Coronary flow reserve is predictive of the risk of cardiovascular death regardless of chronic kidney disease stage.

Microvascular rarefaction is found in experimental uremia, but data from patients with chronic kidney disease (CKD) are limited. We therefore quantified absolute myocardial blood flow and coronary flow reserve (the ratio of peak to resting flow) from myocardial perfusion positron emission tomography scans at a single institution. Individuals were classified into standard CKD categories based on the estimated glomerular filtration rate. Associations of coronary flow reserve with CKD stage and cardiovascular mortality were analyzed in models adjusted for cardiovascular risk factors. The coronary flow reserve was significantly associated with CKD stage, declining in early CKD, but it did not differ significantly among individuals with stage 4, 5, and dialysis-dependent CKD. Flow reserve with preserved kidney function was 2.01, 2.06 in stage 1 CKD, 1.91 in stage 2, 1.68 in stage 3, 1.54 in stage 4, 1.66 in stage 5, and 1.55 in dialysis-dependent CKD. Coronary flow reserve was significantly associated with cardiovascular mortality in adjusted models (hazard ratio 0.76, 95% confidence interval: 0.63-0.92 per tertile of coronary flow reserve) without evidence of effect modification by CKD. Thus, coronary flow reserve is strongly associated with cardiovascular risk regardless of CKD severity and is low in early stage CKD without further decrement in stage 5 or dialysis-dependent CKD. This suggests that CKD physiology rather than the effects of dialysis is the primary driver of microvascular disease. Our findings highlight the potential contribution of microvascular dysfunction to cardiovascular risk in CKD and the need to define mechanisms linking low coronary flow reserve to mortality.

Prognostic Value of Coronary Flow Reserve in Patients with Dialysis-Dependent ESRD.

Capillary rarefaction of the coronary microcirculation is a consistent phenotype in patients with dialysis-dependent ESRD (dd-ESRD) and may help explain their excess mortality. Global coronary flow reserve (CFR) assessed by positron emission tomography (PET) is a noninvasive, quantitative marker of myocardial perfusion and ischemia that integrates the hemodynamic effects of epicardial stenosis, diffuse atherosclerosis, and microvascular dysfunction. We tested whether global CFR provides risk stratification in patients with dd-ESRD. Consecutive patients with dd-ESRD clinically referred for myocardial perfusion PET imaging were retrospectively included, excluding patients with prior renal transplantation. Per-patient CFR was calculated as the ratio of stress to rest absolute myocardial blood flow. Multivariable Cox proportional hazards models, including age, overt cardiovascular disease, and myocardial scar/ischemia burden, were used to assess the independent association of global CFR with all-cause and cardiovascular mortality. The incremental value of global CFR was assessed with relative integrated discrimination index and net reclassification improvement. In 168 patients included, median global CFR was 1.4 (interquartile range, 1.2-1.8). During follow-up (median of 3 years), 36 patients died, including 21 cardiovascular deaths. Log-transformed global CFR independently associated with all-cause mortality (hazard ratio, 0.01 per 0.5-unit increase; 95% confidence interval, <0.01 to 0.14; P<0.001) and cardiovascular mortality (hazard ratio, 0.01 per 0.5-unit increase; 95% confidence interval, <0.01 to 0.15; P=0.002). For all-cause mortality, addition of global CFR resulted in risk reclassification in 27% of patients. Thus, global CFR may provide independent and incremental risk stratification for all-cause and cardiovascular mortality in patients with dd-ESRD.

Red cell distribution width and risk of peripheral artery disease: analysis of National Health and Nutrition Examination Survey 1999-2004.

