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Aims  We analysed whether incorporating electrocardiographic interlead T-wave heterogeneity (TWH) with myocardial perfusion imaging (MPI) during pharmacologic stress improves detection of flow-limiting lesions (FLL). Methods and results  Medical records of all 103 patients at our institution who underwent stress testing with regadenoson (0.4 mg IV bolus) within 3 months of coronary angiography from September 2017 to March 2019 were studied. Cases (N  = 59) had angiographically significant FLL (≥50% of left main or ≥70% of other epicardial coronary arteries ≥2 mm in diameter); controls (N  = 44) were normal or had non-FLL. TWH, i.e. interlead splay of T waves, was assessed from precordial leads V4–6 by second central moment analysis. Maximum TWHV4–6 levels during regadenoson stress were 68% higher in cases than in controls (P  < 0.0001). TWHV4–6 generated areas under the receiver-operating characteristic (ROC) curve of 0.79 in men (P  < 0.0001) and 0.71 in women (P  = 0.007). In men, the ROC-guided 54-µV TWHV4–6 cut-point for FLL produced adjusted odds of 7.3 [95% confidence interval (CI): 1.3–41.5, P  = 0.03], 79% sensitivity, and 78% specificity. In women, the ROC-guided 35-µV TWHV4–6 cut-point produced adjusted odds of 4.5 (95% CI: 1.1–18.9, P  = 0.04), 84% sensitivity, and 52% specificity. Adding TWHV4–6 to MPI determinations reduced false-positive results by 70%, more than doubled true-negative results, and improved adjusted odds ratio to 6.8 (95% CI: 2.2–21.4, P  = 0.001) with specificity of 78% in men and 86% in women. Conclusion  This observational study is the first to demonstrate the benefit of combining TWHV4–6 with MPI to enhance FLL detection during MPI with regadenoson in both men and women. [ABSTRACT FROM AUTHOR]

Background: We investigated whether T‐wave heterogeneity (TWH) can identify patients who are at risk for near‐term cardiac mortality. Methods: A nested case–control analysis was performed in the 888 patients admitted to the Emergency Department (ED) of our medical center in July through September 2018 who had ≥2 serial troponin measurement tests within 6 hr for acute coronary syndrome evaluation to rule‐in or rule‐out the presence of acute myocardial infarction. Patients who died from cardiac causes during 90 days after ED admission were considered cases (n = 20; 10 women) and were matched 1:4 on sex and age with patients who survived during this period (n = 80, 40 women). TWH, that is, interlead splay of T waves, was automatically assessed from precordial leads by second central moment analysis. Results: TWHV4‐6 was significantly elevated at ED admission in 12‐lead resting ECGs of female patients who died of cardiac causes during the following 90 days compared to female survivors (100 ± 14.9 vs. 40 ± 3.6 µV, p <.0001). TWHV4‐6 generated areas under the receiver‐operating characteristic (ROC) curve (AUC) of 0.933 in women (p <.0001) and 0.573 in men (p =.4). In women, the ROC‐guided 48‐µV TWHV4‐6 cut point for near‐term cardiac mortality produced an adjusted odds ratio of 121.37 (95% CI: 2.89–6,699.84; p =.02) with 100% sensitivity and 82.5% specificity. In Kaplan–Meier survival analysis, TWHV4‐6 ≥ 48 µV predicted cardiac mortality in women during 90‐day follow‐up with a hazard ratio of 27.84 (95% CI: 7.29–106.36, p <.0001). Conclusion: Elevated TWHV4‐6 is associated with near‐term cardiac mortality among women evaluated for acute coronary syndrome. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the role of disease conviction in the chest pain and life interference of patients with non-cardiac chest pain (NCCP), after controlling for anxiety sensitivity and body vigilance. While all three psychological constructs are theoretically implicated and empirically associated with the experience of NCCP, no research has examined the influence of disease conviction in the context of other relevant constructs. The sample included 229 participants with NCCP who were recruited after a medical evaluation failed to elicit an organic explanation for their chest pain. Hierarchical regression analyses revealed that while anxiety sensitivity significantly predicted chest pain severity and interference, only body vigilance contributed significant additional variance to chest pain severity, and only disease conviction contributed significant additional variance to chest pain interference. While anxiety sensitivity, body vigilance, and disease conviction all appear to affect those with NCCP, it seems that their impact is manifest in different domains (i.e., pain perception vs. psychosocial impairment). [ABSTRACT FROM AUTHOR]

