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Background We sought to evaluate the prognostic performance of the CHADS 2 score for prediction of ischemic stroke/transient ischemic attack (TIA) in subjects with coronary heart disease (CHD) without atrial fibrillation (AF). Methods In 916 nonanticoagulated outpatients with stable CHD and no AF by baseline electrocardiogram, we calculated CHADS 2 scores (congestive heart failure, hypertension, age ≥75 years, diabetes [1 point each], and prior stroke or TIA [2 points]). The primary outcome was time to ischemic stroke or TIA over a mean follow-up of 6.4 ± 2.3 years. Results Over 5,821 person-years of follow-up, 40 subjects had an ischemic stroke/TIA (rate 0.69/100 person-years, 95% CI 0.50-0.94). Compared with subjects with low (0-1) CHADS 2 scores, those with intermediate (2-3) and high (4-6) CHADS 2 scores had an increased rate of stroke/TIA, even after adjustment for age, tobacco, antiplatelet therapy, statins, and angiotensin inhibitors (CHADS 2 score 2-3: HR 2.4, 95% CI 1.1-5.3, P = .03; CHADS 2 score 4-6: HR 4.0, 95% CI 1.5-10.6, P = .006). Model discrimination (c-statistic = 0.65) was comparable with CHADS 2 model fit in published AF-only cohorts. Conclusions The CHADS 2 score predicts ischemic stroke/TIA in subjects with stable CHD and no baseline AF. The event rate in non-AF subjects with high CHADS 2 scores (5-6) was comparable with published rates in AF patients with moderate CHADS 2 scores (1-2), a population known to derive benefit from stroke prevention therapies. These findings should inform efforts to determine whether stroke prevention therapies or screening for silent AF may benefit subjects with stable CHD and high CHADS 2 scores.

Heart failure (HF) is a common public health problem, and many new cases are now recognized to occur in patients with preserved left ventricular ejection fraction. beta Blockers improve the outcomes of patients with known left ventricular systolic dysfunction, but whether beta blockers provide similar protection among patients with left ventricular diastolic dysfunction is unclear. We studied the association between use of beta blockers and subsequent hospitalization for HF in patients with diastolic dysfunction and stable coronary heart disease. We evaluated medication use and performed echocardiography at baseline in a prospective cohort of 911 outpatients with known coronary heart disease from the Heart and Soul Study. Hospitalizations for HF were assessed by blinded review of the medical records during an average follow-up of 5.2 years. Of the 911 participants, 118 (13%) had diastolic dysfunction, of whom 2 were lost to follow-up. Of the 116 remaining patients, 19 (25%) of the 77 using beta blockers were hospitalized for HF compared to 16 (41%) of the 39 not using beta blockers (age-adjusted hazard ratio 0.51, 95% confidence interval 0.26 to 1.00; p = 0.05). This association remained after additional adjustment for gender, smoking, history of myocardial infarction, diabetes, and creatinine (hazard ratio 0.46, 95% confidence interval 0.23 to 0.93; p = 0.03). The results were similar after excluding 31 participants with a history of self-reported HF (hazard ratio 0.33, 95% confidence interval 0.13 to 0.86; p = 0.02) and 24 participants with concurrent systolic dysfunction (hazard ratio 0.36, 95% confidence interval 0.14 to 0.89; p = 0.03). In conclusion, the use of beta blockers is associated with a decreased risk of hospitalization for HF in patients with diastolic dysfunction and stable coronary heart disease.

Background B-type natriuretic peptide (BNP) is predictive of inducible ischemia in patients with coronary heart disease (CHD). Whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) has a comparable strength of association with ischemia is uncertain. Hypothesis Resting NT-proBNP levels are associated with inducible ischemia in patients with stable CHD. Methods We performed a cross-sectional study of 901 outpatients with stable CHD. NT-proBNP was measured in all patients prior to exercise treadmill testing and stress echocardiography. In addition, plasma BNP was measured in a subset of 355 participants. Logistic regression was used to examine the association of NT-proBNP and BNP quartiles with inducible ischemia. Results Inducible ischemia was found in 216 (24%) patients. The proportion with inducible ischemia ranged from 42% (95/225) in the highest quartile of NT-proBNP levels (>410 pg/ml) to 9% (21/226) in the lowest quartile (0–72 pg/ml). The highest quartile had a 7-fold greater odds of inducible ischemia than the lowest quartile (odds ratio [OR]: 7.1, 95% confidence interval [CI]: 4.2–12; P < 0.0001). This association remained robust after adjustment for traditional cardiovascular risk factors, left ventricular ejection fraction, and diastolic dysfunction (OR: 3.6, 95% CI: 1.4–9.1; P = 0.009). In the subgroup with measurements of both NT-proBNP and BNP, both natriuretic peptides were predictive of ischemia. The multivariable-adjusted c-statistics for inducible ischemia were 0.71 for NT-proBNP and 0.62 for BNP (entered as continuous variables). Conclusions Resting NT-proBNP levels are independently associated with inducible ischemia in outpatients with stable CHD. Baseline elevations of natriuretic peptide may indicate subclinical inducible ischemia in high risk patients with CHD. Copyright © 2009 Wiley Periodicals, Inc.

Aims The predictive value of changes in global left ventricular (LV) size after exercise has not been studied. Left ventricular end-systolic volume (ESV) is a relatively load-independent echocardiographic marker of contractility that is easily measured. We investigated the role of the change in ESV at rest and after peak exercise on mortality among patients with stable coronary heart disease (CHD). Methods and results We performed exercise treadmill testing with stress echocardiography in 934 ambulatory subjects with CHD. End-systolic volume was measured immediately before and after exercise using 2D echocardiography. We defined ESV reversal as an increase in ESV after exercise, and we examined the association of ESV reversal with all-cause mortality during a median follow-up of 3.92 years. Of the 934 participants, 199 (21%) had ESV reversal. At the end of follow-up, mortality was higher among participants with ESV reversal than those without (26 vs. 11%; P < 0.001). After adjustment for clinical covariates, ESV reversal remained predictive of all-cause mortality (HR 2.0; 95% CI 1.4–2.9; P = 0.001). The association of ESV reversal with mortality also persisted after adjustment for exercise-induced wall-motion abnormalities (HR 1.7; 95% CI 1.1–2.3, P = 0.006). To determine if the effect of ESV reversal was independent from other echocardiographic measurements, we created a separate model adjusting for resting LV ejection fraction, ESV, end-diastolic volume, and LV mass. End-systolic volume reversal was the only significant predictor of mortality in this model (HR 2.1, 95% CI 1.4–3.0, P < 0.001). Conclusion End-systolic volume reversal is a novel parameter that independently predicts mortality in patients with CHD undergoing exercise treadmill echocardiography, even after adjustment for a wide range of clinical, echocardiographic, and treadmill exercise variables. Because measurement of ESV is simple, reproducible, and requires no additional imaging views, identification of ESV reversal during exercise echocardiography can provide useful complementary information for risk stratification.