Red cell distribution width (RDW) is an independent predictor of the 10-year estimated risk of coronary heart disease (CHD) events. However, RDW's association with peripheral artery disease (PAD) - a CHD risk equivalent - has not been evaluated to date. In this cross-sectional study, we examined 6950 participants of the National Health and Nutrition Examination Survey, 1999-2004. PAD was defined as an ankle-brachial index below 0.9 (n = 618). RDW was divided into quartiles (Q) (Q1: ≤ 12.2; Q2: 12.3-12.5; Q3: 12.6-13.0; Q4: ≥ 13.1) and PAD risk was compared across these quartiles using adjusted multivariate logistic regression. A graded increase in prevalent PAD with increasing RDW quartiles was observed (4.2% in Q1 vs 13.9% in Q4; test of trend p < 0.001). Risk of PAD was significantly higher (odds ratio (OR) 1.19, 95% confidence interval (CI): 1.06-1.34; p = 0.003) after adjusting for age, sex, race, body mass index, hypertension, hyperlipidemia, diabetes, smoking, estimated glomerular filtration rate, C-reactive protein, hemoglobin, mean corpuscular volume, and nutritional factors (folate, iron and vitamin B(12)) deficiencies with each unit (0.1) increase in RDW. Upon receiver-operating characteristics analysis, the predictive accuracy of the American College of Cardiology / American Heart Association (ACC/AHA)-defined PAD screening criteria (for a high-risk population) was 0.657 at best, but improved significantly (0.727) after addition of RDW (p < 0.0001). In conclusion, higher levels of RDW are independently associated with a higher risk of PAD and can significantly improve the risk prediction beyond that estimated by ACC/AHA-defined PAD screening criteria.

Association between arterial elasticity indices and coronary artery calcium in a healthy multi-ethnic cohort.

OBJECTIVES: Reduced arterial elasticity is a risk factor for coronary artery disease. Our main objective was to evaluate the association between large arterial elasticity (LAE) and small arterial elasticity (SAE) with subclinical atherosclerosis as reflected by the coronary artery calcium score (CACS). METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) includes a multi-ethnic, population-based cohort (n = 6,814), aged 45-84 years, free from clinical cardiovascular disease. We undertook a post hoc analysis of the NHLBI limited access data set of MESA subjects (n = 6,278) to evaluate the association between LAE and SAE with CACS [divided in to 4 categories: none (reference), 1-99, 100-299, and ≥ 300] using multivariable adjusted logistic regression analysis. RESULTS: After adjustments for age, sex, systolic blood pressure, anti-hypertensive medications use, race, smoking, diabetes, high-density lipoprotein and total cholesterol, and high-sensitivity C-reactive protein, both LAE [adjusted odds ratio (aOR) 0.65; 95% CI 0.49-0.87 for CACS ≥ 300] and SAE (aOR 0.68, 95% CI 0.56-0.83 for CACS ≥ 300) were significantly (p < 0.001 for both) associated with a higher CACS. CONCLUSION: Both LAE and SAE, independent of traditional risk factors and inflammation, are associated with subclinical coronary atherosclerosis.

The association of red cell distribution width with glycated hemoglobin among healthy adults without diabetes mellitus.

BACKGROUND: Red cell distribution width (RDW) and hemoglobin A1c (HbA1c) are both known to be predictive of future cardiovascular disease (CVD). OBJECTIVE: We hypothesized that RDW would be associated with HbA1c in adults without diabetes independent of fasting blood glucose (FBG). METHODS: This cross-sectional study included 15,343 nondiabetic adults, free of CVD, enrolled in NHANES 1999-2008. Adjusted means of RDW were calculated across HbA1c categories for the overall population. Multivariable regression analyses were performed analyzing the association between RDW and HbA1c for individuals with available data on FBG (n = 7,454). RESULTS: RDW significantly correlated with HbA1c (r = 0.27, p < 0.001; n = 15,343), with a gradual increase in adjusted mean RDW across HbA1c categories (12.59% ± 0.02% in the group with HbA1c ≤4.8% vs. 12.92% ± 0.02% in the group with HbA1c >5.8%, p < 0.001 for trend). In regression analyses, RDW independently predicted HbA1c (ß-coefficient 0.034, 95% CI 0.026-0.042, p < 0.001). CONCLUSION: RDW significantly predicts HbA1c independent of FBG in healthy nondiabetic adults, suggesting the possibility of chronic hyperglycemia mediating the association between RDW and CVD.

