- Role of Left Ventricular Stiffness in Heart Failure With Normal Ejection Fraction
- Noninvasive Detection and Localization of Vulnerable Plaque and Arterial Thrombosis With Computed Tomography Angiography/Positron Emission Tomography
- Comparison of Coronary Artery Stenting Outcomes in the Eras Before and After the Introduction of Drug-Eluting Stents
- Long-Term Mortality After Percutaneous Coronary Intervention With Drug-Eluting Stent Implantation Versus Coronary Artery Bypass Surgery for the Treatment of Multivessel Coronary Artery Disease
- Genetic Components of the Circadian Clock Regulate Thrombogenesis In Vivo
- Local Delivery of Gene Vectors From Bare-Metal Stents by Use of a Biodegradable Synthetic Complex Inhibits In-Stent Restenosis in Rat Carotid Arteries
- Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-Controlled Trials: The Cross Trial Safety Analysis
- Absence of Cyclooxygenase-2 Exacerbates Hypoxia-Induced Pulmonary Hypertension and Enhances Contractility of Vascular Smooth Muscle Cells
- Increased High-Density Lipoprotein Cholesterol Predicts the Pioglitazone-Mediated Reduction of Carotid Intima-Media Thickness Progression in Patients With Type 2 Diabetes Mellitus
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Role of Left Ventricular Stiffness in Heart Failure With Normal Ejection Fraction
Heart failure with normal ejection fraction (HFNEF) is an increasing problem; today, ≈50% of all heart failure patients have a normal ejection fraction. The mortality rate seems to be similar to that of patients with reduced ejection fraction, but our knowledge about the underlying hemodynamic pathology is limited. We performed a study investigating the diastolic function of patients with HFNEF invasively using pressure-volume loops to obtain the diastolic stiffness of the left ventricle. The highly increased diastolic stiffness in the HFNEF group, the key finding of the present study, shows that diastolic dysfunction can be demonstrated in HFNEF patients. It may further explain their main clinical symptomatology: exercise intolerance. Artificial pacing to mimic tachycardia during exercise reduced the stroke volume resulting from a leftward shift of the pressure-volume loops and therefore blunted the increase in the cardiac output, which is needed to comply with increased oxygen demand during exercise in patients with HFNEF. This was associated with a limitation of workload during exercise. Although it was shown recently that nondiastolic abnormalities also occur in patients with HFNEF, we suggest that diastolic stiffness is another important feature of HFNEF that might trigger heart rate–dependent changes in the global cardiac function and therefore contribute to heart failure symptomatology. These data further suggest that destiffening therapies might be a future goal for treating HFNEF. See p 2051.
Noninvasive Detection and Localization of Vulnerable Plaque and Arterial Thrombosis With Computed Tomography Angiography/Positron Emission Tomography
The identification of vulnerable plaque can add a new dimension to the evaluation of cardiovascular atherosclerosis. Using an atherosclerotic rabbit model of plaque disruption and thrombosis, we demonstrated that positron emission tomography can localize inflamed plaques with high macrophage density and quantify the degree of inflammation in arteries comparable in size to human coronary arteries. These inflamed arteries were significantly more thrombotic. Currently, treatment decisions are based on the degree of stenosis, but this approach frequently fails to predict cardiac events. This was demonstrated recently by the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation trial, the results of which were explained in part by more interventions on severely stenotic but more stable plaques instead of less stenotic but vulnerable plaques. Therefore, localizing inflamed plaques and quantifying their degree of inflammation can potentially enhance the accuracy of decisions regarding therapy. The present study also has shown that computerized tomography angiography can be used accurately to diagnose small thrombi in atherosclerotic arteries similar in size to human coronaries. However, the application of these findings to humans still awaits solutions to multiple technical limitations. Nevertheless, some of our findings can serve as the basis for future research in noninvasive plaque characterization with computerized tomography angiography/positron emission tomography technology. It is expected that such research would be more easily performed in the carotid rather than coronary arteries because of their larger size and proximity to the skin. More investigations are needed to detect vulnerable plaques and arterial thrombosis in humans using the noninvasive computerized tomography angiography/positron emission tomography technology. See p 2061.
