Circulation 2008年11月4日
这个帖子发布于 16 年零 234 天前，其中的信息可能已发生改变或有所发展。
Volume 118, Issue 19; November 4, 2008
Abstracts 1-8
1.
Cardiovascular Surgery
Basic Control of Reperfusion Effectively Protects Against Reperfusion Injury in a Realistic Rodent Model of Acute Limb Ischemia
Background— Reperfusion injury is insufficiently addressed in current clinical management of acute limb ischemia. Controlled reperfusion carries an enormous clinical potential and was tested in a new reality-driven rodent model.
Methods and Results— Acute hind-limb ischemia was induced in Wistar rats and maintained for 4 hours. Unlike previous tourniquets models, femoral vessels were surgically prepared to facilitate controlled reperfusion and to prevent venous stasis. Rats were randomized into an experimental group (n=7), in which limbs were selectively perfused with a cooled isotone heparin solution at a limited flow rate before blood flow was restored, and a conventional group (n=7; uncontrolled blood reperfusion). Rats were killed 4 hours after blood reperfusion. Nonischemic limbs served as controls. Ischemia/reperfusion injury was significant in both groups; total wet-to-dry ratio was 159±44% of normal (P=0.016), whereas muscle viability and contraction force were reduced to 65±13% (P=0.016) and 45±34% (P=0.045), respectively. Controlled reperfusion, however, attenuated reperfusion injury significantly. Tissue edema was less pronounced (132±16% versus 185±42%; P=0.011) and muscle viability (74±11% versus 57±9%; P=0.004) and contraction force (68±40% versus 26±7%; P=0.045) were better preserved than after uncontrolled reperfusion. Moreover, subsequent blood circulation as assessed by laser Doppler recovered completely after controlled reperfusion but stayed durably impaired after uncontrolled reperfusion (P=0.027).
Conclusions— Reperfusion injury was significantly alleviated by basic modifications of the initial reperfusion period in a new in vivo model of acute limb ischemia. With this model, systematic optimizations of according protocols may eventually translate into improved clinical management of acute limb ischemia.
2.
Epidemiology
Dietary Patterns and the Risk of Acute Myocardial Infarction in 52 Countries
Results of the INTERHEART Study
Background— Diet is a major modifiable risk factor for cardiovascular disease, but it varies markedly in different regions of the world. The objectives of the present study were to assess the association between dietary patterns and acute myocardial infarction (AMI) globally.
Methods and Results— INTERHEART is a standardized case-control study involving participants from 52 countries. The present analysis included 5761 cases and 10 646 control subjects. We identified 3 major dietary patterns using factor analysis: Oriental (high intake of tofu and soy and other sauces), Western (high in fried foods, salty snacks, eggs, and meat), and prudent (high in fruit and vegetables). We observed an inverse association between the prudent pattern and AMI, with higher levels being protective. Compared with the first quartile, the adjusted ORs were 0.78 (95% CI 0.69 to 0.88) for the second quartile, 0.66 (95% CI 0.59 to 0.75) for the third, and 0.70 (95% CI 0.61 to 0.80) for the fourth (P for trend <0.001). The Western pattern showed a U-shaped association with AMI (compared with the first quartile, the adjusted OR for the second quartile was 0.87 [95% CI 0.78 to 0.98], whereas it was 1.12 [95% CI 1.00 to 1.25] for the third quartile and 1.35 [95% CI 1.21 to 1.51] for the fourth quartile; P for trend <0.001), but the Oriental pattern demonstrated no relationship with AMI. Compared with the first quartile, the OR of a dietary risk score derived from meat, salty snacks, fried foods, fruits, green leafy vegetables, cooked vegetables, and other raw vegetables (higher score indicating a poorer diet) increased with each quartile: second quartile 1.29 (95% CI 1.17 to 1.42), third quartile 1.67 (95% CI 1.51 to 1.83), and fourth quartile 1.92 (95% CI 1.74 to 2.11; P for trend <0.001). The adjusted population-attributable risk of AMI for the top 3 quartiles compared with the bottom quartile of the dietary risk score was 30%.
Conclusions— An unhealthy dietary intake, assessed by a simple dietary risk score, increases the risk of AMI globally and accounts for 30% of the population-attributable risk.
3.