Induction of the CXC chemokine interferon-gamma-inducible protein 10 regulates the reparative response following myocardial infarction.

RATIONALE: Interferon-gamma-inducible protein (IP)-10/CXCL10, an angiostatic and antifibrotic chemokine with an important role in T-cell trafficking, is markedly induced in myocardial infarcts, and may regulate the reparative response. OBJECTIVE: To study the role of IP-10 in cardiac repair and remodeling. METHODS AND RESULTS: We studied cardiac repair in IP-10-null and wild-type (WT) mice undergoing reperfused infarction protocols and examined the effects of IP-10 on cardiac fibroblast function. IP-10-deficient and WT animals had comparable acute infarct size. However, the absence of IP-10 resulted in a hypercellular early reparative response and delayed contraction of the scar. Infarcted IP-10(-/-) hearts exhibited accentuated early dilation, followed by rapid wall thinning during infarct maturation associated with systolic dysfunction. Although IP-10-null and WT mice had comparable cytokine expression, the absence of IP-10 was associated with marked alterations in the cellular content of the infarct. IP-10(-/-) infarcts had more intense infiltration with CD45(+) leukocytes, Mac-2(+) macrophages, and alpha-smooth muscle actin (alpha-SMA)(+) myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and alpha-SMA(+) cells that expressed CXCR3, the IP-10 receptor. IP-10 did not modulate cardiac fibroblast proliferation and apoptosis but significantly inhibited basic fibroblast growth factor-induced fibroblast migration. In addition, IP-10 enhanced growth factor-mediated wound contraction in fibroblast-populated collagen lattices. CONCLUSIONS: Endogenous IP-10 is an essential inhibitory signal that regulates the cellular composition of the healing infarct and promotes wound contraction, attenuating adverse remodeling. IP-10-mediated actions may be due, at least in part, to direct effects on fibroblast migration and function.

Predictors of residual cardiovascular risk in patients on statin therapy for primary prevention.

BACKGROUND: Low-density lipoprotein cholesterol-lowering therapy is an important aspect of primary prevention of cardiovascular disease (CVD). Statins are the most widely used drug therapy for achieving low-density lipoprotein goals based on an individual's 10-year risk. However, substantial risk of CVD events still exists even when a person is on statins. We sought to explore the predictors of future CVD events in individuals on statins with no pre-existing CVD. METHODS: The analysis was done on subjects who were on statins (n = 919) at baseline in the Multi-Ethnic Study of Atherosclerosis limited access dataset from the National Heart, Lung and Blood Institute. The primary outcome variable was all-cause CVD events (n = 67). Multivariate regression Cox proportional hazard analysis was done to identify potential independent predictors of all-cause CVD. RESULTS: Our cohort consisted of 47% males, with a mean age of 66 ± 9 years. Sixty-seven participants (7.3%) experienced CVD events during a mean follow-up of 4.4 years. A higher coronary artery calcium score, homocysteine levels, waist circumference and a lower large arterial elasticity index were identified as independent predictors of CVD events. CONCLUSION: Homocysteine, waist circumference, coronary artery calcification and the large artery elasticity index appear to be the major independent predictors of CVD events in individuals on statins with no pre-existing CVD. In addition to emphasizing weight loss, alternative approaches beyond lipid reduction may need to be explored to better characterize and attenuate the residual risk in subjects on statin therapy for primary prevention.

Relationship between red cell distribution width and microalbuminuria: a population-based study of multiethnic representative US adults.

