Effects of Age and Sex on Systemic Inflammation and Cardiometabolic Function in Individuals with Type 2 Diabetes.

Objective: Systemic inflammation, aging, and type 2 diabetes (T2DM) all contribute to the development of cardiovascular dysfunction and impaired aerobic exercise capacity but their interplay remains unclear. This study evaluates the impact of age, sex, and inflammation on coronary and peripheral vascular function and exercise capacity in elderly individuals with and without type 2 diabetes (T2DM). Research Design and Methods: Elderly individuals (age ≥65 years) underwent biochemical and tissue inflammatory phenotyping, cardiopulmonary exercise testing (CPET), cardiovascular magnetic resonance (CMR) imaging, and vascular reactivity testing. Correlation and regression analyses determined the effects of systemic inflammation, older age, and sex on cardiovascular health, stratified by T2DM status. Results: For the 133 recruited individuals (44% female; median age 71, IQR=7 years, 41% with T2DM) the presence of T2DM did not have an effect on most blood serum inflammatory markers and skin biopsies. Hyperemic myocardial blood flow (hMBF), flow-mediated, and flow-independent nitroglycerin induced brachial artery dilation were significantly impaired in males, but not females with T2DM. Peak VO2 was lower with T2DM (p=0.022), mostly because of the effect of T2DM in females. Females showed more adverse myocardial remodeling assessed by extracellular volume (p=0.008), independent of T2DM status. Conclusions: Our findings suggest that the pathophysiological manifestations of T2DM on vascular function and aerobic exercise capacity are distinct in elderly males and females and this may reflect underlying differences in vascular and myocardial aging in the presence of T2DM.

Smartphone-recorded physical activity for estimating cardiorespiratory fitness.

While cardiorespiratory fitness is strongly associated with mortality and diverse outcomes, routine measurement is limited. We used smartphone-derived physical activity data to estimate fitness among 50 older adults. We recruited iPhone owners undergoing cardiac stress testing and collected recent iPhone physical activity data. Cardiorespiratory fitness was measured as peak metabolic equivalents of task (METs) achieved on cardiac stress test. We then estimated peak METs using multivariable regression models incorporating iPhone physical activity data, and validated with bootstrapping. Individual smartphone variables most significantly correlated with peak METs (p-values both < 0.001) included daily peak gait speed averaged over the preceding 30 days (r = 0.63) and root mean square of the successive differences of daily distance averaged over 365 days (r = 0.57). The best-performing multivariable regression model included the latter variable, as well as age and body mass index. This model explained 68% of variability in observed METs (95% CI 46%, 81%), and estimated peak METs with a bootstrapped mean absolute error of 1.28 METs (95% CI 0.98, 1.60). Our model using smartphone physical activity estimated cardiorespiratory fitness with high performance. Our results suggest larger, independent samples might yield estimates accurate and precise for risk stratification and disease prognostication.

T-wave heterogeneity in standard resting 12-lead ECGs is associated with 90-day cardiac mortality in women following emergency department admission: A nested case-control study.

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.

Regadenoson-induced T-wave heterogeneity complements coronary stenosis detection by myocardial perfusion imaging in men and women.

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.

Exercise and pharmacologic stress-induced interlead T-wave heterogeneity analysis to detect clinically significant coronary artery stenosis.

BACKGROUND: Despite widespread use of ETT and vasodilator-stress with myocardial perfusion imaging (MPI) for noninvasive detection of flow-limiting coronary artery disease, there is continued need to improve diagnostic accuracy. We examined whether measurement of interlead T-wave heterogeneity (TWH) during exercise tolerance testing (ETT) or pharmacologic stress testing improves detection of stenoses in large epicardial coronary arteries. METHODS: All 137 patients at our institution who underwent diagnostic coronary angiography within 0 to 5 days after ETT (N = 81) or dipyridamole IV infusion (N = 58) in 2016 were studied, including 2 patients with both tests. Cases (N = 93) had angiographically significant stenosis (≥50% of left main or ≥ 70% of an epicardial coronary artery ≥2 mm in diameter); controls (N = 44) did not. TWH, i.e., interlead splay of T waves, was determined by second central moment analysis from precordial leads by an investigator blinded to angiographic results. RESULTS: At rest, TWH levels were similar for cases and controls. ETT and dipyridamole stress testing increased TWH by 69% (p < 0.0001) and 27% (p < 0.0001), respectively, in cases. In controls, TWH did not change. Areas under the ROC curves for TWH increase for any flow-limiting coronary artery stenosis were 0.737 (p < 0.0001) for ETT and 0.818 (p < 0.0001) for dipyridamole stress testing. By contrast, neither ST-segment changes during ETT (p = 0.12) nor MPI during dipyridamole stress testing (p = 0.60) discriminated cases from controls. CONCLUSIONS: TWH measurement is a novel method that improves detection of angiographically confirmed flow-limiting stenoses in large epicardial coronary arteries during both ETT and MPI during pharmacologic stress testing with dipyridamole.

