- Neuronal Nitric Oxide Synthase Protects Against Myocardial Infarction–Induced Ventricular Arrhythmia and Mortality in Mice
- Myocardial Salvage Through Coronary Collateral Growth by Granulocyte Colony-Stimulating Factor in Chronic Coronary Artery Disease: A Controlled Randomized Trial
- Accelerated Telomere Shortening in Leukocyte Subpopulations of Patients With Coronary Heart Disease: Role of Cytomegalovirus Seropositivity
- Declines in Acute Myocardial Infarction After Smoke-Free Laws and Individual Risk Attributable to Secondhand Smoke
- Effects of Telmisartan, Ramipril, and Their Combination on Left Ventricular Hypertrophy in Individuals at High Vascular Risk in the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease
- Complementary Prognostic Values of Stress Myocardial Perfusion and Late Gadolinium Enhancement Imaging by Cardiac Magnetic Resonance in Patients With Known or Suspected Coronary Artery Disease
- Survival and Cardiac Remodeling After Myocardial Infarction Are Critically Dependent on the Host Innate Immune Interleukin-1 Receptor–Associated Kinase-4 Signaling: A Regulator of Bone Marrow–Derived Dendritic Cells
- Regulatory T Cells Modulate Postischemic Neovascularization
- Intra–Cardiopulmonary Resuscitation Hypothermia With and Without Volume Loading in an Ischemic Model of Cardiac Arrest
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Neuronal Nitric Oxide Synthase Protects Against Myocardial Infarction–Induced Ventricular Arrhythmia and Mortality in Mice
Ventricular arrhythmia is a common cause of death after myocardial infarction (MI). Cardiomyocyte Ca2+ overload and diastolic Ca2+ leak are important mechanisms responsible for afterdepolarization and triggered activity leading to ventricular arrhythmia after MI. Emerging evidence suggests that neuronal nitric oxide synthase (nNOS) may inhibit arrhythmogenesis by maintaining intracellular Ca2+ homeostasis in cardiomyocytes. However, the role of nNOS in ventricular arrhythmia after MI in vivo is not clear. In the present study, we demonstrated that nNOS deletion was associated with increased mortality, reactive oxygen species production, and apoptosis after MI. A novel finding from our study is that ventricular arrhythmias were significantly higher in nNOS−/− compared with wild-type mice after MI. Deficiency in nNOS increased Ca2+ transient amplitude and L-type Ca2+ channel activity and increased diastolic Ca2+ levels in cardiomyocytes. Lack of nNOS decreased S-nitrosylation of the L-type Ca2+ channel, ryanodine receptor Ca2+ release channel, and SERCA2 in the myocardium after MI. Thus, nNOS has a beneficial role in Ca2+ homeostasis via S-nitrosylation of Ca2+ handling proteins, leading to reductions in ventricular arrhythmias and death after MI. Our study provides new insights into the protective role of nNOS in arrhythmogenesis and may have therapeutic implications after MI. See p 1345.
Myocardial Salvage Through Coronary Collateral Growth by Granulocyte Colony-Stimulating Factor in Chronic Coronary Artery Disease: A Controlled Randomized Trial
In patients with symptomatic coronary artery disease, the size of myocardial infarction is one of the main determinants of outcome after such an event. Accordingly, therapeutic strategies aim to reduce cardiovascular mortality by shrinking infarct size. Infarct size is influenced directly by the duration of coronary occlusion, by ischemic area at risk for infarction, lack of collateral blood supply to the ischemic zone, absence of ischemic preconditioning before the infarct, myocardial oxygen consumption during the infarct, or some combination of these conditions. Aside from limiting the duration of coronary occlusion, the option of reducing infarct size by promoting collateral artery growth (arteriogenesis) is appealing. In patients with chronic coronary artery disease, a beneficial prognostic effect of well-developed versus poorly developed collaterals has been documented. As there are a number of patients who cannot undergo revascularization by percutaneous coronary intervention or bypass surgery, the finding of the present study that granulocyte—colony stimulating factor is efficacious in promoting collateral growth is important. In addition, granulocyte colony-stimulating factor was found to have a prolonged effect on myocardial perfusion in a vascular area subtended by a nonstenotic vessel and the drug was shown to be safe during the short-term protocol. See p 1355.