Heart-focused anxiety (HFA) is a fear of cardiac sensations driven by worries of physical health catastrophe. HFA is impairing and distressing and has been shown to disproportionately affect individuals with noncardiac chest pain (NCCP), chest pain that persists in the absence of an identifiable source. The Cardiac Anxiety Questionnaire (CAQ) is a measure designed to assess HFA. The aim of this study was to evaluate the psychometric properties and factor structure of the CAQ in a sample of 229 adults diagnosed with NCCP. Results demonstrated that the CAQ is a useful measure of HFA in patients with NCCP and that a four-factor model including fear of cardiac sensations, avoidance of activities that elicit cardiac sensations, heart-focused attention, and reassurance seeking was the best fit for the data. Additionally, associations between CAQ subscales and two measures of health-related behaviors—pain-related interference and health care utilization—provided evidence of concurrent validity. Treatment implications are also discussed. [ABSTRACT FROM AUTHOR]

IMPORTANCE Diabetes is associated with an elevated risk of coronary heart disease (CHD). Previous studies have suggested that the genetic factors predisposing to excess cardiovascular risk may be different in diabetic and nondiabetic individuals. OBJECTIVE To identify genetic determinants of CHD that are specific to patients with diabetes. DESIGN, SETTING, AND PARTICIPANTS We studied 5 independent sets of CHD cases and CHD-negative controls from the Nurses' Health Study (enrolled in 1976 and followed up through 2008), Health Professionals Follow-up Study (enrolled in 1986 and followed up through 2008), Joslin Heart Study (enrolled in 2001-2008), Gargano Heart Study (enrolled in 2001-2008), and Catanzaro Study (enrolled in 2004-2010). Included were a total of 1517 CHD cases and 2671 CHD-negative controls, all with type 2 diabetes. Results in diabetic patients were compared with those in 737 nondiabetic CHD cases and 1637 nondiabetic CHD-negative controls from the Nurses' Health Study and Health Professionals Follow-up Study cohorts. Exposures included 2 543 016 common genetic variants occurring throughout the genome. MAIN OUTCOMES AND MEASURES Coronary heart disease-defined as fatal or nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or angiographic evidence of significant stenosis of the coronary arteries. RESULTS A variant on chromosome lq25 (rs10911021) was consistently associated with CHD risk among diabetic participants, with risk allele frequencies of 0.733 in cases vs 0.679 in controls (odds ratio, 1.36 [95% CI, 1.22-1.51]; P = 2 x 10-8). No association between this variant and CHD was detected among nondiabetic participants, with risk allele frequencies of 0.697 in cases vs 0.696 in controls (odds ratio, 0.99 [95% CI, O.87-1.13]; P = .89), consistent with a significant gene x diabetes interaction on CHD risk (P = 2 x 10-4). Compared with protective allele homozygotes, rs10911021 risk allele homozygotes were characterized by a 32% decrease in the expression of the neighboring glutamate-ammonia ligase (GLUL) gene in human endothelial cells (P = .0048). A decreased ratio between plasma levels of γ-glutamyl cycle intermediates pyroglutamic and glutamic acid was also shown in risk allele homozygotes (P = .029). CONCLUSION AND RELEVANCE A single-nucleotide polymorphism (rsi0911021) was identified that was significantly associated with CHD among persons with diabetes but not in those without diabetes and was functionally related to glutamic acid metabolism, suggesting a mechanistic link. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Insulin resistance (IR) and cardiovascular disease may share a common genetic background. We investigated the role of IR-associated ENPP1 K121Q polymorphism (rs1044498) on cardiovascular disease in high-risk individuals. RESEARCH DESIGN AND METHODS--A prospective study (average follow-up, 37 months) was conducted for major cardiovascular events (myocardial infarction [MI], stroke, cardiovascular death) from the Gargano Heart Study (GHS; n = 330 with type 2 diabetes and coronary artery disease), the Tot Vergata Atherosclerosis Study (TVAS; n = 141 who had MI), and the Cardiovascular Risk Extended Evaluation in Dialysis (CREED) database (n = 266 with end-stage renal disease). Age at MI was investigated in cross-sectional studies of 339 type 2 diabetic patients (n = 169 from Italy, n = 170 from the U.S.). RESULTS--Incidence of cardiovascular events per 100 person-years was 4.2 in GHS, 10.8 in TVAS, and 11.7 in CREED. Hazard ratios (HRs) for KQ+QQ versus individuals carrying the K121/K121 genotype (KK) individuals were 1.47 (95% CI 0.80-2.70) in GHS, 2.31 (95% CI 1.22-4.34) in TVAS, and 1.36 (95% CI 0.88-2.10) in CREED, and 1.56 (95% CI 1.15-2.12) in the three cohorts combined. In the 395 diabetic patients, the Q121 variant predicted cardiovascular events among obese but not among nonobese individuals (HR 5.94 vs. 0.62, P = 0.003 for interaction). A similar synergism was observed in cross-sectional studies, with age at MI being 3 years younger in Q121 carriers than in KK homozygotes among obese but not among nonobese patients (P = 0.035 for interaction). CONCLUSIONS--The ENPP1 K121Q polymorphism is an independent predictor of major cardiovascular events in high-risk individuals. In type 2 diabetes, this effect is exacerbated by obesity. Future larger studies are needed to confirm our finding. [ABSTRACT FROM AUTHOR]