Comparison of Coronary Artery Stenting Outcomes in the Eras Before and After the Introduction of Drug-Eluting Stents
Few studies have compared medium-term outcomes for drug-eluting stents (DES) and bare metal stents, and most of those are relatively small, randomized controlled trials. Furthermore, since the introduction of DES, there has been increased use and duration of use of clopidogrel, statins, and other evidence-based therapies. The purpose of this study was to compare outcomes for patients who underwent stenting in the eras before and after the introduction of DES. In New York state, patients undergoing stenting in nonfederal hospitals who had not undergone any previous revascularization were studied. Risk factors that were significant predictors of adverse outcomes were used to adjust adverse outcome rates. The study included 11 436 patients who received stents between October 1, 2002 and March 31, 2003 (the pre-DES era) and 12 926 patients who underwent stenting between October 1, 2003 and March 31, 2004 (the DES era). Mortality, the combined endpoint mortality/myocardial infarction, target vessel revascularization, and target lesion revascularization rates were compared at 2 years. Patients in the DES era had significantly better risk-adjusted outcomes for mortality/myocardial infarction (adjusted hazard ratio, 0.90; 95% confidence interval, 0.83 to 0.97), 9.9% versus 10.8%; target vessel revascularization (adjusted hazard ratio, 0.60; 95% confidence interval, 0.56 to 0.64), 11.2% versus 17.9%; and target lesion revascularization (hazard ratio, 0.55; 95% confidence interval, 0.51 to 0.59), 8.4% versus 14.7%. In conclusion, patients in the DES era experienced lower mortality/myocardial infarction, target vessel revascularization, and target lesion revascularization rates, but there were no differences in mortality. These improvements are likely to be a result of increased use of clopidogrel, statins, and dual antiplatelet therapy in addition to the introduction of DES. See p 2071.
Long-Term Mortality After Percutaneous Coronary Intervention With Drug-Eluting Stent Implantation Versus Coronary Artery Bypass Surgery for the Treatment of Multivessel Coronary Artery Disease
Several studies have compared the treatment effects of coronary stenting and coronary artery bypass grafting (CABG) for multivessel coronary artery disease, but little information exists since the widespread availability of drug-eluting stents (DES). In the present study, we evaluated 1547 patients with multivessel disease who received DES and 1495 patients who underwent CABG. The primary end point was all-cause mortality. Other outcomes were repeat revascularization and the composite of death, Q-wave myocardial infarction, or cerebrovascular events. After adjustment for differences in baseline risk factors between patients receiving DES and undergoing CABG, the long-term risks of death were similar among all patients (hazard ratio, 0.85; 95% CI, 0.56 to 1.30; P=0.45), diabetic patients (hazard ratio, 1.76; 95% CI, 0.82 to 3.78; P=0.15), and patients with compromised ventricular function (hazard ratio, 1.39; 95% CI, 0.41 to 4.65; P=0.60) during 3 years of follow-up. The adjusted risk of hard end points (death, Q-wave myocardial infarction, or cerebrovascular events) also was similar (hazard ratio, 0.84; 95% CI, 0.57 to 1.23; P=0.36), whereas the risk of revascularization was significantly higher in the DES than in the CABG group (hazard ratio, 2.81; 95% CI, 2.11 to 3.75; P<0.001). Compared with CABG, coronary stenting with DES showed equivalent long-term mortality and serious composite outcomes but a higher rate of repeat revascularization for patients with multivessel coronary artery disease. Our findings need to be ascertained or refuted in ongoing, large randomized clinical trials, which may provide the answer to treatment effects between the 2 primary interventions. See p 2079.