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 x 10(-11); LDL, P = 2.6 x 10(-10)), TMEM57 (TC, P = 5.4 x 10(-10)), CTCF-PRMT8 region (HDL, P = 8.3 x 10(-16)), DNAH11 (LDL, P = 6.1 x 10(-9)), FADS3-FADS2 (TC, P = 1.5 x 10(-10); LDL, P = 4.4 x 10(-13)) and MADD-FOLH1 region (HDL, P = 6 x 10(-11)). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.

The predictive value of left atrial (LA) dilatation in ambulatory adults with coronary artery disease is not known. It was hypothesized that echocardiographic LA volume index (LAVI) predicts heart failure (HF) hospitalization and mortality with similar statistical power as left ventricular ejection fraction (LVEF) in ambulatory adults with coronary artery disease. We measured LAVI in 935 adults without atrial fibrillation, atrial flutter, or significant mitral valve disease in the Heart and Soul Study. LAVI was calculated using the biplane method of disks. Outcomes included HF hospitalization and mortality. Logistic regression odds ratios (ORs) were calculated and adjusted for age, demographics, medical history, left ventricular mass, diastolic function, and LVEF. Mean LAVI was 32 ± 11 ml/m2, and mean LVEF was 62 ± 10%. Sixty-six patients (7%) had LAVI >50 ml/m2. There were 108 HF hospitalizations and 180 deaths at 4.3 years of follow-up. C statistics calculated as the area under the receiver-operator characteristic curve were the same (0.60) for LAVI and LVEF in predicting mortality. The unadjusted OR for HF hospitalization was 4.4 for LAVI > 50 ml/m2 and 5.3 for LVEF 50 ml/m2 were 5.2 for HF hospitalization (p 50 ml/m2 was predictive of HF hospitalization (OR 2.4, p = 0.02), and LAVI >40 ml/m2 was predictive of mortality (OR 1.9, p = 0.005). In conclusion, LAVI had similar predictability as LVEF for HF hospitalization and mortality in ambulatory adults with coronary artery disease.

Pulmonary vascular resistance (PVR) is an important hemodynamic variable that affects prognosis and therapy in a wide range of cardiovascular and pulmonary conditions. We sought to determine whether a noninvasive estimate of PVR predicts adverse outcomes in patients with stable coronary artery disease. Using Doppler echocardiography we measured the estimated PVR (defined as the ratio of the tricuspid regurgitant velocity [TRV] to the velocity-time integral [VTI] of the right ventricular outflow tract [RVOT]) in 795 ambulatory patients with stable coronary artery disease. Participants were categorized by quartiles of the TRV/VTI RVOT ratio. Hazard ratios (HRs) and 95% confidence intervals were calculated for all-cause mortality, heart failure hospitalization, and adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or stroke). After 4.3 years of follow-up there were 161 deaths, 44 deaths from cardiovascular causes, 103 heart failure hospitalizations, and 120 adverse cardiovascular events. Compared with patients in the lowest TRV/VTI RVOT quartile, those in the highest quartile were at increased risk of all-cause mortality (unadjusted HR 1.8, 95% confidence interval 1.3 to 2.5), heart failure hospitalization (unadjusted HR 2.9, 95% confidence interval 2.0 to 4.3), and adverse cardiovascular events (unadjusted HR 2.0, 95% confidence interval 1.4 to 2.9). After multivariate adjustment, patients in the highest quartile were at increased risk of heart failure hospitalizations (adjusted HR 2.5, 95% confidence interval 1.3 to 4.7). In conclusion, a noninvasive estimate of PVR (TRV/VTI RVOT ratio) predicts mortality, heart failure hospitalization, and adverse cardiovascular events in patients with stable coronary artery disease.

Background Patients with stable coronary heart disease ( CHD ) have widely varying prognoses and treatment options. Validated models for risk stratification of patients with CHD are needed. We sought to evaluate traditional and novel risk factors as predictors of secondary cardiovascular ( CV ) events, and to develop a prediction model that could be used to risk stratify patients with stable CHD . Methods and Results We used independent derivation (912 participants in the Heart and Soul Study) and validation (2876 participants in the PEACE trial) cohorts of patients with stable CHD to develop a risk prediction model using Cox proportional hazards models. The outcome was CV events, defined as myocardial infarction, stroke, or CV death. The annual rate of CV events was 3.4% in the derivation cohort and 2.2% in the validation cohort. With the exception of smoking, traditional risk factors (including age, sex, body mass index, hypertension, dyslipidemia, and diabetes) did not emerge as the top predictors of secondary CV events. The top 4 predictors of secondary events were the following: N‐terminal pro‐type brain natriuretic peptide, high‐sensitivity cardiac troponin T, urinary albumin:creatinine ratio, and current smoking. The 5‐year C‐index for this 4‐predictor model was 0.73 in the derivation cohort and 0.65 in the validation cohort. As compared with variables in the Framingham secondary events model, the Heart and Soul risk model resulted in net reclassification improvement of 0.47 (95% CI 0.25 to 0.73) in the derivation cohort and 0.18 (95% CI 0.01 to 0.40) in the validation cohort. Conclusions Novel risk factors are superior to traditional risk factors for predicting 5‐year risk of secondary events in patients with stable CHD .