Context: A common allele on chromosome 9p21 has been repeatedly associated with increased risk of coronary artery disease (CAD) in the general population. However, the magnitude of this effect in the population with diabetes has not been well characterized.Objective: To examine the association of the 9p21 variant with CAD in individuals with type 2 diabetes and evaluate its interaction with poor glycemic control.Design, Setting, and Participants: (1) Case-control study of 734 type 2 diabetes patients (322 with angiographically diagnosed CAD and 412 with no evidence of CAD) who were recruited between 2001 and 2006 at the Joslin Clinic, Beth Israel Deaconess Medical Center; and (2) independent cohort study of 475 type 2 diabetes patients from the Joslin Clinic whose survival status was monitored from their recruitment between 1993 and 1996 until December 31, 2004. Participants for both studies were genotyped for a representative single-nucleotide polymorphism at 9p21 (rs2383206) and characterized for their long-term glycemic control by averaging multiple hemoglobin A(1c) (HbA(1c)) measurements taken in the years before study entry.Main Outcome Measures: For the case-control study, association between single-nucleotide polymorphism rs2383206 and CAD defined as angiographically documented stenosis greater than 50% in a major coronary artery or a main branch thereof was assessed and for the cohort study, cumulative 10-year mortality was documented.Results: Individuals who were homozygous for the risk allele were significantly more frequent among case than control participants (42.3% vs 28.9P = .0002). This association was unaffected by adjustment for cardiovascular risk factors, but the effect of the risk genotype was significantly magnified (adjusted P for interaction = .048) in the presence of poor glycemic control (worst tertile of the distribution of HbA(1c) at examination). Relative to the CAD risk for patients with neither a 9p21 risk allele nor poor glycemic control, the CAD odds for participants having 2 risk alleles but not poor glycemic control were increased 2-fold (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.17-3.41), whereas the odds for study participants with the same genotype and with poor glycemic control were increased 4-fold (OR, 4.27; 95% CI, 2.26-8.01). The interaction was stronger (adjusted P = .005) when a measure of long-term glycemic control (7-year average rather than most recent HbA(1c)) was used with ORs of 7.83 (95% CI, 3.49-17.6) for participants having 2 risk alleles and a history of poor glycemia and 1.54 (95% CI, 0.72-3.30) for participants with the same genotype but without this exposure. A similar interaction between 9p21 variant and poor glycemic control was observed with respect to cumulative 10-year mortality in the cohort study (43.6% in patients with 2 risk alleles and poor glycemic control, 23.1% in individuals with only the 2 risk alleles, 30.0% in individuals with only poor glycemic control, and 31.6% in individuals with neither factor, P for interaction, = .036).Conclusion: In this study population, the CAD risk associated with the 9p21 variant was increased in the presence of poor glycemic control in type 2 diabetes. [ABSTRACT FROM AUTHOR]

