Jamal S. Rana

Obesity as Compared With Physical Activity in Predicting Risk of Coronary Heart Disease in Women

Background— The comparative importance of physical inactivity and obesity as predictors of coronary heart disease (CHD) risk remains unsettled. Methods and Results— We followed 88 393 women, 34 to 59 years of age, in the Nurses’ Health Study from 1980 to 2000. These participants did not have cardiovascular disease and cancer at baseline. We documented 2358 incident major CHD events (including nonfatal myocardial infarction and fatal CHD) during 20 years of follow-up, including 889 cases of fatal CHD and 1469 cases of nonfatal myocardial infarction. In a multivariate model adjusting for cardiovascular risk factors, overweight and obesity were significantly associated with increased risk of CHD, whereas increasing levels of physical activity were associated with a graded reduction in CHD risk (P<0.001). In joint analyses of body mass index (BMI) and physical activity in women who had a healthy weight (BMI, 18.5 to 24.9 kg/m2) and were physically active (exercise ≥3.5 h/wk) as the reference group, the relative risks of CHD were 3.44 (95% confidence interval [CI], 2.81 to 4.21) for women who were obese (BMI ≥30 kg/m2) and sedentary (exercise <1 h/wk), 2.48 (95% CI, 1.84 to 3.34) for women who were active but obese, and 1.48 (95% CI, 1.24 to 1.77) for women who had a healthy weight but were sedentary. In combined analyses of waist-hip ratio and physical activity, both waist-hip ratio and physical activity were significant predictors of CHD, and the highest risk was among women in the lowest category of physical activity and the highest tertile of waist-hip ratio (relative risk=3.03; 95% CI, 1.96 to 4.18). Even a modest weight gain (4 to 10 kg) during adulthood was associated with 27% (95% CI, 12% to 45%) increased risk of CHD compared with women with a stable weight after adjusting for physical activity and other cardiovascular risk factors. Conclusions— Obesity and physical inactivity independently contribute to the development of CHD in women. These data underscore the importance of both maintaining a healthy weight and regular physical activity in preventing CHD.

Cardiovascular metabolic syndrome – an interplay of, obesity, inflammation, diabetes and coronary heart disease

Cardiovascular disease is currently one of the biggest causes of morbidity and mortality facing humanity. Such a paradigm shift of disease pattern over the last century has only worsened due to the alarming global prevalence of obesity and type 2 diabetes. In recent years there is increasing focus on inflammation as one of the key players in the patho‐physiology of these disorders. In addition to these overt risk factors new research is unraveling the significance of a constellation of early metabolic abnormalities that include weight gain, insulin resistance, prehypertension and a specific pattern of dyslipidaemia. There exists a complex interrelationship of these various metabolic disorders and their effect on cardiovascular system. Simplified explanation can be that inflammation increases insulin resistance, which in turn leads to obesity while perpetuating diabetes, high blood pressure, prothrombotic state and dyslipidaemia. While inflammation and insulin resistance have direct adverse effects on cardiac muscle, these metabolic abnormalities as a whole cause causes cardiovascular complications; warranting a multi pronged therapeutic and preventive approach for the ‘Cardiovascular Metabolic Syndrome’ as an entity.

Accuracy of the Atherosclerotic Cardiovascular Risk Equation in a Large Contemporary, Multiethnic Population.