Aims Despite the prevalence of atrial fibrillation (AF) occurring after cardiac surgery, its pathophysiology is incompletely understood. Specifically, whether left atrial (LA) structural remodelling occurs, contributing to a decrement in atrial function and AF has not been previously determined. This study sought to determine the relationship between LA function and post-operative AF. Methods and results Three hundred patients undergoing elective coronary artery bypass graft surgery were monitored with intraoperative transoesophageal echocardiography to determine LA function and dimensions. Post-operative AF was monitored with continuous telemetry until hospital discharge. The relationship between clinical factors versus LA function and dimension was assessed using multi-variate logistic regression. By univariate analysis, patients who subsequently developed post-operative AF had a larger LA area and LA appendage area, and lower LA ejection fraction measured in the pre-bypass period compared to those without subsequent AF. By multivariable analysis, in addition to clinical data including age (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.05–1.16, P

Whether B-type natriuretic peptide (BNP) levels can be used to screen for ventricular dysfunction in patients at risk of heart failure but without overt symptoms is not known. We examined the characteristics of a BNP test for identifying systolic and diastolic dysfunction in outpatients with stable coronary disease.In a cross-sectional study of 293 outpatients who had stable coronary disease and no history of heart failure, we compared elevations in plasma BNP levels with echocardiography for the diagnosis of systolic dysfunction (ejection fraction55%) and diastolic dysfunction (diastolic dominant pulmonary vein flow with ejection fractionor =55%).A total of 48 patients (16%) had systolic dysfunction, and among the remaining 245 with preserved systolic function, 31 (13%) had diastolic dysfunction. At the standard cutpoint of100 pg/mL, an elevated BNP level was 38% sensitive (80% specific) for systolic dysfunction and 55% sensitive (85% specific) for diastolic dysfunction. Negative likelihood ratios were 0.8 (95% confidence interval [CI]: 0.6 to 1.0) for systolic dysfunction and 0.5 (95% CI: 0.4 to 0.8) for diastolic dysfunction. Positive likelihood ratios were 1.9 (95% CI: 1.2 to 2.9) for systolic dysfunction and 3.8 (95% CI: 2.4 to 5.9) for diastolic dysfunction. Areas under the receiver operating characteristic curves were 0.59 (95% CI: 0.49 to 0.69) for systolic dysfunction and 0.79 (95% CI: 0.71 to 0.87) for diastolic dysfunction.These data suggest that BNP is not a useful screening test for asymptomatic ventricular dysfunction in patients with stable coronary disease.

ImportanceLevels of high-sensitivity cardiac troponin T (hs-cTnT) predict secondary cardiovascular events in patients with stable coronary heart disease.ObjectivesTo determine the association of hs-cTnT levels with structural and functional measures of heart disease and the extent to which these measures explain the relationship between hs-cTnT and secondary events.DesignWe measured serum concentrations of hs-cTnT and performed exercise treadmill testing with stress echocardiography in a prospective cohort study of outpatients with coronary heart disease who were enrolled from September 11, 2000, through December 20, 2002, and followed up for a median of 8.2 years.SettingTwelve outpatient clinics in the San Francisco Bay Area.ParticipantsNine hundred eighty-four patients with stable coronary heart disease.Main outcomes and measuresCardiovascular events (myocardial infarction, heart failure, or cardiovascular death), determined by review of medical records and death certificates.ResultsOf 984 participants, 794 (80.7%) had detectable hs-cTnT levels. At baseline, higher hs-cTnT levels were associated with greater inducible ischemia and worse left ventricular ejection fraction, left atrial function, diastolic function, left ventricular mass, and treadmill exercise capacity. During follow-up, 317 participants (32.2%) experienced a cardiovascular event. After adjustment for clinical risk factors, baseline cardiac structure and function, and other biomarkers (N-terminal portion of the prohormone of brain-type natriuretic peptide and C-reactive protein levels), each doubling in hs-cTnT level remained associated with a 37% higher rate of cardiovascular events (hazard ratio, 1.37 [95% CI, 1.14-1.65]; P = .001).Conclusions and relevanceIn outpatients with stable coronary heart disease, higher hs-cTnT levels were associated with multiple abnormalities of cardiac structure and function but remained independently predictive of secondary events. These findings suggest that hs-cTnT levels may detect an element of risk that is not captured by existing measures of cardiac disease severity.

BackgroundThe prognostic value of the 6-minute walk test (6MWT) in patients with stable coronary heart disease is unknown. We sought to determine whether the 6MWT predicted cardiovascular events in ambulatory patients with coronary heart disease.MethodsWe measured 6MWT distance and treadmill exercise capacity in 556 outpatients with stable coronary heart disease from September 11, 2000, through December 20, 2002. Participants were followed up for a median of 8.0 years for cardiovascular events (heart failure, myocardial infarction, and death).ResultsCardiovascular events occurred in 218 of 556 participants (39.2%). Patients in the lowest quartile of 6MWT distance (87-419 m) had 4 times the rate of events as those in the highest quartile (544-837 m) (unadjusted hazard ratio, 4.29; 95% CI, 2.83-6.53; P < .001). Each SD decrease in 6MWT distance (104 m) was associated with a 55% higher rate of cardiovascular events (age-adjusted hazard ratio, 1.55; 95% CI, 1.35-1.78). After adjustment for traditional risk factors and cardiac disease severity measures (ejection fraction, inducible ischemia, diastolic dysfunction, amino-terminal portion of the prohormone of brain-type natriuretic peptide, and C-reactive protein), each SD decrease in 6MWT was associated with a 30% higher rate of cardiovascular events (hazard ratio, 1.30; 95% CI, 1.10-1.53). When added to traditional risk factors, the 6MWT resulted in category-free net reclassification improvement of 39% (95% CI, 19%-60%). The discriminative ability of the 6MWT was similar to that of treadmill exercise capacity for predicting cardiovascular events (C statistics both 0.72; P = .29).ConclusionsDistance walked on the 6MWT predicted cardiovascular events in patients with stable coronary heart disease. The addition of a simple 6MWT to traditional risk factors improved risk prediction and was comparable with treadmill exercise capacity.

ObjectivesThis study sought to determine whether left atrial (LA) dysfunction predicts heart failure (HF) hospitalization in subjects with preserved baseline ejection fraction (EF).BackgroundAmong patients with preserved EF, factors leading to HF are not fully understood. Cross-sectional studies have demonstrated LA dysfunction at the time of HF, but longitudinal data on antecedent atrial function are lacking.MethodsWe performed resting transthoracic echocardiography in 855 subjects with coronary heart disease and EF ≥50%. Left atrial functional index (LAFI) was calculated as ([LA emptying fraction × left ventricular outflow tract-velocity time integral] / [indexed LA end-systolic volume]), where LA emptying fraction was defined as (LA end-systolic volume − LA end-diastolic volume) / LA end-systolic volume. We used Cox models to evaluate the association between LAFI and HF hospitalization.ResultsOver a median follow-up of 7.9 years, 106 participants (12.4%) were hospitalized for HF. Rates of HF hospitalization were inversely proportional to quartile (Q) of LAFI: Q1, 47 per 1,000 person-years; Q2, 18.3; Q3, 9.6; and Q4, 5.3 (p < 0.001). Each standard deviation decrease in LAFI was associated with a 2.6-fold increased hazard of adverse cardiovascular outcomes (unadjusted hazard ratio: 2.6, 95% confidence interval: 2.1 to 3.3, p < 0.001), and the association persisted even after adjustment for clinical risk factors, N-terminal pro–B-type natriuretic peptide, and a wide range of echocardiographic parameters (adjusted hazard ratio: 1.5, 95% confidence interval: 1.0 to 2.1, p = 0.05).ConclusionsLeft atrial dysfunction independently predicts HF hospitalization in subjects with coronary heart disease and preserved baseline EF. The LAFI may be useful for HF risk stratification, and LA dysfunction may be a potential therapeutic target.