The article presents medical research involving two studies which examine the association of the 9p21 chromosome variant with coronary artery disease (CAD) in type 2 diabetes patients and the interaction of 9p21 with poor glycemic control. Angiographically documented stenosis greater than 50% in a major coronary artery or a main branch was assessed for the case-control study. Participants were genotyped for a single-nucleotide polymorphism at 9p21. The severity of their hypoglycemia was assessed with multiple hemoglobin A1c measurements. Cumulative 10-year mortality was documented for the cohort study. CAD risk associated with the 9p21 variant was increased with poor glycemic control in patients with type 2 diabetes.

A20 or tumor necrosis factor (TNF)-induced protein 3 (TNFAIP3) is a negative regulator of nuclear factor-κB (NF-κB). We have investigated whether polymorphisms in this gene are associated with increased atherosclerosis in diabetic patients. Five tag single nucleotide polymorphisms (SNPs) were typed in 479 type 2 diabetic patients from Boston, including 239 coronary artery disease (CAD)-positive case subjects and 240 CAD-negative control subjects. Two tag SNPs (rs5029930 and rs610604) were independently associated with CAD; adjusted odds ratios (ORs) for minor allele carriers were 2.3 (95% CI 1.4-3.8, P = 0.001) and 2.0 (1.3-2.9, P = 0.0008), respectively. The association with rs610604 was dependent on glycemic control, with ORs of 3.9 among subjects with A1C ≤7.0% and 1.2 for those with A1C >7.0% (P for interaction = 0.015). A similar interaction pattern was found among 231 CAD-positive and 332 CAD-negative type 2 diabetic patients from Italy (OR 2.2, P = 0.05 vs. OR 0.9, P = 0.63 in the low vs. high A1C strata, P for interaction = 0.05). Quantitative RT-PCR in blood mononuclear cells from 83 nondiabetic subjects showed that rs610604 and rs5029930 minor allele homozygotes have 30-45% lower levels of A20 mRNA than major allele homozygotes, and heterozygotes have intermediate levels (P = 0.04 and 0.028, respectively). These findings point to variability in the A20/TNFAIP3 gene as a modulator of CAD risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression. Diabetes 56:499-505, 2007 [ABSTRACT FROM AUTHOR]

Adiponectin, an adipokine facilitating insulin action, has antiatherogenic effects. This study investigated whether common polymorphisms in the adiponectin receptor 1 (ADIPOR1) gene mediating these effects influence the risk of coronary artery disease (CAD) in type 2 diabetes. Linkage disequilibrium analysis of 28 single nucleotide polymorphisms (SNPs) spanning the entire ADIPOR1 locus revealed two haplotype blocks that could be tagged by six SNPs. These six markers were typed in two populations of CAD-positive and -negative subjects with type 2 diabetes, one from Boston (n = 411) and the other from Italy (n = 533). In the Boston population, the three tags of the more 3' block were all significantly associated with CAD (P = 0.001-0.01). A similar trend, although not significant, was found in Italian subjects. Haplotype analysis of the combined populations revealed different haplotype distributions in case and control subjects (P = 0.0002), with one common haplotype being associated in homozygotes with a greater than threefold increase in cardiovascular risk (odds ratio 3.6 [95% CI 1.8-7.2]). Some of the genotypes associated with increased cardiovascular risk were associated with 30-40% lower ADIPOR1 mRNA levels in blood mononuclear cells (n = 60) and adipose tissue biopsies (n = 28) (P = 0.001-0.014). Our findings point to genetic variability at the ADIPOR1 locus as a strong determinant of CAD susceptibility in type 2 diabetes. Diabetes 55:2763-2770, 2006 [ABSTRACT FROM AUTHOR]