The Role of Disease Conviction: Exploring Its Effects on Chest Pain and Anxiety-Related Models of Non-cardiac Chest Pain.

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).

Marked exercise-induced T-wave heterogeneity in symptomatic diabetic patients with nonflow-limiting coronary artery stenosis.

BACKGROUND: T-wave heterogeneity (TWH) independently predicted cardiovascular mortality in Health Survey 2000 based on 12-lead ECGs recorded at rest. We investigated whether TWH is elevated during exercise tolerance testing (ETT) in symptomatic diabetic patients with nonflow-limiting coronary artery stenosis compared to control subjects without diabetes. METHODS: Cases were all patients (n = 20) with analyzable ECG recordings during both rest and ETT who were enrolled in the Effects of Ranolazine on Coronary Flow Reserve (CFR) in Symptomatic Patients with Diabetes and Suspected or Known Coronary Artery Disease (RAND-CFR) study (NCT01754259); median CFR was 1.44; 80% of cases had CFR <2. Control subjects (n = 9) were nondiabetic patients who had functional flow reserve (FFR) >0.8, a range not associated with inducible ischemia. TWH was analyzed from precordial leads V4 , V5 , and V6 by second central moment analysis, which assesses the interlead splay of T-waves about a mean waveform. RESULTS: During exercise to similar rate-pressure products (p = .31), RAND-CFR patients exhibited a 49% increase in TWH during exercise (rest: 49 ± 5 µV; exercise: 73 ± 8 µV, p = .003). By comparison, in control subjects, TWH was not significantly altered (rest: 52 ± 11 µV; ETT: 38 ± 5 µV, p = .19). ETT-induced ST-segment depression >1 mm (p = .11) and Tpeak -Tend (p = .18) and QTc intervals (p = .80) failed to differentiate cases from controls. CONCLUSIONS: TWH is capable of detecting latent repolarization abnormalities, which are present during ETT in diabetic patients with nonflow-limiting stenosis but not in control subjects. The technique developed in this study permits TWH analysis from archived ECGs and thereby enables mining of extensive databases for retrospective studies and hypothesis testing.

Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health: brief report.

Exercise improves cardiometabolic and vascular function, although the mechanisms remain unclear. Our objective was to demonstrate the diversity of circulating extracellular RNA (ex-RNA) release during acute exercise in humans and its relevance to exercise-mediated benefits on vascular inflammation. We performed plasma small RNA sequencing in 26 individuals undergoing symptom-limited maximal treadmill exercise, with replication of our top candidate miRNA in a separate cohort of 59 individuals undergoing bicycle ergometry. We found changes in miRNAs and other ex-RNAs with exercise (e.g., Y RNAs and tRNAs) implicated in cardiovascular disease. In two independent cohorts of acute maximal exercise, we identified miR-181b-5p as a key ex-RNA increased in plasma after exercise, with validation in a separate cohort. In a mouse model of acute exercise, we found significant increases in miR-181b-5p expression in skeletal muscle after acute exercise in young (but not older) mice. Previous work revealed a strong role for miR-181b-5p in vascular inflammation in obesity, insulin resistance, sepsis, and cardiovascular disease. We conclude that circulating ex-RNAs were altered in plasma after acute exercise target pathways involved in inflammation, including miR-181b-5p. Further investigation into the role of known (e.g., miRNA) and novel (e.g., Y RNAs) RNAs is warranted to uncover new mechanisms of vascular inflammation on exercise-mediated benefits on health.NEW & NOTEWORTHY How exercise provides benefits to cardiometabolic health remains unclear. We performed RNA sequencing in plasma during exercise to identify the landscape of small noncoding circulating transcriptional changes. Our results suggest a link between inflammation and exercise, providing rich data on circulating noncoding RNAs for future studies by the scientific community.