BACKGROUNDnThe accuracy of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Risk Equation for atherosclerotic cardiovascular disease (ASCVD) events in contemporary and ethnically diverse populations is not well understood.nnnOBJECTIVESnThe goal of this study was to evaluate the accuracy of the 2013 ACC/AHA Pooled Cohort Risk Equation within a large, multiethnic population in clinical care.nnnMETHODSnThe target population for consideration of cholesterol-lowering therapy in a large, integrated health care delivery system population was identified in 2008 and followed up through 2013. The main analyses excluded those with known ASCVD, diabetes mellitus, low-density lipoprotein cholesterol levelsxa0<70 orxa0≥190 mg/dl, prior lipid-lowering therapy use, or incomplete 5-year follow-up. Patient characteristics were obtained from electronic medical records, and ASCVD events were ascertained by using validated algorithms for hospitalization databases and death certificates. We compared predicted versus observed 5-year ASCVD risk, overall and according to sex and race/ethnicity. We additionally examined predicted versus observed risk in patients with diabetes mellitus.nnnRESULTSnAmong 307,591 eligible adults without diabetes between 40 and 75 years of age, 22,283 were black, 52,917 were Asian/Pacific Islander, and 18,745 were Hispanic. We observed 2,061 ASCVD events during 1,515,142 person-years. In each 5-year predicted ASCVD risk category, observed 5-year ASCVD risk was substantially lower: 0.20% for predicted riskxa0<2.50%; 0.65% for predicted risk 2.50% toxa0<3.75%; 0.90% for predicted risk 3.75% toxa0<5.00%; and 1.85% for predicted riskxa0≥5.00% (C statistic: 0.74). Similar ASCVD risk overestimation and poor calibration with moderate discrimination (C statistic: 0.68 to 0.74) were observed in sex, racial/ethnic, and socioeconomic status subgroups, and in sensitivity analyses among patients receiving statins for primary prevention. Calibration among 4,242 eligible adults with diabetes was improved, but discrimination was worse (C statistic: 0.64).nnnCONCLUSIONSnIn a large, contemporary real-world population, the ACC/AHA Pooled Cohort Risk Equation substantially overestimated actual 5-year risk in adults without diabetes, overall and across sociodemographic subgroups.

Cardiomyocytes overexpressing TNF-α attract migration of embryonic stem cells via activation of p38 and c-Jun amino-terminal kinase

Tumor necrosis factor‐α (TNF‐α) plays an important role in the pathogenesis of myocardial infarction. Stem cells are able to regenerate infarcted myocardium. This study investigated whether TNF‐α was able to induce migration of embryonic stem cells (ESCs) in vitro. We used a Transwell assay in which neonatal rat cardiomyocytes, with or without transfection of TNF‐α cDNA, were plated in the lower compart‐ ments and mouse ESCs tagged with green fuorescent protein were added to the upper compartments. TNF‐α level was significantly increased in the medium of the lower compartments seeded with TNF‐α‐transfected cardiomyocytes. Compared with the controls, overex‐ pression of TNF‐α significantly enhanced migration of ESCs to the lower compartments. This enhancement was attenuated by preincubation of ESCs with the antibody against the type II TNF‐α receptor (TNF‐RII), but not by the antibody against the type I TNF‐α receptor (TNF‐RI). Western blot analysis showed that the phosphorylated protein levels of p38 and c‐Jun amino‐terminal kinase (JNK) were significantly in‐ creased in TNF‐α‐treated ESCs. Inhibition of the activ‐ ity of p38 or JNK significantly attenuated TNF‐α‐in‐ duced ESC migration. Our data demonstrate that excessive TNF‐α stimulates TNF‐RII and enhances mi‐ gration of ESCs in vitro. Activation of p38 and JNK is required for TNF‐α‐enhanced ESC migration.—Chen, Y., Ke, Q., Yang, Y., Rana, J. S., Tang, J., Morgan, J. P., Xiao, Y.‐F. Cardiomyocytes overexpressing TNF‐α at‐ tract migration of embryonic stem cells via activation of p38 and c‐Jun amino‐terminal kinase. FASEB J. 17, 2231‐2239 (2003)

Exercise-induced expression of VEGF and salvation of myocardium in the early stage of myocardial infarction

The mechanism of exercise-induced benefit and angiogenesis in ischemic heart disease remains poorly defined. This study was designed to investigate the effects of exercise training on the expression of angiogenic factors and angiogenesis in the infarcted myocardium [myocarial infaction (MI)]. Sixty-three male FVB mice were used for study and were divided into subgroups to test the response to exercise: the time-dependent expression of angiogenic factors to exercise training in normal (group 1; n = 12) and infarcted myocardium (group 2; n = 15) and the exercise-induced angiogenic response in normal and infarcted myocardium (group 3; n = 20) as well as the impact of exercise preconditioning on infarcted myocardium (group 4; n = 26). Exercise training consisted of daily treadmill exercise for 1 h for 3 days. Expression of VEGF and its receptors Flt-1 and Flk-1 was upregulated by exercise training in mice with MI. Exercise-induced VEGF expression in the MI group was higher than that in the sham (control) group. Cell proliferation assessment showed a significantly higher (P < 0.05) number of bromodeoxyuridine-positive cells in post-MI mice in the exercise group as opposed to post-MI mice in the sedentary group. 2,3,5-Triphenyltetrazolium chloride staining revealed a profound difference in the size of MI (18.25 +/- 2.93%) in the exercise group versus the sedentary group (29.26 +/- 7.64%, P = 0.02). Moreover, exercise preconditioning before MI promoted VEGF expression at both mRNA and protein levels. In conclusion, activation of VEGF and its receptors occurs in the infarcted mice heart in response to exercise, which results in decreased infarct size and improved angiogenesis.