INTRODUCTION: Microalbuminuria (MA), a renal marker of vascular injury, is an independent predictor of cardiovascular (CV) events. Red cell distribution width (RDW), an emerging CV risk predictor, has not been evaluated for its association with MA. METHODS: We evaluated 8,499 participants of the National Health and Nutrition Examination Survey (NHANES) 1999-2006, where RDW was evaluated as a continuous variable and in quartiles (Q(1) ≤ 12.1, Q(2) 12.2-12.5, Q(3) 12.6-13 and Q(4) >13). Multivariate adjusted logistic regression analysis was performed to estimate the odds of having MA (n = 1,736; adjusted for traditional CV risk factors, race, BMI, estimated glomerular filtration rate, hemoglobin, mean corpuscular volume, high-sensitivity C-reactive protein and nutritional factors deficiencies of iron, folate and vitamin B(12)). RESULTS: The prevalence of MA increased with increasing RDW (13.52% in Q(1) vs. 30.02% in Q(4), p < 0.001). The odds of having MA for those in Q(4) was 2.49 (95% CI: 1.95-3.18, p < 0.001) compared to those in Q(1) after the adjustments. No effect modification was observed by covariates on the association between RDW and MA. CONCLUSION: Elevated RDW is independently associated with a higher risk of MA. An interaction between chronic inflammation, oxidative stress, neurohumoral overactivity and endothelial dysfunction may explain this association and the attendant elevated CV/renal risk.

Preserved or slightly depressed ejection fraction and outcomes after myocardial infarction.

BACKGROUND Left ventricular ejection fraction (EF) in post-myocardial infarction (MI) patients is a strong predictor of adverse cardiovascular events. Although resting EF as measured by transthoracic echocardiography (TTE), contrast ventriculography (CNV), and radionuclide angiography (RNA) exhibit high correlation, there is only modest agreement between these modalities. This study sought to explore whether modality of EF assessment influences prognostication of post-MI patients with normal or slightly reduced EF. METHODS AND RESULTS The National Heart, Lung, and Blood Institute (NHLBI) limited access dataset of the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial (1996-2003, n=8290) comparing trandolapril versus placebo was used. The cohort was partitioned into TTE (n=2582), RNA (n=816), and CNV (n=1155) groups based on modality of EF assessment. EF was a significant predictor of cardiovascular mortality (HR 0.97, 95% CI 0.95 to 0.98; p<0.005) and all cause mortality (HR 0.98, 95% CI 0.97 to 0.99; p=0.0002) on multivariate analysis in this population with preserved or mildly depressed EF. Although CNV, TTE, and RNA groups differed significantly in terms of baseline variables, no appreciable differences were noted between RNA (HR 1.13, 95% CI 0.85 to 1.50; ns) and CNV (HR 1.13, 95% CI 0.99 to 1.27; ns) groups, compared with TTE for all cause mortality. Similarly, no significant differences were observed for cardiovascular mortality between RNA (HR 1.23, 95% CI 0.82 to 1.84; p=0.31) and CNV (HR 1.14, 95% CI 0.78 to 1.67, p=0.49) versus TTE. CONCLUSION EF is a significant predictor of all-cause mortality and cardiovascular mortality in patients with preserved or mildly depressed EF. Modalities of EF measurement are interchangeable and do not play a significant role in prognostication in a post-MI population.

Global and regional left ventricular contractile impairment in patients with wolff-Parkinson-white syndrome.

BACKGROUND: To assess regional systolic function and global contractile function in patients with WPW Syndrome. METHOD: Eleven cases with manifest Wolff-Parkinson-White (WPW) syndrome in sinus rhythm were compared to 11 age matched controls. 2D strain analysis was performed and peak segmental radial strain (pRS) values obtained from basal ventricular parasternal short-axis images (70 +/- 5 frames/sec) using a dedicated software package. Heterogeneity of radial strain pattern in six circumferential basal left ventricular segments was measured in terms of standard deviations of peak RS (SD(pRS)) or range (difference between maximum and minimum peak RS i.e. Range(pRS)). Spectral Doppler (continuous wave) measurements were acquired through the left ventricular outflow tract to determine Pre Ejection Period (PEP), Left Ventricular Ejection Time (LVET) and measures of left ventricular systolic performance. RESULTS: LV segmental radial strain was profoundly heterogeneous in WPW cases in contrast to fairly homogenous strain pattern in normal subjects. Wide SD(pRS) values 17.5 +/- 8.9 vs 3.3 +/- 1.4, p<0.001 and Range(pRS) 42.7 +/- 20.8 vs.8.5 +/- 3.6 , p<0.001 were observed among WPW and healthy subjects respectively. PEP (132.4 +/- 14.7 vs 4.7 +/- 0.5ms, p<0.001) and corrected PEP (76.1 +/- 8.0 vs 2.7 +/- 0.4ms, p<0.001) were significantly longer in WPW patients compared to controls. The PEP/LVET ratio was also significantly greater in WPW cohort (0.49 +/- 0.04 vs. 0.28 +/- 0.05, p <0.001) suggesting global systolic dysfunction. CONCLUSIONS: Patients with manifest preexcitation (predominantly those with right-sided pathways) have regional and global contractile dysfunction resulting from aberrant impulse propagation inherent to the preexcited state.