Total GLUT4 content in skeletal muscle from individuals with type 2 diabetes is normal; however, recent studies have demonstrated that translocation of GLUT4 to the plasma membrane is decreased in response to insulin stimulation. It is not known whether physical exercise stimulates GLUT4 translocation in skeletal muscle of individuals with type 2 diabetes. Five subjects (two men, three women) with type 2 diabetes and five normal control subjects (5 men), as determined by a standard 75-g oral glucose tolerance test, were recruited to determine whether an acute bout of cycle exercise activates the translocation of GLUT4 to the plasma membrane in skeletal muscle. Each subject had two open biopsies of vastus lateralis muscle; one at rest and one 3-6 weeks later from the opposite leg after 45-60 min of cycle exercise at 60-70% of VO2max. Skeletal muscle plasma membranes were prepared by subcellular fractionation, and GLUT4 content was determined by Western blotting. Plasma membrane GLUT4 increased in each subject in response to exercise. The mean increase in plasma membrane GLUT4 for the subjects with type 2 diabetes was 74 +/-20% above resting values, and for the normal subjects the increase was 71+/-18% above resting values. Although plasma membrane GLUT4 content was approximately 32% lower at rest and after exercise in the muscle of the subjects with type 2 diabetes, the differences were not statistically significant. We conclude that in contrast to the previously reported defect in insulin-stimulated GLUT4 translocation in skeletal muscle of individuals with type 2 diabetes, a single bout of exercise results in the translocation of GLUT4 to the plasma membrane in skeletal muscle of individuals with type 2 diabetes. These data provide the first direct evidence that GLUT4 translocation is an important cellular mechanism through which exercise enhances skeletal muscle glucose uptake in individuals with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Study Objective: To determine whether acute oral caffeine ingestion by patients with coronary artery disease results in decreased treadmill exercise performance or deterioration of echocardiographic measures of systolic or diastolic left ventricular function.Design: Randomized, double-blind, placebo-controlled trial.Setting: Referral-based cardiovascular exercise laboratory at an urban teaching hospital.Patients: Thirteen volunteers with clinically stable coronary artery disease who had exercise tests after a 2-week caffeine-free washout period. Patients continued treatment with standard antianginal medications during the study period.Interventions: Maximal exercise treadmill testing and exercise echocardiography were done at baseline, after acute ingestion of a placebo beverage (97% caffeine-free coffee), or after drinking an identical beverage containing 250 mg of caffeine sodium benzoate.Measurements and Main Results: Acute ingestion of caffeine produced a serum level of 4.50 +/- 0.16 micrograms/mL, but had no effect on resting supine heart rate, blood pressure, left ventricular fractional shortening, posterior left ventricular wall thinning or peak rates of increase in left ventricular diastolic dimension. Despite a small increase in peak systolic blood pressure during exercise (baseline, 153 +/- 8; placebo, 154 +/- 8; caffeine, 161 +/- 7 mm Hg; P less than 0.05), exercise duration, time to onset of angina, and time to 0.1 mV ST depression did not differ after ingestion of placebo or caffeine. Rate-pressure product at onset of angina and onset of 0.1 mV of ST depression were also unchanged. In response to exercise, echocardiographic measures of left ventricular systolic and diastolic function were unchanged after caffeine compared with placebo ingestion.Conclusions: These data suggest that patients with exercise-induced ischemia who are receiving appropriate antianginal therapy tolerate the caffeine-equivalent of three cups of coffee without detrimental effect on intensity of ischemia, myocardial function, or exercise duration. [ABSTRACT FROM AUTHOR]