Successful implantation of intravenously administered stem cells correlates with severity of inflammation in murine myocarditis

The present study was designed to determine whether cardiac inflammation is important for the successful homing of stem cells to the heart after intravenous injection in a murine myocarditis model. Male Bagg albino/c mice were infected with encephalomyocarditis virus (EMCV) to produce myocarditis. Subgroups of mice received single injections by tail vein of embryonic stem cells (ESCs) transfected with green fluorescent protein (GFP) as a marker at daysxa03, 14, or 60 after infection; other subgroups without stem cell injections were killed at each of these time points to assess the degree of inflammation present. The surviving mice were killed at dayxa090 after virus infection and hemodynamics, gross pathology, histology, and inflammatory cytokine production in the hearts were measured. Our results indicate that myocardial inflammation was most severe and cytokine production highest at dayxa014 after EMCV inoculation, and in particular, was strongly positive for interleukin 6. Mice receiving intravenous ESC injections on dayxa014 after EMCV inoculation showed the largest number of GFP-positive cells at the time of death and the greatest functional improvement compared to uninfected controls without inflammation. We conclude that factors released from myocardium during inflammation are important for enhancing the homing, migration, and implantation of systemically infused stem cells.

Evolution of Percutaneous Coronary Intervention in Patients with Diabetes A report from the National Heart, Lung, and Blood Institute-sponsored PTCA (1985-1986) and Dynamic (1997-2006) Registries

OBJECTIVE To evaluate the association of successive percutaneous coronary intervention (PCI) modalities with balloon angioplasty (BA), bare-metal stent (BMS), drug-eluting stents (DES), and pharmacotherapy over the last 3 decades with outcomes among patients with diabetes in routine clinical practice. RESEARCH DESIGN AND METHODS We examined outcomes in 1,846 patients with diabetes undergoing de novo PCI in the multicenter, National Heart, Lung, and Blood Institute–sponsored 1985–1986 Percutaneous Transluminal Coronary Angioplasty (PTCA) Registry and 1997–2006 Dynamic Registry. Multivariable Cox regression models were used to estimate the adjusted risk of events (death/myocardial infarction [MI], repeat revascularization) over 1 year. RESULTS Cumulative event rates for postdischarge (31–365 days) death/MI were 8% by BA, 7% by BMS, and 7% by DES use (P = 0.76) and for repeat revascularization were 19, 13, and 9% (P < 0.001), respectively. Multivariable analysis showed a significantly lower risk of repeat revascularization with DES use when compared with the use of BA (hazard ratio [HR] 0.41 [95% CI 0.29–0.58]) and BMS (HR 0.55 [95% CI 0.39–0.76]). After further adjustment for discharge medications, the lower risk for death/MI was not statistically significant for DES when compared with BA. CONCLUSIONS In patients with diabetes undergoing PCI, the use of DES is associated with a reduced need for repeat revascularization when compared with BA or BMS use. The associated death/MI benefit observed with the DES versus the BA group may well be due to greater use of pharmacotherapy.