Health Services and Outcomes Research
Patient Satisfaction and Its Relationship With Quality and Outcomes of Care After Acute Myocardial Infarction
Background— Patient satisfaction is a widely used measurement for the evaluation of medical care. We examined the extent to which quality of care received after acute myocardial infarction predicted subsequent patient satisfaction with care and whether patient satisfaction itself was associated with long-term survival after acute myocardial infarction.
Methods and Results— In a longitudinal cohort of acute myocardial infarction, we examined the associations of patient-reported satisfaction with care with clinical characteristics, physical and psychological function measures, quality indicators of myocardial infarction care, and outcomes. Among 1933 eligible patients (mean age 62.9±12.8 years, 70.5% men), 1866 survey respondents were analyzed. Of the study cohort, 1711 (91.7%) reported that they were satisfied with their overall care. Patients who reported satisfaction with care were older (mean age 63.1±12.7 versus 60.1±13.3 years, P=0.005), had improved physical function, and were less likely to be depressed. Better physical function, measured by the Specific Activity Scale, predicted higher satisfaction, with an OR of 1.75 (95% CI 1.17 to 2.68, P=0.008) for intermediate versus poor function and 2.96 (1.39 to 7.34, P=0.009) for high versus poor function, after adjustment for age, sex, income tertile, and ethnicity. Depression was the major predictor of dissatisfaction with overall care, with an OR of 0.44 (95% CI 0.29 to 0.67, P<0.001). Quality indicators for myocardial infarction care and clinical outcomes were not associated with patient satisfaction.
Conclusions— Satisfaction with care was more likely in patients who were older, in those without depression, and in those with better functional capacity, but it was not associated with the quality of myocardial infarction care or survival.
4.
Heart Failure
Heart Failure Is a Risk Factor for Orthopedic Fracture
A Population-Based Analysis of 16 294 Patients
Background— Heart failure (HF) is associated with factors that may contribute to accelerated bone loss and subsequent fractures. Whether it leads to an increased fracture risk is unknown.
Methods and Results— A population-based cohort of consecutive patients 65 years of age with cardiovascular disease presenting to all emergency rooms between 1998 and 2001 in Alberta, Canada (n=16294 patients), was used. The 2041 patients with a new diagnosis of HF were compared with a control group of 14 253 patients with non-HF cardiovascular diagnoses. The primary outcome was any orthopedic fracture requiring hospital admission in the year after the emergency room visit. Patients with HF had a median age of 78 years (interquartile range, 72 to 84 years), and 51.9% were female; control subjects had a median age of 73 years (interquartile range, 68 to 79 years), and 53.2% were female. In the first year after the emergency room visit, 4.6% of the HF cohort (n=93) and 1.0% of patients without HF (n=147) sustained an orthopedic fracture (P<0.001). Hip fractures occurred in 26 HF patients (1.3%) and 18 patients (0.1%) without HF (P<0.001). After multivariable adjustment, HF was independently associated with a greater risk of any orthopedic fracture (adjusted odds ratio, 4.0; 95% CI, 2.9 to 5.3) or hip fracture (adjusted odds ratio, 6.3; 95% CI, 3.4 to 11.8).
Conclusions— HF is associated with an increased risk of subsequent orthopedic fracture, particularly hip fracture. This suggests that screening for and treatment of osteoporosis to reduce fracture risk need to be considered in those with HF.
5.
Imaging
Molecular Imaging of Activated Matrix Metalloproteinases in Vascular Remodeling
Background— Matrix metalloproteinase (MMP) activation plays a key role in vascular remodeling. RP782 is a novel indium 111In–labeled tracer with specificity for activated MMPs. We hypothesized that RP782 can detect injury-induced vascular remodeling in vivo.
Methods and Results— Left common carotid artery injury was induced with a guidewire in apolipoprotein E–/– mice. Sham surgery was performed on the contralateral artery, which served as control for imaging experiments. Carotid wire injury led to significant hyperplasia and expansive remodeling over a period of 4 weeks. MMP activity, detected by in situ zymography, increased in response to injury and was maximal by 3 to 4 weeks after injury. RP782 (11.1 MBq) was injected intravenously into apolipoprotein E–/– mice at 1, 2, 3, and 4 weeks after left carotid injury. MicroSPECT imaging was performed at 2 hours and was followed by CT angiography to localize the carotid arteries. In vivo images revealed focal uptake of RP782 in the injured carotid artery at 2, 3, and 4 weeks. Increased tracer uptake in the injured artery was confirmed by quantitative autoradiography. Pretreatment with 50-fold excess nonlabeled tracer significantly reduced RP782 uptake in injured carotids, thus demonstrating uptake specificity. Weekly changes in the vessel-wall area closely paralleled and correlated with RP782 uptake (Spearman r=0.95, P=0.001).