Background Echocardiographic measurements of left ventricular (LV) mass, left atrial (LA) volume, and LV end-systolic volume (ESV) predict heart failure (HF) hospitalization and mortality. Indexing measurements by body size is thought to establish limits of normality among individuals varying in body habitus. The American Society of Echocardiography recommends dividing measurements by body surface area (BSA), but others have advocated alternative indexing methods. Methods Echocardiographic measurements were collected in 1024 ambulatory adults with coronary artery disease. LV mass, LA volume, and LV ESV were calculated using truncated ellipse method and biplane method of disk formulae. Comparison between raw measurements and measurements divided by indexing parameters was made by hazard ratios per standard deviation increase in variable and c-statistics for BSA, BSA 0.43 , BSA 1.5 , height, height 0.25 , height 2 , height 2.7 , body weight (BW), BW 0.26 , body mass index (BMI), and BMI 0.27 . Results Mean LV mass was 192 ± 57 g, mean LA volume was 65 ± 24 mL, and mean LV ESV was 41 ± 26 mL. Average height was 171 ± 9 cm, average BSA was 1.94 ± 0.22 m 2 , and average BMI was 28.4 ± 5.3 kg/m 2 . At an average follow-up of 5.6 ± 1.8 years, there were 148 HF hospitalizations, 71 cardiovascular (CV) deaths, and 269 all-cause deaths. There was excellent correlation between raw measurements and those indexed by height ( r = 0.98-0.99), and moderate correlation between raw measurements and those indexed by BW ( r = 0.73-0.94). C-statistics and hazard ratios per standard deviation increase in indexed variables were similar for HF hospitalization, CV mortality, and all-cause mortality. There were no significant differences among indexing methods in ability to predict outcomes. Conclusion The choice of indexing method by parameters of BSA, height, BW, and BMI does not affect the clinical usefulness of LV mass, LA volume, and LV ESV in predicting HF hospitalization, CV mortality, or all-cause mortality among ambulatory adults with coronary artery disease. Continued use of BSA to index measurements of LV mass, LA volume, and LV ESV is acceptable.

Background Elevated concentrations of cystatin C are associated with greater cardiovascular morbidity and mortality. We sought to determine whether elevated concentrations of cystatin C were associated with inducible ischemia in patients with coronary heart disease (CHD). Methods We measured serum cystatin C and performed exercise treadmill testing with stress echocardiography in a cross-sectional study of 899 outpatients with CHD. Results Among the 241 participants in the highest quartile of cystatin C (>1.30 mg/L), 38% had inducible ischemia, compared with 13% of those in the lowest quartile of cystatin C < 0.92 mg/L; adjusted odds ratio [OR]: 2.1; 95% confidence interval [CI]: 1.2 to 3.8; p = 0.01). However, this association differed in participants with and without a history of coronary artery bypass graft (CABG), as well as in users and nonusers of beta-blockers and statins (p values for interaction < 0.1). Among participants without a history of CABG, 35% of those in the highest quartile and 9% of those in the lowest quartile of cystatin C had inducible ischemia (adjusted OR: 3.05; 95% CI: 1.3–6.9; p = 0.008). Among participants who were not using beta-blockers, 44% of those in the highest quartile and 7% in the lowest quartile of cystatin C had inducible ischemia (adjusted OR: 5.3; 95% CI: 1.8–15.5; p = 0.002). Among participants who were not using statins, 39% of participants in the highest quartile and 4% of those in the lowest quartile had inducible ischemia (adjusted OR: 10.3; 95% CI: 2.5–43.3; p = 0.001). Conclusions Elevated levels of cystatin C are independently associated with inducible ischemia among outpatients with stable coronary disease. Copyright © 2009 Wiley Periodicals, Inc.

CONTEXT: Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain. OBJECTIVE: To investigate association of genetic loci with CRP levels and risk of coronary heart disease. DESIGN, SETTING, AND PARTICIPANTS: We first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls. MAIN OUTCOME MEASURE: Risk of coronary heart disease. RESULTS: Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease. CONCLUSION: The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease. JAMA

Diastolic dysfunction is usually identified by the combination of characteristic mitral and pulmonary vein flow patterns. However, obtaining a complete set of echocardiographic parameters can be technically difficult and data may conflict. We hypothesized that, as a stand alone variable, diastolic (ventricular diastole) dominant pulmonary vein flow predicts heart failure (HF) hospitalizations and cardiovascular (CV) death. Standard transthoracic echocardiograms were performed in 906 participants from the Heart and Soul Study, a prospective study of the effects of depression on coronary heart disease. Pulmonary vein flow pattern was determined by the dominant velocity time integral. Cardiac events were determined by two independent adjudicators and Cox proportional hazards models were used. Systolic dominant pulmonary vein flow was present in 89% of the participants, and diastolic dominant in the remaining 11%. During an average 4.1 years of follow-up, participants with diastolic dominant pulmonary vein flow had a 25% rate of HF hospitalization and 9% rate of CV death. After multivariate adjustment including left ventricular ejection fraction, diastolic pulmonary vein flow was associated with a three-fold risk for HF hospitalization (p=0.001) and a two-fold risk for HF hospitalization or death (p=0.004). In conclusion, diastolic dominant pulmonary vein flow pattern is a stand alone predictor of adverse cardiac events and its presence is associated with significantly higher rates of HF hospitalizations and CV death.