Heart-Focused Anxiety in Patients With Noncardiac Chest Pain: Structure and Validity.

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.

Independent, Community-Based Aerobic Exercise Training for People With Moderate-to-Severe Traumatic Brain Injury.

OBJECTIVE: To determine whether people with moderate-to-severe traumatic brain injury (TBI) can adhere to a minimally supervised, community-based, vigorous aerobic exercise program. DESIGN: Prospective trial. SETTING: Young Men's Christian Association (YMCA) facilities. PARTICIPANTS: Community-dwelling volunteers (N=10; 8 men, 2 women; age range, 22-49y) 6 to 15 months after moderate-to-severe TBI. INTERVENTION: Participants received memberships to local YMCAs and brief orientations to exercise. They were then asked to independently complete ≥12 weeks of ≥3 training sessions per week, performed at 65% to 85% of maximum heart rate for ≥30 minutes per session. Participants could self-select exercise modality, provided they met intensity and duration targets. Programmable heart rate monitors captured session intensity and duration. MAIN OUTCOME MEASURES: Independence with equipment and facility use and compliance with training goals (session frequency, duration, intensity, total weeks of training). RESULTS: All participants achieved independence with equipment and facility use. All met at least 2 of 4 training goals; half met all 4 goals. Participants averaged (±SD) 3.3±0.7 sessions per week for 13 weeks (range, 6-24). Average ± SD session duration was 62±23 minutes, of which 51±22 minutes occurred at or above individuals' heart rate training targets. CONCLUSIONS: People in recovery from moderate-to-severe TBI can, with minimal guidance, perform vigorous, community-based exercise. This suggests that decentralized exercise may be logistically and economically sustainable after TBI, expanding its potential therapeutic utility and rendering longer-duration exercise studies more feasible.

Painful left bundle branch block syndrome: Clinical and electrocardiographic features and further directions for evaluation and treatment.

BACKGROUND: Painful left bundle branch block (LBBB) is a rarely diagnosed chest pain syndrome caused by intermittent LBBB in the absence of myocardial ischemia. Its prevalence, mechanism, detailed electrocardiographic (ECG) features, and effective treatments are not well described. OBJECTIVES: The purpose of this study was to characterize clinical and ECG features of patients with painful LBBB syndrome with respect to the LBBB ECG morphology (in particular QRS axis and the precordial S/T wave ratio), clarify diagnostic criteria and possible mechanisms, and provide directions for further evaluation and treatment. METHODS: We analyzed clinical (n = 50) and ECG (n = 15) features of patients with painful LBBB syndrome (4 patients in our practice and 46 cases identified in the literature). RESULTS: All 15 ECGs of patients with painful LBBB syndrome had an inferior QRS axis and a very low (<1.8) precordial S/T wave ratio, which was consistent with the "new LBBB" pattern. We report a case of painful LBBB syndrome coexisting with coronary artery disease. Right ventricular apical pacing resolved intractable chest pain in 1 case of painful LBBB. CONCLUSION: Painful LBBB ECG morphology within seconds/minutes of its onset is consistent with the new LBBB pattern with a very low (<1.8) precordial S/T wave ratio and inferior QRS axis. Painful LBBB syndrome can coexist with coronary artery disease, complicating the assessment of chest pain in the setting of LBBB. An electrophysiology study might be considered to investigate whether changing ventricular activation pattern by pacing provides consistent pain control and to select the most effective pacing configuration.

Illness perceptions, negative emotions, and pain in patients with noncardiac chest pain.