Conclusions— Injury-induced MMP activation in the vessel wall can be detected by RP782 microSPECT/CT imaging in vivo. RP782 uptake tracks the hyperplastic process in vascular remodeling and provides an opportunity to track the remodeling process in vivo.
6.
Molecular Cardiology
Repetitive Ischemia by Coronary Stenosis Induces a Novel Window of Ischemic Preconditioning
Background— The hypothesis of the present study was that molecular mechanisms differ markedly when mediating ischemic preconditioning induced by repetitive episodes of ischemia versus classic first- or second-window preconditioning.
Methods and Results— To test this, chronically instrumented conscious pigs were subjected to either repetitive coronary stenosis (RCS) or a traditional protocol of second-window ischemic preconditioning (SWIPC). Lethal ischemia, induced by 60 minutes of coronary artery occlusion followed by reperfusion, resulted in an infarct size/area at risk of 6±3% after RCS and 16±3% after SWIPC (both groups P<0.05, less than shams 42±4%). Two molecular signatures of SWIPC, the increased expression of the inducible isoform of nitric oxide synthase and the translocation of protein kinase C to the plasma membrane, were observed with SWIPC but not with RCS. Confirming this, pretreatment with a nitric oxide synthase inhibitor prevented the protection conferred by SWIPC but not by RCS. Microarray analysis revealed a qualitatively different genomic profile of cardioprotection between ischemic preconditioning induced by RCS and that induced by SWIPC. The number of genes significantly regulated was greater in RCS (5739) than in SWIPC (2394) animals. Of the 5739 genes regulated in RCS, only 31% were also regulated in SWIPC. Broad categories of genes induced by RCS but not SWIPC included those involved in autophagy, endoplasmic reticulum stress, and mitochondrial oxidative metabolism. The upregulation of these pathways was confirmed by Western blotting.
Conclusions— RCS induces cardioprotection against lethal myocardial ischemia that is at least as powerful as traditional ischemic preconditioning but is mediated through radically different mechanisms.
7.
Molecular Cardiology
Cardiac Myocyte–Specific Expression of Inducible Nitric Oxide Synthase Protects Against Ischemia/Reperfusion Injury by Preventing Mitochondrial Permeability Transition
Background— Inducible nitric oxide synthase (iNOS) is an obligatory mediator of the late phase of ischemic preconditioning, but the mechanisms of its cardioprotective actions are unknown. In addition, it remains unclear whether sustained elevation of iNOS in myocytes provides chronic protection against ischemia/reperfusion injury.
Methods and Results— Constitutive overexpression of iNOS in transgenic mice ( -myosin heavy chain promoter) did not induce contractile dysfunction and did not affect mitochondrial respiration or biogenesis, but it profoundly decreased infarct size in mice subjected to 30 minutes of coronary occlusion and 24 hours of reperfusion. In comparison with wild-type hearts, isolated iNOS-transgenic hearts subjected to ischemia for 30 minutes followed by 40 minutes of reperfusion displayed better contractile recovery, smaller infarct size, and less mitochondrial entrapment of 2-deoxy-[3H]-glucose. Reperfusion-induced loss of NAD+ and mitochondrial release of cytochrome c were attenuated in iNOS-transgenic hearts, indicating reduced mitochondrial permeability transition. The NO donor NOC-22 prevented permeability transition in isolated mitochondria, and mitochondrial permeability transition–induced NAD+ loss was decreased in wild-type but not iNOS-null mice treated with the NO donor diethylene triamine/NO 24 hours before ischemia and reperfusion ex vivo. iNOS-mediated cardioprotection was not abolished by atractyloside. Reperfusion-induced production of oxygen-derived free radicals (measured by electron paramagnetic resonance spectroscopy) was attenuated in iNOS-transgenic hearts and was increased in wild-type hearts treated with the mitochondrial permeability transition inhibitor cyclosporin A.