Data are limited about the significance of left ventricular (LV) hypertrophy or mass in patients with coronary heart disease (CHD), particularly in the setting of normal ejection fraction (EF). The association of LV mass index with all-cause mortality and sudden death in a cohort with CHD was evaluated. Using transthoracic echocardiography, LV mass normalized to body surface area was measured in 1,016 subjects with stable CHD. Cox proportional hazards models were used to examine the association of LV mass index and LV hypertrophy (LV mass index95 g/m(2) in women and115 in men) with time to death and time to sudden or arrhythmic death. Mean LV mass index was 101 +/- 27 g/m(2) in men and 88 +/- 23 in women. During a mean follow-up of 3.55 years, there were 146 deaths and 34 sudden or arrhythmic deaths. Total mortality was higher in subjects with LV hypertrophy (25% vs 11%, p0.001), as was mortality from sudden or arrhythmic death (6.7% vs 2.2%, p = 0.001). After adjustment for age, gender, cardiovascular risk factors, and medical therapy, LV hypertrophy was associated with both all-cause mortality (hazard ratio 2.0, p0.001) and sudden or arrhythmic death (hazard ratio 3.1, p = 0.003). Findings were similar in the subgroup with EFor =55% (mortality hazard ratio 1.8, p = 0.02; sudden and arrhythmic death hazard ratio 3.1, p = 0.02). Analyzed as a continuous variable, every 20-unit increase in LV mass index increased the adjusted hazard of death by 22% (p = 0.001) and adjusted hazard of sudden or arrhythmic death by 40% (p = 0.004). In conclusion, in patients with stable CHD, increased LV mass index was independently associated with all-cause mortality and sudden or arrhythmic death, even in subjects with normal EF.

Current guidelines do not recommend routine cardiac stress testing in patients with stable coronary heart disease (CHD) unless they report symptoms of angina. Our objective was to compare the prognosis of self-reported angina symptoms, inducible ischemia, or both in patients with stable CHD.We measured self-reported angina by questionnaire and inducible ischemia using treadmill stress echocardiography in 937 outpatients with stable CHD. We used Cox proportional hazard models, adjusted for traditional cardiovascular risk factors, to evaluate the independent association of angina and inducible ischemia with CHD events (myocardial infarction or CHD death) during a mean of 3.9 years of follow-up.Of the study participants, 129 (14%) had angina alone, 188 (20%) had inducible ischemia alone, and 40 (4%) had both angina and ischemia. Recurrent CHD events occurred in 7% of participants without angina or inducible ischemia, 10% of those with angina alone, 21% of those with inducible ischemia alone, and 23% of those with both angina and inducible ischemia (P.001). The presence of angina alone was not associated with recurrent CHD events (adjusted hazard ratio, 1.4; 95% confidence interval, 0.7-2.9) (P = .31). However, the presence of inducible ischemia without self-reported angina strongly predicted recurrent CHD events (adjusted hazard ratio, 2.2; 95% CI, 1.4-3.5) (P = .005).We found that 24% of patients with stable CHD had inducible ischemia, and more than 80% of these patients did not report angina. The presence of inducible ischemia without self-reported angina is associated with a greater than 2-fold increased rate of recurrent CHD events.

Elevated concentrations of adiponectin are associated with a favorable metabolic profile but also with adverse cardiovascular outcomes. This apparent discrepancy has raised questions about whether adiponectin is associated with an increased or decreased risk of coronary heart disease (CHD). We sought to determine whether higher adiponectin levels are associated with exercise-induced ischemia in patients with stable CHD.We measured total serum adiponectin concentrations and evaluated exercise-induced ischemia by stress echocardiography in a cross-sectional study of 899 outpatients with documented stable CHD. Of these, 217 (24%) had inducible ischemia. Although adiponectin levels correlated negatively with diabetes prevalence, body mass index, serum insulin, fasting glucose, low-density lipoprotein cholesterol, and triglycerides and positively with high-density lipoprotein cholesterol (all P0.005), elevated adiponectin concentrations were also associated with a greater risk of inducible ischemia. Each standard deviation (0.08 microg/mL) increase in log adiponectin was associated with a 35% greater odds of inducible ischemia (unadjusted odds ratio 1.35; 95% confidence interval 1.15-1.57; P=0.0002). Although attenuated, this association remained present after multivariable adjustment for traditional cardiovascular risk factors and other measures of cardiac function (adjusted odds ratio 1.21; 95% confidence interval 1.02-1.43; P=0.03).Elevated concentrations of adiponectin are independently associated with inducible ischemia in patients with stable CHD. These findings raise the possibility that the presence of chronic inducible ischemia may alter the cardio-protective effects afforded by adiponectin secretion in the healthy population.

Background: High-sensitivity C-reactive protein (CRP) is an inflammatory marker that predicts coronary heart disease (CHD) and, in recent studies, incident heart failure (HF). Whether the association of inflammation with incident HF is explained by worse baseline left ventricular dysfunction or by underlying CHD is unknown. Methods and results: Serum CRP was measured in a cohort of 985 outpatients with established CHD from the Heart and Soul Study. During 3 years of follow-up, 15% of the participants with elevated CRP levels (>3mg/L) were hospitalised for HF, compared with 7% of those with CRP ≤3 mg/L. In multivariate analysis, elevated CRP was associated with HF after adjustment for traditional risk factors, baseline CHD severity and interim MI (adjusted HR 2.1, 95% CI, 1.2–3.6; p=0.009). However, elevated CRP was no longer associated with HF after further adjustment for the presence of diastolic dysfunction on echocardiography (adjusted HR 1.6, 95% CI, 0.8–3.2; p=0.1). Conclusions: Among outpatients with stable CHD, elevated CRP levels predict hospitalisation for heart failure, independent of baseline heart failure, medication use, CHD severity, and subsequent MI events. This relationship appears to be at least partly explained by abnormal diastolic function in patients with elevated CRP levels.

The association of asymptomatic left ventricular (LV) diastolic dysfunction with cardiovascular outcomes in ambulatory patients with coronary heart disease (CHD) and no history of heart failure (HF) was examined. LV diastolic HF predicts adverse cardiovascular outcomes. However, the prevalence and prognosis of asymptomatic LV diastolic dysfunction in patients with established CHD in the absence of clinical HF is unknown. Six hundred ninety-three patients with stable CHD, normal systolic function (LV ejection fraction ≥50%), and no history of HF were evaluated. Echocardiography was used to classify LV diastolic function, and Cox proportional hazards models were used to evaluate the association of LV diastolic dysfunction with cardiovascular outcomes during 3 years of follow-up. Of 693 subjects with normal systolic function and no history of HF, 455 (66%) had normal LV diastolic function, 166 (24%) had mild LV diastolic dysfunction, and 72 (10%) had moderate to severe LV diastolic dysfunction. After multivariable adjustment, the presence of moderate to severe LV diastolic dysfunction was strongly predictive of incident hospitalization for HF (hazard ratio 6.3, 95% confidence interval 2.4 to 16.1, p = 0.0003) and death from heart disease (HR 3.9, 95% confidence interval 1.0 to 14.8, p = 0.05). In conclusion, moderate to severe LV diastolic dysfunction was present in 10% of patients with stable CHD with normal ejection fraction and no history of HF and predicts subsequent hospitalization for HF and death from heart disease. Patients with asymptomatic LV diastolic dysfunction may benefit from more aggressive therapy to prevent or delay the development of HF.