-455 G/A polymorphism and preprocedural plasma levels of fibrinogen show no association with the risk of clinical restenosis in patients with coronary stent placement

The effect of preprocedural fibrinogen levels on in-stent restenosis is largely unknown. The -455G/A polymorphism of the fibrinogen beta-gene is associated with baseline plasma level or acute phase increase of fibrinogen. Therefore, we hypothesized that there is a relationship between this polymorphism and preprocedural fibrinogen level and clinical restenosis at follow-up among patients with coronary stent placement. The GENetic DEterminants of Restenosis (GENDER) project is a multicenter follow-up study that enrolled 3,146 consecutive patients after successful percutaneous coronary intervention. A coronary stent was placed in 2,309 patients. Of these, 2,257 (97.7%) patients were successfully genotyped for the -455G/A polymorphism. Plasma fibrinogen levels were measured at baseline in a subpopulation of 623 stented patients with the von Clauss method and patients were grouped into tertiles according to fibrinogen levels. Primary endpoint was target vessel revascularization (TVR); secondary combined endpoint was defined as death presumably from cardiac causes, MI not attributable to another coronary artery than the target vessel, and TVR. No association was observed between the -455G/A polymorphism and TVR or combined endpoint (p=0.99, p=0.97, respectively). Multivariate regression analysis revealed that the risk of TVR and combined endpoint was not higher for patients in the highest tertile for fibrinogen versus the lowest tertile (RR=0.60, 95% CI: 0.26-1.37 for TVR, RR=0.64, 95% CI: 0.29-1.44 for combined endpoint). In conclusion, the presence of -455G/A polymorphism in the fibrinogen beta-gene and preprocedural fibrinogen level is not associated with an increased risk of TVR or combined endpoint in a patient population with coronary stent placement. Therefore, these parameters are not worthwhile for stratifying patients at risk for restenosis pre-stenting.

Role of A20 in cIAP-2 Protection against Tumor Necrosis Factor α (TNF-α)-Mediated Apoptosis in Endothelial Cells

Tumor necrosis factor α (TNF-α) influences endothelial cell viability by altering the regulatory molecules involved in induction or suppression of apoptosis. However, the underlying mechanisms are still not completely understood. In this study, we demonstrated that A20 (also known as TNFAIP3, tumor necrosis factor α-induced protein 3, and an anti-apoptotic protein) regulates the inhibitor of apoptosis protein-2 (cIAP-2) expression upon TNF-α induction in endothelial cells. Inhibition of A20 expression by its siRNA resulted in attenuating expression of TNF-α-induced cIAP-2, yet not cIAP-1 or XIAP. A20-induced cIAP-2 expression can be blocked by the inhibition of phosphatidyl inositol-3 kinase (PI3-K), but not nuclear factor (NF)-κB, while concomitantly increasing the number of endothelial apoptotic cells and caspase 3 activation. Moreover, TNF-α-mediated induction of apoptosis was enhanced by A20 inhibition, which could be rescued by cIAP-2. Taken together, these results identify A20 as a cytoprotective factor involved in cIAP-2 inhibitory pathway of TNF-α-induced apoptosis. This is consistent with the idea that endothelial cell viability is dependent on interactions between inducers and suppressors of apoptosis, susceptible to modulation by TNF-α.

Should we change our lipid management strategies to focus on non-high-density lipoprotein cholesterol?

Purpose of review Despite aggressive low-density lipoprotein cholesterol lowering, patients continue to be at significant risk of cardiovascular events. Assessment of non-high-density lipoprotein cholesterol (non-HDL-C) provides a measure of cholesterol contained in all atherogenic particles. In the third Adult Treatment Panel guidelines, non-HDL-C was introduced as a secondary target of therapy. Recent findings A combined post-hoc analysis of data from two prospective, randomized trials assessing the role of statins in patients with established coronary heart disease showed that on-treatment levels of non-HDL-C were more closely associated with cardiovascular outcomes than levels of low-density lipoprotein cholesterol. A recent meta-analysis of the relationship between non-HDL-C reduction and coronary heart disease risk showed that most lipid-modifying drugs used as monotherapy have a 1: 1 relationship between percentage non-HDL-C lowering and percentage coronary heart disease reduction. In the European Prospective Investigation Into Cancer and Nutrition-Norfolk prospective population study (n = 21 448), participants with high non-HDL-C levels were at increased coronary heart disease risk independently of their low-density lipoprotein cholesterol levels. Summary Because non-HDL-C appears to be superior for risk prediction beyond low-density lipoprotein cholesterol, future guidelines should emphasize the importance of non-HDL-C for guiding cardiovascular prevention strategies. There is an increased need to have non-HDL-C reported on routine lipid panels, especially because it would be at no added cost.