Conclusions— Cardiomyocyte-restricted expression of iNOS provides sustained cardioprotection. This cardioprotection is associated with a decrease in reperfusion-induced oxygen radicals and inhibition of mitochondrial swelling and permeability transition.
8.
Molecular Cardiology
Cardiac-Specific Overexpression of Caveolin-3 Induces Endogenous Cardiac Protection by Mimicking Ischemic Preconditioning
Background— Caveolae, lipid-rich microdomains of the sarcolemma, localize and enrich cardiac-protective signaling molecules. Caveolin-3 (Cav-3), the dominant isoform in cardiac myocytes, is a determinant of caveolar formation. We hypothesized that cardiac myocyte–specific overexpression of Cav-3 would enhance the formation of caveolae and augment cardiac protection in vivo.
Methods and Results— Ischemic preconditioning in vivo increased the formation of caveolae. Adenovirus for Cav-3 increased caveolar formation and phosphorylation of survival kinases in cardiac myocytes. A transgenic mouse with cardiac myocyte–specific overexpression of Cav-3 (Cav-3 OE) showed enhanced formation of caveolae on the sarcolemma. Cav-3 OE mice subjected to ischemia/reperfusion injury had a significantly reduced infarct size relative to transgene-negative mice. Endogenous cardiac protection in Cav-3 OE mice was similar to wild-type mice undergoing ischemic preconditioning; no increased protection was observed in preconditioned Cav-3 OE mice. Cav-3 knockout mice did not show endogenous protection and showed no protection in response to ischemic preconditioning. Cav-3 OE mouse hearts had increased basal Akt and glycogen synthase kinase-3β phosphorylation comparable to wild-type mice exposed to ischemic preconditioning. Wortmannin, a phosphoinositide 3-kinase inhibitor, attenuated basal phosphorylation of Akt and glycogen synthase kinase-3β and blocked cardiac protection in Cav-3 OE mice. Cav-3 OE mice had improved functional recovery and reduced apoptosis at 24 hours of reperfusion.
Conclusions— Expression of caveolin-3 is both necessary and sufficient for cardiac protection, a conclusion that unites long-standing ultrastructural and molecular observations in the ischemic heart. The present results indicate that increased expression of caveolins, apparently via actions that depend on phosphoinositide 3-kinase, has the potential to protect hearts exposed to ischemia/reperfusion injury.
Abstracts 1-8
1.
Cardiovascular Surgery
Basic Control of Reperfusion Effectively Protects Against Reperfusion Injury in a Realistic Rodent Model of Acute Limb Ischemia
Background— Reperfusion injury is insufficiently addressed in current clinical management of acute limb ischemia. Controlled reperfusion carries an enormous clinical potential and was tested in a new reality-driven rodent model.
Methods and Results— Acute hind-limb ischemia was induced in Wistar rats and maintained for 4 hours. Unlike previous tourniquets models, femoral vessels were surgically prepared to facilitate controlled reperfusion and to prevent venous stasis. Rats were randomized into an experimental group (n=7), in which limbs were selectively perfused with a cooled isotone heparin solution at a limited flow rate before blood flow was restored, and a conventional group (n=7; uncontrolled blood reperfusion). Rats were killed 4 hours after blood reperfusion. Nonischemic limbs served as controls. Ischemia/reperfusion injury was significant in both groups; total wet-to-dry ratio was 159±44% of normal (P=0.016), whereas muscle viability and contraction force were reduced to 65±13% (P=0.016) and 45±34% (P=0.045), respectively. Controlled reperfusion, however, attenuated reperfusion injury significantly. Tissue edema was less pronounced (132±16% versus 185±42%; P=0.011) and muscle viability (74±11% versus 57±9%; P=0.004) and contraction force (68±40% versus 26±7%; P=0.045) were better preserved than after uncontrolled reperfusion. Moreover, subsequent blood circulation as assessed by laser Doppler recovered completely after controlled reperfusion but stayed durably impaired after uncontrolled reperfusion (P=0.027).
Conclusions— Reperfusion injury was significantly alleviated by basic modifications of the initial reperfusion period in a new in vivo model of acute limb ischemia. With this model, systematic optimizations of according protocols may eventually translate into improved clinical management of acute limb ischemia.
2.
Epidemiology
Dietary Patterns and the Risk of Acute Myocardial Infarction in 52 Countries
Results of the INTERHEART Study
Background— Diet is a major modifiable risk factor for cardiovascular disease, but it varies markedly in different regions of the world. The objectives of the present study were to assess the association between dietary patterns and acute myocardial infarction (AMI) globally.