Illness-specific cognitions are associated with outcomes in numerous health conditions, however, little is known about their role in noncardiac chest pain (NCCP). NCCP is prevalent, impairing, and associated with elevated health care utilization. Our objective was to investigate the relations between illness perceptions, emotion, and pain in a sample of 196 adult patients diagnosed with NCCP. We found that negative illness perceptions were associated with greater anxiety, depression, chest pain, and pain-related life interference while controlling for the effects of demographic and pain-related variables. These results expand current NCCP theory and may inform future treatment development.

Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes.

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 1q25 (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 × 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, 0.87-1.13]; P = .89), consistent with a significant gene × diabetes interaction on CHD risk (P = 2 × 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 (rs10911021) 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.

Health care utilisation in patients with non-cardiac chest pain: a longitudinal analysis of chest pain, anxiety and interoceptive fear.

Chest pain can be a frightening experience that leads many to seek medical evaluation. The symptom results in costly health care utilisation. Over half of patients referred for cardiac evaluations of chest pain do not obtain definitive medical explanations for their symptoms; these cases are described as non-cardiac chest pain (NCCP). Some patients with NCCP are not reassured after being informed their chest pain is non-cardiac in origin and seek repeated medical evaluation. Co-morbid anxiety and mood disorders often coexist with NCCP and are associated with health care utilisation. The current study examined chest pain, general anxiety, interoceptive fear and health care utilisation in a sample of 196 chest pain patients near the time of cardiac evaluation (Time 1), and 70 of these patients one year later (Time 2). Results indicate that anxiety and interoceptive fear were significantly associated with health care utilisation at Time 1, and only interoceptive fear (at Time 1) predicted health care utilisation at Time 2. This study develops research in this area by examining the relation of anxiety and health care utilisation longitudinally in patients with NCCP.

The 9p21 coronary artery disease locus and kidney dysfunction in patients with Type 2 diabetes mellitus.

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/1.73m(2)) 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.

The impact of perceived stress and perceived control on anxiety and mood disorders in noncardiac chest pain.

Chest pain without detectable heart disease, noncardiac chest pain (NCCP), is linked with anxiety and depression. Theory posits stress and perceived control may relate to NCCP. We hypothesized stress would have direct and mediated effects via perceived control on anxiety and mood disorders in NCCP. Patients (N = 113) completed questionnaires and a structured diagnostic interview. Stress and perceived control were associated with anxiety and mood disorder severity. Perceived control fully mediated the relation between stress and mood disorder severity but not anxiety disorder severity. Results are partially supportive of anxiety-based theories of NCCP.

Genetic susceptibility to coronary heart disease in type 2 diabetes: 3 independent studies.

OBJECTIVES: The aim of this study was to evaluate whether coronary heart disease (CHD)-susceptibility loci identified by genome-wide association studies of the general population also contribute to CHD in type 2 diabetes. BACKGROUND: No study has examined the effects of these genetic variants on CHD in diabetic patients. METHODS: We genotyped 15 genetic markers of 12 loci in 3 studies of diabetic patients: the prospective Nurses' Health Study (309 CHD cases, and 544 control subjects) and Health Professional Follow-up Study (345 CHD cases, and 451 control subjects) and the cross-sectional Joslin Heart Study (422 CHD cases, and 435 control subjects). RESULTS: Five single-nucleotide polymorphisms, rs4977574 (CDKN2A/2B), rs12526453 (PHACTR1), rs646776 (CELSR2-PSRC1-SORT1), rs2259816 (HNF1A), and rs11206510 (PCSK9) showed directionally consistent associations with CHD in the 3 studies, with combined odds ratios (ORs) ranging from 1.17 to 1.25 (p = 0.03 to 0.0002). None of the other single-nucleotide polymorphisms reached significance in individual or combined analyses. A genetic risk score (GRS) was created by combining the risk alleles of the 5 significantly associated loci. The OR of CHD/GRS unit was 1.19 (95% confidence interval: 1.13 to 1.26; p < 0.0001). Individuals with GRS ≥8 (19% of diabetic subjects) had almost a 2-fold increase in CHD risk (OR: 1.94, 95% confidence interval: 1.60 to 2.35) as compared with individuals with GRS ≤5 (30% of diabetic subjects). Prediction of CHD was significantly improved (p < 0.001) when the GRS was added to a model including clinical predictors in the combined samples. CONCLUSIONS: Our results illustrate the consistency and differences in the determinants of genetic susceptibility to CHD in diabetic patients and the general populations.

