods: Retrospective cohort review from the Texas Heart Institute research database was performed. Patients were divided into two groups: those who received preoperative statins and those who did not. Primary outcome was the development of postoperative renal insufficiency (requiring dialysis or not). Outcomes were assessed in the entire cohort and in subgroups undergoing isolated coronary artery bypass grafting (CABG), isolated valve surgery, or combined CABG and valve surgery. Results: Of 3001 patients, 56 received preoperative statins. In multivariate logistic regression analysis, preoperative statins were associated with significant reductions in risk for postoperative renal insufficiency in the entire cohort (odds ratio OR 0.60, 95 confidence interval CI 0.38-0.95) and in patients undergoing isolated CABG (OR 0.34, 95 CI 0.17-0.68). In patients undergoing isolated valve surgery (OR 1.35, 95 CI 0.61-2.96) or combined CABG and valve surgery (OR 1.39, 95 CI 0.48-3.99), preoperative statins were not associated with decreased incidence of postoperative renal insufficiency. Age >65 years, preoperative renal insufficiency, history of congestive heart failure, preoperative intra-aortic balloon pump insertion, and total cardiopulmonary bypass time >80 min were also independent predictors associated with increased risk for postoperative renal insufficiency. Conclusions: Preoperative statin therapy was associated with decreased incidence of postoperative renal insufficiency in patients undergoing cardiac surgeries, particularly in patients undergoing isolated CABG.

As recently demonstrated, random allocation to rosuvastatin results in large relative risk reductions for first cardiovascular events among apparently healthy men and women with low levels of low-density lipoprotein cholesterol but elevated levels of high-sensitivity C-reactive protein. However, whether the absolute risk reduction among such individuals justifies wide application of statin therapy in primary prevention is a controversial issue with broad policy and public health implications.

Despite the wealth of research into C-reactive protein (CRP), it remains unclear which patient populations would benefit from and should be targeted for high-sensitivity assay CRP testing. In this important Review, Musunuruet al. address the relevance of CRP in a variety of scenarios encountered in clinical practice—from primary prevention of cardiovascular disease, stroke and diabetes mellitus, to secondary prevention of cardiovascular disease.

Se desconoce si la administración de células madre tiene el mismo efecto en pacientes diabéticos y en no diabéticos. Para ello se estudió a 26 pacientes consecutivos, incluidos en dos estudios, tratados con células mononucleadas de médula ósea (CMNMO), con miocardiopatía isquémica crónica y sin opción a revascularización. Se les realizó un mapeo electromecánico con NOGA para identificar miocardio viable (voltaje unipolar≥6,9 mV) y se les inyectó una media de 28,5±4,7 millones de CMNMO. Se realizó un seguimiento a los 6 meses. En los pacientes no diabéticos, se observó una reducción significativa del volumen telesistólico a los 6 meses en comparación con el basal, una disminución significativa de la clase NYHA (de 3 [1,75-3] a 1 [1-2]; p=0,04), de la puntuación de angina de la clasificación canadiense (de 3 [2-4] a 1 [1-1,5]; p=0,04) y un aumento del consumo de oxígeno (de 16,4 [13,1-21,5] a 24,5 [17,3-29,2] ml/kg/min; p=0,04). Estas diferencias no se observaron en los pacientes diabéticos. Éste es el primer estudio clínico que observa que la inyección de CMNMO podría tener un menor efecto en los diabéticos.

The incidence of coronary artery disease has been shown to be greater in patients with calcific deposits than in those without. It has been suggested that the pattern of distribution of coronary calcific deposits within coronary arteries is of greater predictive value for acute coronary events than the overall quantity. Whether roughness of calcific deposits is a predictor of acute coronary events is not known. We derived and tested an algorithm, Voxel-Based Bosselation (VBB), for noninvasive quantification of roughness of calcific deposits in human coronary arteries imaged by computed tomography (CT).

Purpose: Because multiple genetic variants influence risk for coronary heart disease, we combined multiple variants that had been associated with coronary heart disease in several studies into a genetic risk score and asked whether a high genetic risk score would be significantly associated with coronary heart disease after accounting for traditional risk factors.Methods: We considered five variants that were associated with coronary heart disease in two studies and confirmed in the Atherosclerosis Risk in Communities study: rs20455 (KIF6), rs3900940 (MYH15), rs7439293 (PALLD), rs2298566 (SNX19), and rs1010 (VAMP8). We calculated a genetic risk score for each Atherosclerosis Risk in Communities study participant and estimated the hazard ratio for incident coronary heart disease of a high genetic risk score (compared with not-high) in Cox models that adjusted for traditional risk factors during a median of 13 years of follow-up.Results: For white participants with a high genetic risk score (4% of the 9129 whites), compared with those without a high genetic risk score, the hazard ratio for incident coronary heart disease was 1.57 (95% confidence interval 1.21–2.04; P = 0.001). Internal validation using bootstrap samples estimated that a hazard ratio of 1.43 could be expected in external populations.Conclusions: After adjusting for traditional risk factors, those with a high genetic risk score had a 57% increased risk of incident coronary heart disease in the Atherosclerosis Risk in Communities study.