Methods and Results— INTERHEART is a standardized case-control study involving participants from 52 countries. The present analysis included 5761 cases and 10 646 control subjects. We identified 3 major dietary patterns using factor analysis: Oriental (high intake of tofu and soy and other sauces), Western (high in fried foods, salty snacks, eggs, and meat), and prudent (high in fruit and vegetables). We observed an inverse association between the prudent pattern and AMI, with higher levels being protective. Compared with the first quartile, the adjusted ORs were 0.78 (95% CI 0.69 to 0.88) for the second quartile, 0.66 (95% CI 0.59 to 0.75) for the third, and 0.70 (95% CI 0.61 to 0.80) for the fourth (P for trend <0.001). The Western pattern showed a U-shaped association with AMI (compared with the first quartile, the adjusted OR for the second quartile was 0.87 [95% CI 0.78 to 0.98], whereas it was 1.12 [95% CI 1.00 to 1.25] for the third quartile and 1.35 [95% CI 1.21 to 1.51] for the fourth quartile; P for trend <0.001), but the Oriental pattern demonstrated no relationship with AMI. Compared with the first quartile, the OR of a dietary risk score derived from meat, salty snacks, fried foods, fruits, green leafy vegetables, cooked vegetables, and other raw vegetables (higher score indicating a poorer diet) increased with each quartile: second quartile 1.29 (95% CI 1.17 to 1.42), third quartile 1.67 (95% CI 1.51 to 1.83), and fourth quartile 1.92 (95% CI 1.74 to 2.11; P for trend <0.001). The adjusted population-attributable risk of AMI for the top 3 quartiles compared with the bottom quartile of the dietary risk score was 30%.
Conclusions— An unhealthy dietary intake, assessed by a simple dietary risk score, increases the risk of AMI globally and accounts for 30% of the population-attributable risk.
3.
Health Services and Outcomes Research
Patient Satisfaction and Its Relationship With Quality and Outcomes of Care After Acute Myocardial Infarction
Background— Patient satisfaction is a widely used measurement for the evaluation of medical care. We examined the extent to which quality of care received after acute myocardial infarction predicted subsequent patient satisfaction with care and whether patient satisfaction itself was associated with long-term survival after acute myocardial infarction.
Methods and Results— In a longitudinal cohort of acute myocardial infarction, we examined the associations of patient-reported satisfaction with care with clinical characteristics, physical and psychological function measures, quality indicators of myocardial infarction care, and outcomes. Among 1933 eligible patients (mean age 62.9±12.8 years, 70.5% men), 1866 survey respondents were analyzed. Of the study cohort, 1711 (91.7%) reported that they were satisfied with their overall care. Patients who reported satisfaction with care were older (mean age 63.1±12.7 versus 60.1±13.3 years, P=0.005), had improved physical function, and were less likely to be depressed. Better physical function, measured by the Specific Activity Scale, predicted higher satisfaction, with an OR of 1.75 (95% CI 1.17 to 2.68, P=0.008) for intermediate versus poor function and 2.96 (1.39 to 7.34, P=0.009) for high versus poor function, after adjustment for age, sex, income tertile, and ethnicity. Depression was the major predictor of dissatisfaction with overall care, with an OR of 0.44 (95% CI 0.29 to 0.67, P<0.001). Quality indicators for myocardial infarction care and clinical outcomes were not associated with patient satisfaction.
Conclusions— Satisfaction with care was more likely in patients who were older, in those without depression, and in those with better functional capacity, but it was not associated with the quality of myocardial infarction care or survival.
4.
Heart Failure
Heart Failure Is a Risk Factor for Orthopedic Fracture
A Population-Based Analysis of 16 294 Patients
Background— Heart failure (HF) is associated with factors that may contribute to accelerated bone loss and subsequent fractures. Whether it leads to an increased fracture risk is unknown.