Background N-terminal pro–B-type natriuretic peptide (NT-proBNP) testing is useful for diagnosing acute decompensated heart failure. Whether NT-proBNP can be used to detect ventricular dysfunction in patients with stable coronary heart disease (CHD) and no history of heart failure is unknown. Methods We measured NT-proBNP levels and performed transthoracic echocardiography in 815 participants from the Heart and Soul Study, who had stable CHD and no history of heart failure. We hypothesized that NT-proBNP concentrations lower than 100 pg/mL would rule out ventricular dysfunction and concentrations higher than 500 pg/mL would identify ventricular dysfunction. We calculated sensitivities, specificities, likelihood ratios, and areas under the receiver operating characteristic curves for NT-proBNP as a case-finding instrument for systolic and diastolic dysfunction. Results Of the 815 participants with no history of heart failure, 68 (8%) had systolic dysfunction defined as a left ventricular ejection fraction of 50% or lower. Of the 730 participants for whom the presence or absence of diastolic dysfunction could be determined, 78 (11%) had diastolic dysfunction defined as a pseudonormal or restrictive filling pattern. The overall area under the receiver operating characteristic curve for detecting systolic or diastolic dysfunction was 0.78 (95% confidence interval, 0.74-0.82). Likelihood ratios were 0.28 for NT-proBNP concentrations lower than 100 pg/mL, 0.95 for concentrations between 100 and 500 pg/mL, and 4.1 for concentrations higher than 500 pg/mL. A test result lower than 100 pg/mL reduced the probability of ventricular dysfunction from a pretest probability of 18% to a posttest probability of 6%. A test result higher than 500 pg/mL increased the probability of ventricular dysfunction from a pretest probability of 18% to a posttest probability of 47%. A test result between 100 and 500 pg/mL did not change the probability of ventricular dysfunction. Conclusion In patients with stable CHD and no history of heart failure, NT-proBNP levels lower than 100 pg/mL effectively rule out ventricular dysfunction, with a negative likelihood ratio of 0.28.

ContextIdentification of individuals at high risk for cardiovascular events is important for the optimal use of primary and secondary prevention measures.ObjectiveTo determine whether plasma levels of amino terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) predict cardiovascular events or death independent of other available prognostic tests.Design, Setting, and ParticipantsProspective cohort study (2000-2002) of 987 individuals in California with stable coronary heart disease in the Heart and Soul Study, who were followed up for a mean of 3.7 (range, 0.1-5.3) years.Main Outcome MeasuresThe association of baseline NT-proBNP levels with death or cardiovascular events (myocardial infarction, stroke, or heart failure). Traditional clinical risk factors, echocardiographic measures, ischemia, other biomarkers, and New York Heart Association classification were adjusted for to determine whether NT-proBNP levels were independent of other prognostic factors. Receiver operating characteristic (ROC) curves were used to assess the incremental prognostic value of adding NT-proBNP level to these other measures.ResultsA total of 256 participants (26.2%) had a cardiovascular event or died. Each increasing quartile of NT-proBNP level (range of quartile 1, 8.06-73.95 pg/mL; quartile 2, 74-174.5 pg/mL; quartile 3, 175.1-459 pg/mL; quartile 4, ≥460 pg/mL) was associated with a greater risk of cardiovascular events or death, ranging from 23 of 247 (annual event rate, 2.6%) in the lowest quartile to 134 of 246 (annual event rate, 19.6%) in the highest quartile (unadjusted hazard ratio [HR] for quartile 4 vs quartile 1, 7.8; 95% confidence interval [CI], 5.0-12.1; P

Aortic sclerosis is associated with cardiovascular events in patients without coronary heart disease (CHD), but it is unclear whether this association exists in patients with established CHD or is independent of baseline cardiac disease severity. It is also unclear whether statins modify this association. In a prospective cohort study of 814 outpatients with established CHD and no evidence of aortic stenosis, the association of aortic sclerosis with subsequent cardiovascular events was examined using a multivariable Cox proportional hazards model. Of 814 participants, 324 (40%) had aortic sclerosis. During 4 years of follow-up, 10% with aortic sclerosis experienced a myocardial infarction (MI) compared with 5% of those without aortic sclerosis (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.1 to 3.1, p = 0.02). This association was unchanged after adjustment for potential confounders and mediators (HR 2.4, 95% CI 1.3 to 4.8, p = 0.009). However, the association between aortic sclerosis and MI appeared to differ by statin use (p = 0.15 for interaction). Aortic sclerosis predicted subsequent MI in subjects not administered statins (adjusted HR 4.1, 95% CI 1.1 to 15.7, p = 0.04), but not in those administered statins (adjusted HR 1.7, 95% CI 0.8 to 3.9, p = 0.18). In conclusion, aortic sclerosis was present in 40% of patients with CHD and is independently associated with a 2.4-fold increased rate of subsequent MI. Statins may attenuate the increased risk of future MI in patients with aortic sclerosis.

It is not known whether the metabolic syndrome is associated with poor exercise capacity among patients who have established coronary heart disease. We evaluated the association of the metabolic syndrome with treadmill exercise capacity and heart rate recovery among patients who had coronary heart disease. We measured treadmill exercise capacity (METs) and heart rate recovery (beats per minute) in 943 subjects who had known coronary heart disease. Of these, 377 (40%) had the metabolic syndrome as defined by criteria of the National Cholesterol Education Program. Participants who had the metabolic syndrome were more likely to have poor exercise capacity (METs

We performed a cross-sectional study to evaluate the association of anemia with diastolic dysfunction and left ventricular hypertrophy (LVH) in outpatients who had coronary artery disease. Logistic regression was used to examine the association of blood hemoglobin (Hb) concentrations with diastolic dysfunction and LVH in 822 participants in the Heart and Soul Study who had normal sinus rhythm and preserved systolic function (left ventricular ejection fraction ≥50%). Using transthoracic echocardiography, diastolic dysfunction was defined as diastolically dominant pulmonary vein flow, and LVH was defined as left ventricular mass index >90 g/m2. Anemia (Hb