Genetic Components of the Circadian Clock Regulate Thrombogenesis In Vivo
Clinical cardiovascular events such as myocardial infarction and stroke undergo diurnal variation, but it has been unclear whether this reflects a role for the molecular clock or temporal variation in exposure to environmental triggers. Studies of platelet aggregation ex vivo may be confounded by selection of subpopulations because of platelet activation in vivo. Here we describe diurnal variation in the time to thrombotic vascular occlusion in vivo, subsequent to a photochemical vascular injury. This pattern was disrupted or altered when circadian clock genes (Bmal1, Clock, or Npas2) were either mutated or deleted, manipulations that also affect blood pressure. Selective deletion of a single circadian clock gene, Bmal1, from the endothelium alone was sufficient to alter thrombogenesis in vivo. The impact of molecular clock components on thrombogenesis and blood pressure may interact with environmental variables to contribute to the diurnal variation in cardiovascular events observed in humans. See p 2087.
Local Delivery of Gene Vectors From Bare-Metal Stents by Use of a Biodegradable Synthetic Complex Inhibits In-Stent Restenosis in Rat Carotid Arteries
Stent angioplasty for coronary disease has made a major impact on improved therapeutic outcomes, and local delivery of highly potent drugs, such as paclitaxel or sirolimus, with polymer-coated drug-eluting stents is effective clinically for inhibiting the development of in-stent restenosis; however, it is also apparent that the current drug-eluting stents do not represent an ideal approach. Nevertheless, recent clinical and experimental results concerning drug-eluting stents indicate that local-delivery therapeutic strategies for cardiovascular disease will become increasingly important. The present study investigated local delivery of gene therapy from stent surfaces by use of a novel strategy of reversible chemical attachment of vectors to bare-metal stents via a 3-component, hydrolyzable synthetic complex. Adenoviral (Ad) vectors immobilized on the surfaces of stents with a packing density up to 5×109 adenovirus particles/cm2 exhibited prolonged (>1 month) release kinetics and demonstrated highly efficient site-specific transduction of target cell types in vitro and in vivo in rat carotid stent angioplasty studies. Moreover, the tethering of adenovirus vectors to steel surfaces allowed effective transduction in vitro in the presence of neutralizing anti-Ad knob antibodies that otherwise completely blocked activity of nonimmobilized vector. In rat carotid stent studies, the deployment of stents configured with 109 adenovirus vectors that were encoded for the inducible form of nitric oxide synthase (Ad-iNOS) resulted in a significant reduction of in-stent restenosis compared with bare-metal stents. These findings validate the concept of gene-eluting stents and warrant further translational investigations. See p 2096.
Cardiovascular Risk of Celecoxib in 6 Randomized Placebo-Controlled Trials: The Cross Trial Safety Analysis
Cyclooxygenase-2 inhibitors have been associated with increased cardiovascular risk. We performed a patient-level pooled analysis of 6 randomized controlled trials comparing 3 dose regimens of celecoxib—400 mg QD, 200 mg BID, and 400 mg BID—with placebo for conditions other than arthritis. We observed a dose regimen–dependent increase in risk, with the 400-mg-QD dose associated with the lowest risk (hazard ratio, 1.1; 95% CI, 0.6 to 2.0), the 200-mg-BID dose associated with an intermediate risk (hazard ratio, 1.8; 95% CI, 1.1 to 3.1), and the 400-mg-BID dose associated with the highest risk (hazard ratio, 3.1; 95% CI, 1.5 to 6.1). Moreover, we observed that patients with the lowest baseline risk were at the lowest relative risk for celecoxib-related events, with an interaction between baseline risk and celecoxib-related risk. Although the doses tested in these trials were higher than typical doses used in osteoarthritis patients, these data suggest that celecoxib-related cardiovascular risk is related to dose regimen and that twice-daily dosing may be associated with greater risk than once-daily dosing. Moreover, patients who are at higher a priori risk for atherosclerotic events appear to be most vulnerable to celecoxib-related risk. These data should help guide rational decision making for patients who derive clinical benefit from cyclooxygenase-2 inhibitors. See p 2104.