Methods and Results— A population-based cohort of consecutive patients 65 years of age with cardiovascular disease presenting to all emergency rooms between 1998 and 2001 in Alberta, Canada (n=16294 patients), was used. The 2041 patients with a new diagnosis of HF were compared with a control group of 14 253 patients with non-HF cardiovascular diagnoses. The primary outcome was any orthopedic fracture requiring hospital admission in the year after the emergency room visit. Patients with HF had a median age of 78 years (interquartile range, 72 to 84 years), and 51.9% were female; control subjects had a median age of 73 years (interquartile range, 68 to 79 years), and 53.2% were female. In the first year after the emergency room visit, 4.6% of the HF cohort (n=93) and 1.0% of patients without HF (n=147) sustained an orthopedic fracture (P<0.001). Hip fractures occurred in 26 HF patients (1.3%) and 18 patients (0.1%) without HF (P<0.001). After multivariable adjustment, HF was independently associated with a greater risk of any orthopedic fracture (adjusted odds ratio, 4.0; 95% CI, 2.9 to 5.3) or hip fracture (adjusted odds ratio, 6.3; 95% CI, 3.4 to 11.8).
Conclusions— HF is associated with an increased risk of subsequent orthopedic fracture, particularly hip fracture. This suggests that screening for and treatment of osteoporosis to reduce fracture risk need to be considered in those with HF.
5.
Imaging
Molecular Imaging of Activated Matrix Metalloproteinases in Vascular Remodeling
Background— Matrix metalloproteinase (MMP) activation plays a key role in vascular remodeling. RP782 is a novel indium 111In–labeled tracer with specificity for activated MMPs. We hypothesized that RP782 can detect injury-induced vascular remodeling in vivo.
Methods and Results— Left common carotid artery injury was induced with a guidewire in apolipoprotein E–/– mice. Sham surgery was performed on the contralateral artery, which served as control for imaging experiments. Carotid wire injury led to significant hyperplasia and expansive remodeling over a period of 4 weeks. MMP activity, detected by in situ zymography, increased in response to injury and was maximal by 3 to 4 weeks after injury. RP782 (11.1 MBq) was injected intravenously into apolipoprotein E–/– mice at 1, 2, 3, and 4 weeks after left carotid injury. MicroSPECT imaging was performed at 2 hours and was followed by CT angiography to localize the carotid arteries. In vivo images revealed focal uptake of RP782 in the injured carotid artery at 2, 3, and 4 weeks. Increased tracer uptake in the injured artery was confirmed by quantitative autoradiography. Pretreatment with 50-fold excess nonlabeled tracer significantly reduced RP782 uptake in injured carotids, thus demonstrating uptake specificity. Weekly changes in the vessel-wall area closely paralleled and correlated with RP782 uptake (Spearman r=0.95, P=0.001).
Conclusions— Injury-induced MMP activation in the vessel wall can be detected by RP782 microSPECT/CT imaging in vivo. RP782 uptake tracks the hyperplastic process in vascular remodeling and provides an opportunity to track the remodeling process in vivo.
6.
Molecular Cardiology
Repetitive Ischemia by Coronary Stenosis Induces a Novel Window of Ischemic Preconditioning
Background— The hypothesis of the present study was that molecular mechanisms differ markedly when mediating ischemic preconditioning induced by repetitive episodes of ischemia versus classic first- or second-window preconditioning.
Methods and Results— To test this, chronically instrumented conscious pigs were subjected to either repetitive coronary stenosis (RCS) or a traditional protocol of second-window ischemic preconditioning (SWIPC). Lethal ischemia, induced by 60 minutes of coronary artery occlusion followed by reperfusion, resulted in an infarct size/area at risk of 6±3% after RCS and 16±3% after SWIPC (both groups P<0.05, less than shams 42±4%). Two molecular signatures of SWIPC, the increased expression of the inducible isoform of nitric oxide synthase and the translocation of protein kinase C to the plasma membrane, were observed with SWIPC but not with RCS. Confirming this, pretreatment with a nitric oxide synthase inhibitor prevented the protection conferred by SWIPC but not by RCS. Microarray analysis revealed a qualitatively different genomic profile of cardioprotection between ischemic preconditioning induced by RCS and that induced by SWIPC. The number of genes significantly regulated was greater in RCS (5739) than in SWIPC (2394) animals. Of the 5739 genes regulated in RCS, only 31% were also regulated in SWIPC. Broad categories of genes induced by RCS but not SWIPC included those involved in autophagy, endoplasmic reticulum stress, and mitochondrial oxidative metabolism. The upregulation of these pathways was confirmed by Western blotting.