Accelerated Telomere Shortening in Leukocyte Subpopulations of Patients With Coronary Heart Disease: Role of Cytomegalovirus Seropositivity
Previous studies have provided evidence of an inverse association between telomere length in peripheral blood leukocytes and cardiovascular morbidity or mortality. Using a complex cell-fractionation protocol, we were able to measure telomere length in leukocyte subpopulations of patients with coronary heart disease and age-matched control subjects. Our results show that in patients with coronary heart disease, almost all leukocyte populations, including peripheral blood stem cells and progenitor cells, are affected equally by telomere shortening, which argues in favor of an inherited rather than an acquired cause. The mechanism by which shorter telomere length and the risk of developing coronary heart disease are linked remains to be investigated. It can be speculated whether impaired telomere biology in bone marrow–residing precursors could impose on vascular repair mechanisms. Finally, telomere length specifically in CD8+ cytotoxic T cells was shorter in cytomegalovirus-seropositive than cytomegalovirus-seronegative patients with coronary heart disease and was associated with decreased left ventricular function. Future research should investigate whether in patients with coronary heart disease, the coexistence of cytomegalovirus accelerates immunosenescence and imposes on the course of coronary heart disease. See p 1364.
Declines in Acute Myocardial Infarction After Smoke-Free Laws and Individual Risk Attributable to Secondhand Smoke
Smoking restriction laws for public areas and workplaces have become increasingly common in the last decade. A number of studies of these laws have found that they have a significant effect in reducing the community rate of heart attack. The estimated size of the reductions attributable to the smoking restriction laws has varied widely, and their consistency with existing estimates of the individual relative risks attributable to exposure to passive smoke exposure is unknown. This study shows that the results of these studies are consistent if the follow-up periods of the individual studies of community rates of heart attack are taken into account and that the estimated effects of smoking restriction laws on community rates are consistent with individual risks of heart attack attributable to exposure to passive smoking. These results strengthen the case that passive smoking is a serious risk factor for acute coronary heart disease and that its elimination reduces the community rate of heart attack quickly. Physicians should counsel their patients to avoid exposure to passive smoking whenever possible, and all healthcare professionals should strongly advocate more, and stronger, public area and workplace smoking restriction laws. See p 1373.
Effects of Telmisartan, Ramipril, and Their Combination on Left Ventricular Hypertrophy in Individuals at High Vascular Risk in the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease
In patients with high vascular risk resulting from coronary artery disease, stroke, peripheral occlusive disease, or diabetes mellitus, the effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on left ventricular (LV) hypertrophy (LVH) is unknown. In the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET), patients at high vascular risk and tolerant of angiotensin-converting enzyme inhibitors were randomly assigned to ramipril, telmisartan, or their combination. In the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND), telmisartan was more effective than placebo in preventing the appearance of ECG-based LVH (odds ratio, 0.63; 95% confidence interval, 0.51 to 0.79; P=0.0001), whereas LVH regression was not affected. In ONTARGET, LVH occurred slightly less frequently with telmisartan and the combination than with ramipril, but differences between groups were not significant. The risk of primary outcome during follow-up increased progressively when the diagnosis of LVH at entry was based on high voltage alone, strain alone, and their combination compared with the absence of LVH. New-onset LVH was associated with a higher risk of primary outcome during follow-up (hazard ratio, 1.77; 95% confidence interval, 1.50 to 2.07). Overall, these results are consistent with the main results of the study. The different pattern in LVH changes did not translate into a prognostic benefit, possibly because of the inadequate time for translation of the gradual LVH reduction into harder clinical events. These findings substantiate the efficacy of telmisartan in preventing the appearance of LVH in patients at increased vascular risk. The data also suggest that LVH defined on ECG by the combination of elevated voltages and strain is associated with a markedly increased risk in these patients. See p 1380.
Complementary Prognostic Values of Stress Myocardial Perfusion and Late Gadolinium Enhancement Imaging by Cardiac Magnetic Resonance in Patients With Known or Suspected Coronary Artery Disease
Cardiac magnetic resonance (CMR) reversible myocardial perfusion defect (RevPD) has demonstrated not only high accuracy in detection of flow-limiting coronary stenosis but also strong prognostic value in risk stratifying patients presenting with suspected ischemia. With high tissue contrast and spatial resolution, CMR late gadolinium enhancement (LGE) imaging is the most sensitive current imaging technique for detecting small subendocardial infarction that elevates a patient’s risk of cardiac events. In a clinical cohort of 254 patients referred for stress CMR imaging, we tested the hypothesis that RevPD and LGE imaging in a single CMR study can provide complementary prognostic values for major adverse events, including cardiac death or nonfatal myocardial infarction (MI). Although RevPD and LGE both demonstrated strong unadjusted association with death/MI (hazard ratio, 6.88 and 5.32, respectively; both P<0.0001), robust association with death/MI by RevPD and LGE was maintained when the effects of these variables were adjusted for each other and for patient age and gender. In patients without a history of MI who were found to have no RevPD, the presence of LGE portended a >11-fold hazards increase in death/MI. We found that patients with both RevPD and LGE absent had the most favorable annual negative event rate for death/MI at >98%. We therefore conclude that CMR stress myocardial perfusion and LGE imaging performed in a CMR study provide complementary prognostic implication for cardiac death or acute nonfatal MI. See p 1390.