Absence of Cyclooxygenase-2 Exacerbates Hypoxia-Induced Pulmonary Hypertension and Enhances Contractility of Vascular Smooth Muscle Cells
Pulmonary hypertension is a severe disease commonly associated with chronic hypoxemia in disorders such as chronic obstructive pulmonary disease and interstitial lung disease. It is characterized by the development of pulmonary vascular remodeling, leading to elevated pulmonary vascular resistance and ultimately progression to right ventricular dysfunction and often death. Despite state-of-the-art therapy, morbidity and mortality rates remain high as a result of irreversible vascular remodeling. Cyclooxygenase-2 (COX-2) is upregulated in pulmonary artery smooth muscle cells during hypoxia and may play a protective role in the vascular response of the lung to hypoxia. In the present study, we investigated the role of COX-2 in a mouse model of hypoxia-induced pulmonary hypertension. The absence of COX-2 or pharmacological inhibition of COX-2 led to severe pulmonary hypertension after hypoxia with exaggerated elevation of right ventricular systolic pressure, significant right ventricular hypertrophy, and striking vascular remodeling. Vascular remodeling was characterized by pulmonary artery smooth muscle cell hypertrophy and significant upregulation of the endothelin-1 (ETA) receptor in the lung during hypoxia. Our findings also demonstrate that COX-2–deficient pulmonary artery smooth muscle cells have enhanced contractility after exposure to hypoxia that can be rescued by COX-2–derived prostaglandin E2 or prostaglandin I2. The results of our study suggest that COX-2 plays an important protective role in the lung under hypoxic conditions and that selective COX-2 inhibition may have detrimental pulmonary vascular consequences in patients with hypoxemic lung diseases or preexisting pulmonary hypertension. These findings have significant clinical implications and raise the possibility that selective COX-2 inhibitors might worsen symptoms in patients with pulmonary hypertension. See p 2114.
Increased High-Density Lipoprotein Cholesterol Predicts the Pioglitazone-Mediated Reduction of Carotid Intima-Media Thickness Progression in Patients With Type 2 Diabetes Mellitus
As the prevalence of type 2 diabetes mellitus increases in the United States and worldwide, it remains important to evaluate new ways of addressing the accelerated rates of atherosclerosis and cardiovascular disease (CVD) seen in these patients. Even in the statin era, residual incremental CVD risk compared with patients without diabetes remains. One notable accompaniment of type 2 diabetes mellitus is a low level of high-density lipoprotein (HDL) cholesterol. Cross-sectional and observational studies, as well as observations in atherosclerosis-prone animals, indicate that raising HDL cholesterol should be a powerful tool for reducing atherosclerosis and CVD risk in patients with diabetes. We have previously demonstrated that treating type 2 diabetic subjects with pioglitazone reduced progression of carotid intima-media thickness, a measure of carotid atherosclerosis and marker of CVD risk, compared with treatment with glimepiride. In the present analysis, we examined changes in individual cardiovascular risk factors after 24 weeks of treatment for their relationship to carotid intima-media thickness change at 72 weeks. Although treatment with pioglitazone led to improvement in multiple CVD risk parameters, only the increased HDL cholesterol and reduced insulin levels appeared to explain the treatment benefit. Of these, the HDL effect was larger and more consistent. Quartiles of HDL cholesterol change were progressively associated with more carotid intima-media thickness benefit, with an increment of 5% to 16% sufficient to produce a significant benefit for carotid intima-media thickness. These results demonstrate an important relationship between increases in HDL cholesterol produced by pioglitazone treatment and reduced progression of atherosclerosis in subjects with type 2 diabetes mellitus. They also underscore the potential of raising HDL cholesterol as a high-value therapeutic target for reducing atherosclerosis and CVD risk in patients with diabetes. See p 2123.
- Role of Left Ventricular Stiffness in Heart Failure With Normal Ejection Fraction
- Genetic Components of the Circadian Clock Regulate Thrombogenesis In Vivo
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