Comparison of five-year outcome in African Americans versus Caucasians following percutaneous coronary intervention.

BACKGROUND: Studies regarding short-term outcomes after percutaneous coronary intervention (PCI) have reported no ethnic differences and data on long-term follow-up is conflicting and sparse. METHODS: 730 consecutive patients (67% African American) undergoing PCI from January 1999 to December 2000 at a tertiary care center in Detroit, MI, were followed up. End points studied included either all cause mortality collected from Social Security Death Index or first hospital admission after the index procedure due to myocardial infarction(MI), congestive heart failure(CHF), and revascularization (PCI or coronary artery bypass graft surgery). RESULTS: African-Americans undergoing PCI had significant differences in baseline cardiovascular co-morbidity and were more likely to present with acute myocardial infarction than Caucasians. On Kaplan Meier survival analysis and log rank test, each ethnic group had equivalent survival for cumulative end points upto 6-month follow-up, however longer follow-up to 5 year was characterized by lower survival rate in African Americans compared to Caucasians (41% vs. 54%, log rank P 0.01). After adjustment for potential confounders, AA ethnicity (Adjusted HR 1.62, 95% CI 1.01-1.28, P 0.04) remained a predictor of adverse cardiac outcome (Death/MI/CHF) at five-year follow-up (Cox regression propensity adjusted hazard analysis). CONCLUSIONS: African American patients undergoing PCI had unfavorable baseline cardiovascular characteristics but comparable short-term outcome compared to whites. However, at 5-year follow-up, African Americans had worse clinical outcome, higher incidence of acute myocardial infarction, congestive heart failure and significantly lower long-term survival.

Ethnic and sex differences in disease burden in patients undergoing coronary angiography: the confounding influence of obesity.

BACKGROUND: Data from cohort studies, predominantly in Caucasians, have identified obesity as a major risk factor for coronary artery disease (CAD), irrespective of sex. In contrast, reports examining the effects of obesity on mortality in African Americans suggest a weak relationship between body mass index (BMI) and mortality, particularly among women. Data correlating body weight with angiographic severity of CAD is sparse in minority populations. We sought to investigate ethnic-sex differences in the influence of obesity on the extent and severity of CAD. METHODS: We studied 640 patients (66.9% African American) who underwent coronary angiography at a tertiary care center. Cardiovascular risk factor profiles and CAD burden, quantified by the Duke Myocardial Jeopardy scoring system, a validated prognostication tool, were compared across ethnic and sex groups. RESULTS: Clustering of major cardiovascular risk factors, a higher prevalence of obesity classes II and III, and a statistically significant inverse correlation between BMI and Duke scores were observed among the cohort of African American women. General linear model analysis and stepwise multiple linear regression analysis revealed Duke score to be negatively associated with BMI and higher classes of obesity after adjustment for age and other cardiovascular risk factors in African American women but not in other subgroups. CONCLUSIONS: The observed inverse relationship between BMI and angiographic severity of CAD in African American women is novel and appears to support prior data on the weak association between BMI and cardiovascular mortality in this subgroup.