Survival and Cardiac Remodeling After Myocardial Infarction Are Critically Dependent on the Host Innate Immune Interleukin-1 Receptor–Associated Kinase-4 Signaling: A Regulator of Bone Marrow–Derived Dendritic Cells
Cardiac remodeling after myocardial infarction is a major substrate for the development of heart failure. A significant component of this remodeling is orchestrated by the inflammatory response of the host. Innate immunity is the first-line defense mechanism of the host against external injury, triggering pathways involved in Toll/interleukin-1 receptor signaling. We found that interleukin-1 receptor–associated kinase (IRAK-4), a major regulator of innate immune response, has a surprising but essential role in modulating the post–myocardial infarction remodeling process through the functional regulation of dendritic cells. Targeted removal of IRAK-4 led to major benefits in survival and cardiac remodeling after infarction. This was accompanied by decreased bone marrow dendritic cell mobilization and impaired maturation. However, transfer of adult mature dendritic cells, after infarction was completed, annulled this protective benefit. Thus, the Toll/IRAK-4–dendritic cell axis has a detrimental effect on cardiac remodeling and may constitute a hitherto unrecognized new therapeutic target after infarction. See p 1401.
Regulatory T Cells Modulate Postischemic Neovascularization
A specific component of the immune system known as the CD4+CD25+ regulatory T cell (Treg) repertoire is specialized for the suppression of both T helper 1 and T helper 2 pathogenic immune responses against self-antigens or foreign antigens and controls T-cell homeostasis. Interestingly, modulation of Treg cell levels controls the progression of inflammatory diseases. In this regard, the reduction of Treg cell number and function in both B7-1/2– and CD28-deficient diabetic mice exacerbates diabetes mellitus. In addition, it has been shown that modulation of the Treg cell response controls the development of atherosclerotic lesions. However, the role of Treg cells in the control of postischemic neovascularization remains unknown. In the present study, we report that Treg cells are a critical modulator of vessel growth. We observed that profound Treg cell reduction caused by B7/CD28 deficiency or anti-CD25 treatment increased postischemic revascularization, and we showed that exogenous administration of Treg cells reduced vessel growth in this setting. These results provide new insights into the immune regulation of vessel growth and may lead to new therapeutic approaches that involve immune modulation with Treg cells. In particular, our findings suggest that modulation of the regulatory arm of the immune response could provide novel strategies for the treatment of ischemic diseases that target angiogenesis. See p 1415.
Intra–Cardiopulmonary Resuscitation Hypothermia With and Without Volume Loading in an Ischemic Model of Cardiac Arrest
Therapeutic hypothermia has been shown to improve neurological outcomes in humans when applied in comatose victims of cardiac arrest. In animal studies, intra–cardiopulmonary resuscitation application of hypothermia further improves neurologically intact survival. Most of the out-of-hospital cardiac arrests are due to ischemic complications of coronary artery disease. We investigated the effects of intra–cardiopulmonary resuscitation hypothermia with and without volume loading on resuscitation rates and infarction size in a porcine ischemia/reperfusion model (left anterior descending artery occlusion) of cardiac arrest and resuscitation. The findings of this study suggest that intra–cardiopulmonary resuscitation hypothermia can limit the size of myocardial infarction and improve postresuscitation cardiac function. Compared with hypothermia achieved with infusion of cold saline, application of hypothermia with an intravascular device without volume loading improved resuscitation rates and postresuscitation LV function and further limited the size of myocardial infarction. It also appears that faster cooling improves protection against myocardial infarction. An intravascular device that can be readily deployed in the field does not currently exist. On the basis of this study, methods to achieve fast and effective hypothermia without volume loading should improve the effect of early application of this therapy during cardiopulmonary resuscitation and warrant further investigation. See p 1426.
- Regulatory T Cells Modulate Postischemic Neovascularization
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