Background— In patients with symptoms of heart failure, elevations in B-type natriuretic peptide (BNP) accurately identify ventricular dysfunction. However, BNP levels are not specific for ventricular dysfunction in patients who do not have overt symptoms of heart failure, suggesting that other cardiac processes such as myocardial ischemia may also cause elevations in BNP. Methods and Results— To determine whether BNP elevations are associated with myocardial ischemia, we measured plasma BNP levels before performing exercise treadmill testing with stress echocardiography in outpatients with stable coronary disease. Of the 355 participants, 113 (32%) had inducible ischemia. Compared with participants in the lowest BNP quartile (0 to 16.4 pg/mL), those in the highest quartile of BNP (≥105 pg/mL) had double the risk of inducible ischemia (adjusted relative risk, 2.0; 95% CI, 1.2 to 2.6; P =0.008). The relation between elevated BNP levels and inducible ischemia was especially evident in the 206 participants who had a history of myocardial infarction (adjusted relative risk, 2.6; 95% CI, 1.5 to 3.7, P =0.002) and was absent in those without a history of myocardial infarction (adjusted relative risk, 1.0; 95% CI, 0.3 to 2.2; P =0.9). This association between BNP levels and inducible ischemia remained strong after adjustment for measures of systolic and diastolic dysfunction. Conclusions— Elevated levels of BNP are independently associated with inducible ischemia among outpatients with stable coronary disease, particularly among those with a history of myocardial infarction. The observed association between BNP levels and ischemia may explain why tests for BNP are not specific for ventricular dysfunction among patients with coronary disease.

A stress test that can be performed intraoperatively might be valuable for cardiac risk stratification in patients needing urgent noncardiac surgery and for early evaluation of coronary reserve in patients undergoing aortocoronary bypass surgery. Therefore, we evaluated the sensitivity and safety of rapid atrial pacing combined with electrocardiography and transesophageal echocardiography for inducing and detecting provokable demand ischemia in 20 anesthetized patients with multivessel coronary artery disease. Rapid atrial pacing induced ST segment changes or new segmental wall motion abnormalities (SWMA), which were defined as evidence of induced ischemia in 15 of the 20 patients. Unexpectedly, the new SWMA normalized during the first beat after abrupt cessation of pacing in three patients who did not show any ST segment changes. Simultaneously, left ventricular preload was severely decreased during pacing and recovered to baseline immediately when pacing was abruptly discontinued. Rapid atrial pacing was safe in all patients, but the target heart rate could not be achieved because of heart block or arterial hypotension in 4 of the 20 patients. These findings raise the question of whether rapid atrial pacing is the most appropriate approach for inducing provokable demand ischemia in anesthetized patients. However, its potential usefulness for predicting adverse cardiac outcomes has not been evaluated and would require larger studies. In addition, the immediate normalization of new SWMA after abrupt cessation of pacing in some patients calls into question the validity of new SWMA as evidence of myocardial ischemia when left ventricular preload is severely decreased.

The evidence of myocardium at potential ischemic risk on preoperative dipyridamole perfusion scintigraphy was compared with that of manifest ischemia on intraoperative transesophageal echocardiography in 26 patients at high risk of a coronary event undergoing noncardiac surgery. The clinical outcome was also assessed. Induced intraoperative wall motion abnormalities were more common in patients and myocardial segments with, than in those without, a preoperative reversible perfusion defect (both p less than 0.05). Conversely, a preoperative reversible perfusion defect was more common in patients and segments with, than in those without, a new intraoperative wall motion abnormality (both p less than 0.05). Six patients, five with a reversible scintigraphic defect but only three with a new wall motion abnormality, had a hard perioperative ischemic event. Events occurred more often among patients with, than in those without, a reversible perioperative scintigraphic defect (5 [33%] of 15 vs. 1 [9%] of 11) but this difference did not reach significance (p = 0.14), probably owing to the sample size. Intraoperative wall motion abnormalities were all reversible and did not differentiate between risk groups; these findings were possibly influenced by treatment. These preliminary data support the known relation between reversible scintigraphic defects and perioperative events and identify another manifestation of ischemic risk in the relation between reversible scintigraphic defects and induced intraoperative wall motion abnormalities. The value of intraoperative echocardiography in identifying ischemia and guiding therapy in patients with a reversible scintigraphic abnormality should be further assessed.

Context Depressive symptoms predict adverse cardiovascular outcomes in patients with coronary heart disease, but the mechanisms responsible for this association are unknown. Objective To determine why depressive symptoms are associated with an increased risk of cardiovascular events. Design and Participants The Heart and Soul Study is a prospective cohort study of 1017 outpatients with stable coronary heart disease followed up for a mean (SD) of 4.8 (1.4) years. Setting Participants were recruited between September 11, 2000, and December 20, 2002, from 12 outpatient clinics in the San Francisco Bay Area and were followed up to January 12, 2008. Main Outcome Measures Baseline depressive symptoms were assessed using the Patient Health Questionnaire (PHQ). We used proportional hazards models to evaluate the extent to which the association of depressive symptoms with subsequent cardiovascular events (heart failure, myocardial infarction, stroke, transient ischemic attack, or death) was explained by baseline disease severity and potential biological or behavioral mediators. Results A total of 341 cardiovascular events occurred during 4876 person-years of follow-up. The age-adjusted annual rate of cardiovascular events was 10.0% among the 199 participants with depressive symptoms (PHQ score ≥10) and 6.7% among the 818 participants without depressive symptoms (hazard ratio [HR], 1.50; 95% confidence interval, [CI], 1.16-1.95; P = .002). After adjustment for comorbid conditions and disease severity, depressive symptoms were associated with a 31% higher rate of cardiovascular events (HR, 1.31; 95% CI, 1.00-1.71; P = .04). Additional adjustment for potential biological mediators attenuated this association (HR, 1.24; 95% CI, 0.94-1.63; P = .12). After further adjustment for potential behavioral mediators, including physical inactivity, there was no significant association (HR, 1.05; 95% CI, 0.79-1.40; P = .75). Conclusion In this sample of outpatients with coronary heart disease, the association between depressive symptoms and adverse cardiovascular events was largely explained by behavioral factors, particularly physical inactivity.