The SH2B1 obesity locus is associated with myocardial infarction in diabetic patients and with NO synthase activity in endothelial cells.

OBJECTIVE: Obesity and cardiovascular disease recognize a common metabolic soil and may therefore share part of their genetic background. Genome-wide association studies have identified variability at the SH2B1 locus as a predictor of obesity. We investigated whether SNP rs4788102, which captures the entire SH2B1 variability, is associated with coronary artery disease (CAD) and/or myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM). DESIGN AND SETTING: SNP rs4788102 was typed in 2015 White subjects with T2DM from three CAD case-control studies [n=740 from the Gargano Hearth Study (GHS, Italy); n=818 from the Joslin Hearth Study (JHS, Boston); n=457 from the University of Catanzaro (CZ, Italy)]. RESULTS: SNP rs4788102 (G/A) was not associated with CAD (overall allelic OR=1.06, 95% CI=0.93-1.21; p=0.37). On the contrary, it was associated with MI in GHS (1.42, 1.12-1.81; p=0.004) and in the three samples analyzed together (1.21, 1.04-1.41; p=0.016). Insulin stimulated nitric oxide synthase (NOS) activity in human vein endothelial cells from G/G (n=4, p=0.03) but not the G/A (n=5, p=0.83) genotype. Of the SNPs in perfect LD with rs4788102, one (rs7498665) affects amino acid polarity (Ala484Thr) and falls into a highly conserved protein segment of SH2B1 containing a class II SH3 domain binding site. CONCLUSIONS: Variability at the SH2B1 obesity locus is associated with MI in diabetic patients and with reduced insulin-stimulated NOS activity in human endothelial cells. Further studies are needed to replicate this association and dissect the biology underlying this finding.

Alexithymia and anxiety sensitivity in patients with non-cardiac chest pain.

The aim of this study was to examine independent and combined influences of alexithymia and anxiety sensitivity on chest pain and life interference in patients with non-cardiac chest pain (NCCP). Theories of NCCP posit a central role for emotion in the experience of chest pain, however, studies have not examined how alexithymia characterized by a difficulty identifying or verbalizing emotions, may influence this relationship. This study examined 231 patients (56% females, M age=50 years) with chest pain seeking cardiac evaluation, who showed no abnormalities during exercise tolerance testing. Forty percent (40%) scored at or above the moderate range of alexithymia. Whereas health care utilization was associated with elevated alexithymia among men, health care utilization was associated with elevated anxiety sensitivity among women. Hierarchical regression analyses revealed that alexithymia and anxiety sensitivity were both uniquely and independently associated with pain severity and life interference due to pain. Alexithymia-pain links were stronger for men compared to women. Secondary analyses conducted with a subsample suggest that alexithymia may be increasingly stable over time (i.e., 18-month follow-up). Findings are largely congruent with theoretical models of NCCP showing that personality and emotional factors are important in this medically unexplained syndrome.

The type 2 diabetes and insulin-resistance locus near IRS1 is a determinant of HDL cholesterol and triglycerides levels among diabetic subjects.

OBJECTIVE: SNP rs2943641 near the insulin receptor substrate 1 (IRS1) gene has been found to be associated with type 2 diabetes (T2D) and insulin-resistance in genome-wide association studies. We investigated whether this SNP is associated with cardiovascular risk factors and coronary artery disease (CAD) among diabetic individuals. METHODS: SNP rs2943641 was typed in 2133 White T2D subjects and tested for association with BMI, serum HDL cholesterol and triglycerides, hypertension history, and CAD risk. RESULTS: HDL cholesterol decreased by 1mg/dl (p = 0.004) and serum triglycerides increased by 6 mg/dl (p = 0.016) for each copy of the insulin-resistance allele. Despite these effects, no association was found with increased CAD risk (OR = 1.00, 95% CI 0.88-1.13). CONCLUSIONS: The insulin-resistance and T2D locus near the IRS1 gene is a determinant of lower HDL cholesterol among T2D subjects. However, this effect is small and does not translate into a detectable increase in CAD risk in this population.