The response to injury in the vasculature and the heart is inflammation. Atherosclerosis is often the result of injury followed by inflammation and atherosclerosis. Vascular and myocardial infections from various pathogens, including viruses, bacteria, chlamydia, and other infections result in vascular inflammation and almost certainly play a role in the development of atherosclerosis and acute coronary heart disease syndromes in at least some patients. Current evidence favors prior exposure to multiple pathogens as most likely playing a role in initiating inflammation and contributing to atherosclerosis. Genetic predisposition is almost certainly an important factor in the development of inflammation, impaired endothelial vascular repair, vascular infection, thrombosis, and atherosclerosis. The aging process itself is most likely associated with altered vascular and myocardial defense mechanisms predisposing to inflammation. The oxidation of cholesterol and low-density lipoprotein (LDL) leads to the production of oxidized radicals that promote vascular inflammation. Interventional injury, including angioplasty and stenting, causes endothelial inflammation, thrombosis, and fibroproliferation. Systemic evidence of inflammation identifies patients at high risk of future coronary events, including those who appear to be healthy initially as well as those with stable and unstable coronary heart disease syndromes. Increases in serum C-reactive protein (CRP) identify individuals at risk for future vascular events, including unstable angina, acute myocardial infarction, acute cerebrovascular accident, and sudden death. Similarly, systemic elevations in serum troponin 1, serum amyloid-like protein, fibrinogen, and interleukins-1, 2, 6, 8, and 18 identify patients with unstable angina and non–Q-wave myocardial infarction at increased risk for future coronary events. The presence of vascular inflammation may be detected by identifying temperature heterogeneity within plaques that demonstrate inflammation. In the future, the local evaluation of atherosclerotic plaques to detect the presence of inflammation coupled to measurements of systemic markers of inflammation, such as C-reactive protein, may help identify patients at increased risk and allow both local and systemic therapies that reduce their risk and prevent the development of acute coronary syndromes in at least some patients. Copyright 2002, Elsevier Science (USA). All rights reserved.

OBJECTIVES

BackgroundPlatelets play a key role in the pathogenesis of atherosclerosis, thrombosis, and acute coronary and cerebrovascular syndromes. Inhibition of platelet function by acetylsalicylic acid (aspirin) has been shown to reduce the incidence atherothrombotic events in patients with coronary, cerebrovascular, or peripheral vascular disease. Thienopyridine agents, however, including ticlopidine and clopidogrel, inhibit the adenosine diphosphate receptor and have modestly superior effects compared with aspirin on reduction of death, myocardial infarction, and stroke among a broad group of patients with vascular disease. More effective antithrombotic agents are still required to treat patients at high risk for recurrent vascular events. MethodsLotrafiban, a selective, nonpeptide antagonist of the human platelet fibrinogen receptor (glycoprotein [GP] IIb/IIIa [αIIb/β3 integrin]), blocks the binding of fibrinogen to the GP IIb/IIIa receptor, which is the final common pathway of platelet aggregation. Lotrafiban at doses of up to 50 mg twice daily was well-tolerated in a 12-week, double-blind, placebo-controlled, dose-ranging study in patients with recent myocardial infarction, unstable angina, transient ischemic attack, or stroke when added to aspirin therapy. On the basis of these results, a dosing regimen was selected for the phase III Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial based on pharmacodynamics and drug tolerability. In the pivotal BRAVO study, lotrafiban therapy is being evaluated in patients who have had a recent myocardial infarction, unstable angina, transient ischemic attack, or ischemic stroke, or who present at any time after a diagnosis of peripheral vascular disease combined with either cardiovascular or cerebrovascular disease. ResultsThe efficacy evaluation will be based on a composite end point of clinical events (death by any cause, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, or urgent ischemia-driven revascularization). The target enrollment is 9200 patients worldwide. Approximately 700 centers will participate and will be distributed within 30 countries across North America, Europe, Australia, and Asia. (Am Heart J 2000;139:927-33.)

Gene therapy–mediated disruption of Hippo signaling results in tissue renewal and improved function in pigs after myocardial infarction.