Nitrous oxide (N2O) has been implicated as a cause of myocardial ischemia. We investigated whether substitution of N2O for a portion of the anesthesia supplied by isoflurane increased myocardial ischemia in patients at risk for such ischemia. Seventy patients having carotid endarterectomies (63 patients) or other carotid surgery (seven patients) were prospectively, randomly assigned to an anesthetic regimen that included or excluded N2O. All other aspects of anesthetic management were similar, except for greater concentrations of oxygen and isoflurane in patients not given N2O. Perioperative monitoring for myocardial ischemia and infarction included 12- or 5-lead electrocardiography, transesophageal echocardiography, and creatine kinase isoenzyme levels. By transesophageal echocardiographic or electrocardiographic criteria, 44% of patients given oxygen but only 21% of those given N2O had myocardial ischemia intraoperatively (P = 0.065). Similarly, myocardial infarction, identified by changes in creatine kinase isoenzymes, occurred in only one patient given N2O but in three given oxygen (not significantly different). Thus we found no trend indicating a greater incidence of myocardial ischemia or infarction associated with the use of N2O.

To evaluate the applicability of two-dimensional echocardiography to left ventricular volume determination, 30 consecutive patients undergoing biplane left ventricular cineangiography were studied with a wide-angle (84 degrees), phased-array, two-dimensional echocardiographic system. Two echographic projections were used to obtain paired, biplane, tomographic images of the left ventricle. We used the short-axis view (from the precordial window) as an anolog of the left anterior oblique angiogram, and the long-axis, two-chamber view (from the apex impulse window) as a right anterior oblique angiographic equivalent. A modified Simpson's rule formula was used to calculate systolic and diastolic left ventricular volumes from the biplane echogram and the biplane angiogram. These methods correlated well for ejection fraction (r = 0.87) and systolic volume (r = 0.90), but only modestly for diastolic volume (r = 0.80). These correlations are noteworthy because 65% of the patients had significant segmental wall motion abnormalities. The volumes determined from the minor-axis dimensions of M-mode echograms in 23 of the same patients correlated poorly with angiography.

Lung uptake, ventricular cavitary dilation and basal myocardial uptake represent abnormalities that have been associated with myocardial ischemia on stress thallium-201 images, but that are supplementary to the conventional assessment of perfusion distribution. These “supplementary” indicators of ischemia were related to the coronary distribution of perfusion abnormalities, the results of electrocardiographic stress testing and to the findings on coronary angiography in 73 patients. Forty patients had multivessel coronary disease; 19 of these had three vessel disease. Perfusion abnormalities were seen in 39 of these 40 patients but were indicative of multivessel coronary disease in only 28 and of three vessel disease in only 6. However, supplementary indicators were present in 33 of 40 patients with multivessel disease and in 15 of 19 with three vessel disease. Furthermore, they were seen in 16 of 22 patients with multivessel disease in whom conventional perfusion abnormalities underestimated the extent of disease, but in only 4 of 12 patients in whom the extent of disease was overestimated. The presence of either perfusion abnormalities in a multivessel distribution or supplementary indicators identified 38 (95%) of 40 patients with multivessel disease.A markedly positive electrocardiographic treadmill test was a less sensitive indicator of multivessel disease, appearing in only 15 of 40 patients. However, it was present in only 4 of 33 patients without multivessel coronary disease and was more specific for that diagnosis than were supplementary scintigraphic indicators (88 versus 67%, p < 0.05). All 13 patients with both a markedly positive treadmill test and supplementary indicators had coronary artery disease; 12 had multivessel disease and 7 had three vessel disease, a predictive value of 93% for multivessel disease. Conversely, among 17 patients with a normal treadmill test without supplementary indicators, only 1 had multivessel disease, a negative predictive value of 97% for multivessel coronary disease exclusion. The utilization of scintigraphic supplementary indicators in the routine assessment of thallium scintigrams, applied in association with the electrocardiographic treadmill result, significantly improves diagnostic accuracy in detecting multivessel coronary disease.

Since the introduction of insulin, heart disease has become a major impediment to survival in persons with diabetes mellitus. Coronary disease has increased severity and accelerated development in diabetic persons compared with an age- and sex-matched nondiabetic population. A peculiar vulnerability of women to the influence of diabetes with loss of premenopausal coronary disease protection has been found. The symptomatology of coronary events may differ and coronary care data show a higher incidence of sudden death in diabetic patients who have a myocardial infarction than in their non-diabetic counterparts. Insulin may play a role in the myocardial adjustment to an ischemic insult by enhancing glucose intake and suppressing lipolysis and ketogenesis. Carbohydrate intolerance in dogs, rhesus monkeys and humans appears associated with similar histologic and compositional changes in the myocardium. Abnormalities in diastolic ventricular function not attributable to large- or small-vessel coronary disease have been found in the diabetic subjects of each species. Studies in humans who have diabetes have assessed single pressure-volume relationships and more exacting measures of ventricular compliance are needed. Abnormalities of myocardial function in patients with diabetes have been found using echo and radionuclide techniques. Many of these findings need to be correlated with invasive data or confirmed in larger populations. Autonomic dysfunction is common in diabetic persons and may imply an associated poor prognosis. Reflex abnormalities in parasympathetic function are most prevalent and occur before sympathetic dysfunction.

Patients with mitral valve prolapse (MVP) frequently experience chest pain which may, expecially in older subjects and males, be difficult to differentiate from angina pectoris. Electrocardiographic (ECG) changes, ventricular arrhythmias, metabolic abnormalities and rare reports of myocardial infarction and sudden death further suggest the presence of an ischemic process in these patients. The recognition of accompanying coronary artery disease (CAD) and exclusion of other causes of ischemia, therefore, may be important in determining the prognosis and appropriate therapy for such patients.

Cardiac anatomy was defined by gated nuclear magnetic resonance (NMR) imaging at a magnetic field strength of 3.5 kGauss in eight normal subjects and 10 patients with chronic myocardial infarctions. Multisectional imaging was performed with the spin-echo technique and encompassed most of the left ventricle in an imaging time of 5 to 12 min. In all subjects internal cardiac structure was well delineated without the use of any type of contrast medium. The myocardial wall-blood interface was sharply defined, resulting in visualization of trabeculations, papillary muscle, and chordal structures in both ventricles. In patients with ischemic heart disease, the extent of postinfarctional wall thinning, aneurysms, and mural thrombi were depicted on NMR images. Images obtained with the second spin-echo (delay time = 56 msec) demonstrated high signal intensity in regions of the left ventricular chamber adjacent to the site of aneurysms or infarctions; this finding suggested stasis of blood in a region of akinesis or dyskinesis. The results of this study show that gated NMR is feasible as a technique for imaging the human heart and is capable of demonstrating a variety of left ventricular abnormalities associated with chronic myocardial infarction. NMR is a completely noninvasive technique for clinical imaging of the cardiovascular system.