Conclusions— RCS induces cardioprotection against lethal myocardial ischemia that is at least as powerful as traditional ischemic preconditioning but is mediated through radically different mechanisms.
7.
Molecular Cardiology
Cardiac Myocyte–Specific Expression of Inducible Nitric Oxide Synthase Protects Against Ischemia/Reperfusion Injury by Preventing Mitochondrial Permeability Transition
Background— Inducible nitric oxide synthase (iNOS) is an obligatory mediator of the late phase of ischemic preconditioning, but the mechanisms of its cardioprotective actions are unknown. In addition, it remains unclear whether sustained elevation of iNOS in myocytes provides chronic protection against ischemia/reperfusion injury.
Methods and Results— Constitutive overexpression of iNOS in transgenic mice ( -myosin heavy chain promoter) did not induce contractile dysfunction and did not affect mitochondrial respiration or biogenesis, but it profoundly decreased infarct size in mice subjected to 30 minutes of coronary occlusion and 24 hours of reperfusion. In comparison with wild-type hearts, isolated iNOS-transgenic hearts subjected to ischemia for 30 minutes followed by 40 minutes of reperfusion displayed better contractile recovery, smaller infarct size, and less mitochondrial entrapment of 2-deoxy-[3H]-glucose. Reperfusion-induced loss of NAD+ and mitochondrial release of cytochrome c were attenuated in iNOS-transgenic hearts, indicating reduced mitochondrial permeability transition. The NO donor NOC-22 prevented permeability transition in isolated mitochondria, and mitochondrial permeability transition–induced NAD+ loss was decreased in wild-type but not iNOS-null mice treated with the NO donor diethylene triamine/NO 24 hours before ischemia and reperfusion ex vivo. iNOS-mediated cardioprotection was not abolished by atractyloside. Reperfusion-induced production of oxygen-derived free radicals (measured by electron paramagnetic resonance spectroscopy) was attenuated in iNOS-transgenic hearts and was increased in wild-type hearts treated with the mitochondrial permeability transition inhibitor cyclosporin A.
Conclusions— Cardiomyocyte-restricted expression of iNOS provides sustained cardioprotection. This cardioprotection is associated with a decrease in reperfusion-induced oxygen radicals and inhibition of mitochondrial swelling and permeability transition.
8.
Molecular Cardiology
Cardiac-Specific Overexpression of Caveolin-3 Induces Endogenous Cardiac Protection by Mimicking Ischemic Preconditioning
Background— Caveolae, lipid-rich microdomains of the sarcolemma, localize and enrich cardiac-protective signaling molecules. Caveolin-3 (Cav-3), the dominant isoform in cardiac myocytes, is a determinant of caveolar formation. We hypothesized that cardiac myocyte–specific overexpression of Cav-3 would enhance the formation of caveolae and augment cardiac protection in vivo.
Methods and Results— Ischemic preconditioning in vivo increased the formation of caveolae. Adenovirus for Cav-3 increased caveolar formation and phosphorylation of survival kinases in cardiac myocytes. A transgenic mouse with cardiac myocyte–specific overexpression of Cav-3 (Cav-3 OE) showed enhanced formation of caveolae on the sarcolemma. Cav-3 OE mice subjected to ischemia/reperfusion injury had a significantly reduced infarct size relative to transgene-negative mice. Endogenous cardiac protection in Cav-3 OE mice was similar to wild-type mice undergoing ischemic preconditioning; no increased protection was observed in preconditioned Cav-3 OE mice. Cav-3 knockout mice did not show endogenous protection and showed no protection in response to ischemic preconditioning. Cav-3 OE mouse hearts had increased basal Akt and glycogen synthase kinase-3β phosphorylation comparable to wild-type mice exposed to ischemic preconditioning. Wortmannin, a phosphoinositide 3-kinase inhibitor, attenuated basal phosphorylation of Akt and glycogen synthase kinase-3β and blocked cardiac protection in Cav-3 OE mice. Cav-3 OE mice had improved functional recovery and reduced apoptosis at 24 hours of reperfusion.
Conclusions— Expression of caveolin-3 is both necessary and sufficient for cardiac protection, a conclusion that unites long-standing ultrastructural and molecular observations in the ischemic heart. The present results indicate that increased expression of caveolins, apparently via actions that depend on phosphoinositide 3-kinase, has the potential to protect hearts exposed to ischemia/reperfusion injury.