Background We investigated whether the coronary artery disease (CAD) locus on chromosome 9p21 (as represented by single nucleotide polymorphism rs2383206) is associated with low estimated glomerular filtration rate (eGFR) or increased urinary albumin excretion in patients with Type 2 diabetes mellitus (T2DM). Methods Four samples, including a total of 3167 patients, were studied. The presence of low eGFR (<60 mL/min/1.73m2) was estimated from serum creatinine by means of the Modification of Diet in Renal Disease Study equation. Increased urinary albumin excretion was defined as an albumin–creatinine ratio (ACR) ≥2.5 mg/mmol in men and ≥3.5 mg/mmol in women. Results No association was found between rs2383206 and low eGFR or increased ACR in each sample as well as in a pooled analysis (overall odds ratio = 1.07, 95% confidence interval 0.94–1.22, P = 0.31 and overall odds ratio = 1.00, 95% confidence interval 0.90–1.12, P = 0.95, respectively). No interaction was observed between rs2383206 and poor glycemic control [HbA1c was above the median in the pooled sample (7.7%) in modulating eGFR or ACR (P for interaction = 0.42 and 0.90, respectively)]. Conclusion Variability at the 9p21 CAD locus is unlikely to play a role in modulating susceptibility to kidney dysfunction in patients with T2DM. [ABSTRACT FROM PUBLISHER]

Adiponectin -- an adipokine facilitating insulin action -- has direct protective effects on the arterial wall through inhibition of monocyte adhesion, SMC proliferation, and foam cell formation. We previously identified two haplotypes at the adiponectin receptor 1 (ADIPOR1) locus that are associated with an increased risk of coronary artery disease (CAD) risk in type 2 diabetes. In the present study we investigated whether genetic variability in another adiponectin receptor -- T-cadherin -- similarly modulates cardiovascular risk in type 2 diabetes. The T-cadherin gene (CDH13) is located on chromosome 16q23.3 and includes 14 exons spanning a total of 1.17 Mb. Sequencing of all the exons, exon-intron boundaries, and 2.5 kb of the upstream and downstream regions in 24 healthy individuals led to the identification of 34 SNPs. Twelve of these SNPs, which were placed in the coding, 5'-flanking or 3'-flanking regions were typed in 290 T2DM cases with angiographically diagnosed CAD and 353 T2DM controls with negative CAD history and normal exercise treadmill test. Two coding, synonymous SNPs (rs6565105 on exon 3 and rs17852798 on exon 13) showed nominal evidence of association with CAD (p=0.014 and 0.043, respectively). To further locate the polymorphism(s) that are responsible for the observed association, we extended the study to 13 other SNPs that were in high LD with these two SNPs (r²>0.5). Four of these other SNPs -- all placed in introns -- were found to be associated with CAD (p=0.012, 0.019, 0.033 and 0.054, respectively). Further studies are underway to replicate these association and define the functional variants as well as the mechanisms underlying this genetic effect. These findings potentially expand the evidence implicating adiponectin as one of the links between increased adipose mass and atherogenesis. [ABSTRACT FROM AUTHOR]

Normal aging is associated with an impairment in early left ventricular diastolic filling. To test the hypothesis that long-term endurance exercise training is associated with enhanced ventricular diastolic filling indices, we compared transmitral pulsed Doppler inflow spectra in healthy young adults; healthy elderly, sedentary subjects (sedentary old); and healthy elderly, endurance athletes (master athletes). Our data demonstrate that, despite an increase in left ventricular mass, early diastolic filling was enhanced in master athletes compared to the sedentary old. Blood pressure of both master athletes and the sedentary olds was greater than the young adults, but the higher blood pressure did not correlate to changes infilling parameters. Resting systolic function and heart rate were not significantly different in all three different groups. Early left ventricular filling indices in master athletes more closely resemble transmitral inflow patterns of healthy young adults. Long-term endurance exercise is associated with physiologic hypertrophy and ventricular filling dynamics more characteristic of the young than the old [ABSTRACT FROM PUBLISHER]