Aspirin is the most widely prescribed agent to reduce the platelet-mediated contributions to atherosclerosis, coronary thrombosis and restenosis after angioplasty. While aspirin treatment has led to significant reductions in morbidity and mortality in many clinical trials, there are several scenarios in which aspirin may fail to provide a full antithrombotic benefit. The cyclic flow model of experimental coronary thrombosis suggests that elevations of plasma catecholamines, high shear forces acting on the platelets in the stenosed lumen and the presence of multiple, input stimuli can activate platelets through different mechanisms that may lead to thrombosis despite aspirin therapy. Aspirin therapy is limited because it only blocks some of the input stimuli, leaving aspirin-independent pathways through which coronary thrombosis can be precipitated. These include thrombin and thrombogenic arterial wall substrates such as tissue factor. New agents that block the adenosine diphosphate (ADP) receptor, or regulate platelet free cytosolic calcium, such as direct nitric oxide donors, may be more potent overall than aspirin. Agents that block the platelet integrin GPIIb-IIIa receptor inhibit the binding of fibrinogen to platelets regardless of which input stimuli activate the platelet and, thus, as demonstrated in the cyclic flow model, would be much more potent than aspirin as an antithrombotic agent. The cyclic flow model has been useful in predicting which agents are likely to be of benefit in clinical trials.

Detection and evaluation of aortic root and other cardiovascular abnormalities in patients with Marfan's syndrome are important in determining appropriate therapy and preventing premature mortality. To evaluate the role of nuclear magnetic resonance imaging (NMR) in this syndrome, 10 patients were evaluated using a 0.35 tesla commercial nuclear magnetic resonance imaging system. Findings from these studies were compared with data from other noninvasive tests as well as surgical follow-up. Results from these examinations indicate that NMR-derived measurements of aortic root diameter agree closely with echocardiography measurements. In addition, NMR provides more complete anatomic detail than does echocardiography and can be utilized to assess and follow up virtually all patients with this syndrome.

Controversy has arisen concerning whether gender influences the prognosis after myocardial infarction. Although some studies have shown there to be no difference between the sexes, most have indicated a worse prognosis for women, attributing this to differences in baseline characteristics. It has been further suggested that black women have a particularly poor prognosis after infarction. To determine the contribution of gender and race to the course of infarction, 816 patients with confirmed myocardial infarction who were enrolled in the Multi-center Investigation of the Limitation of Infarct Size (MILIS) were analyzed. Of those patients, 226 were women and 590 were men, 142 were black and 674 were white.

• The serum ionized calcium, phosphate parathyroid hormone, and myoglobin levels were observed in a patient with idiopathic hypoparathyroidism and rhabdomyolysis. Since calcium levels best correlate inversely with serum myoglobin and lactic dehydrogenase, we suggest that these two enzymes are better markers of the activity of rhabdomyolysis than serum creatine phosphokinase or SGOT. Furthermore, a non-hormonal, nonrenal mechanism is important in the fluxes of serum calcium and phosphate in rhabdomyolysis.(Arch Intern Med 1983;143:154-157)

Hypertonic mannitol previously has been shown to improve cardiac function, increase collateral flow, and decrease epicardial ST segment elevation following coronary occlusion in anesthetized or awake dogs. The present study quantitates by morphologic techniques, the effect of hypertonic mannitol on infarct size. Ischemic injury was produced by proximal occlusion of the circumflex artery for 40 min and necrosis was assessed after 48 hr of reflow. One group of dogs was given isotonic saline and the other hypertonic mannitol beginning the infusions just prior to, during, and for a short period after the release of the circumflex coronary artery occlusion. Serum osmolality increased by approximately 40 mOsm in the mannitol group. The administration of hypertonic mannitol was associated with a 40-50% reduction in infarct size measured histologically. The incidence of ventricular fibrillation during occlusion and following release of the circumflex coronary artery occlusion was greater in mannitol-treated dogs although the difference was not statistically significant. Thus, the data obtained in this study extend previous observations and provide direct evidence that hypertonic mannitol can reduce infarct size in dogs with temporary circumflex artery occlusion and reflow.

The purpose of this study was to test the hypothesis that combined thromboxane A2synthetase inhibition and receptor blockade is superior to either action alone in preventing cyclic flow variations in stenosed and endothelially injured canine coronary arteries. Forty-five dogs developed coronary cyclic flow variations after a plastic constrictor was placed around the left anterior descending coronary artery at the site where the endothelium was injured and received different interventions. In Group I, 17 dogs were treated with SQ 29,548, a thromboxane A2-prostaglandin H2receptor antagonist. In Group II, 11 dogs received dazoxiben, a thromboxane A2synthetase inhibitor. In Group III, R 68,070, a dual thromboxane A2synthetase inhibitor and thromboxane A2-prostaglandin H2receptor antagonist, was administered to 11 dogs. Group IV comprised six dogs that received aspirin before receiving R 68,070.