The Effects of a High-Carbohydrate versus a High-Fat Shake on Biomarkers of Metabolism and Glycemic Control When Used to Interrupt a 38-h Fast: A Randomized Crossover Study.

This study aimed to determine the impact of various fast-interrupting shakes on markers of glycemic control including glucose, ß-hydroxybutyrate (BHB), insulin, glucagon, GLP-1, and GIP. Twenty-seven sedentary adults (twelve female, fifteen male) with overweight or obesity completed this study. One condition consisted of a 38-h water-only fast, and the other two conditions repeated this, but the fasts were interrupted at 24 h by either a high carbohydrate/low fat (HC/LF) shake or an isovolumetric and isocaloric low carbohydrate/high fat (LC/HF) shake. The water-only fast resulted in 135.3% more BHB compared to the HC/LF condition (p < 0.01) and 69.6% more compared to the LC/HF condition (p < 0.01). The LC/HF condition exhibited a 38.8% higher BHB level than the HC/LF condition (p < 0.01). The area under the curve for glucose was 14.2% higher in the HC/LF condition than in the water condition (p < 0.01) and 6.9% higher compared to the LC/HF condition (p < 0.01), with the LC/HF condition yielding 7.8% more glucose than the water condition (p < 0.01). At the 25-h mark, insulin and glucose-dependent insulinotropic polypeptide (GIP) were significantly elevated in the HC/LF condition compared to the LC/HF condition (p < 0.01 and p = 0.02, respectively) and compared to the water condition (p < 0.01). Furthermore, insulin, GLP-1, and GIP were increased in the LC/HF condition compared to the water condition at 25 h (p < 0.01, p = 0.015, and p < 0.01, respectively). By the 38-h time point, no differences were observed among the conditions for any of the analyzed hormones. While a LC/HF shake does not mimic a fast completely, it does preserve some of the metabolic changes including elevated BHB and glucagon, and decreased glucose and insulin compared to a HC/LF shake, implying a potential for improved metabolic health.

Importance of Intermittent Fasting Regimens and Selection of Adequate Therapy on Inflammation and Oxidative Stress in SARS-CoV-2 Infection.

The unpredictable nature of new variants of coronavirus 2 (SARS-CoV-2)-highly transmissible and some with vaccine-resistance, have led to an increased need for feasible lifestyle modifications as complementary therapies. Systemic inflammation is the common hallmark of communicable diseases like severe coronavirus disease 2019 (COVID-19) and non-communicable chronic diseases (NCDs) such as obesity, cardiovascular diseases (CVD), diabetes mellitus, and cancers, all for which mitigation of severe outcomes is of paramount importance. Dietary quality is associated with NCDs, and intermittent fasting (IF) has been suggested as an effective approach for treatment and prevention of some NCDs, similar to that of caloric restriction. There is a paucity of high-quality data from randomized controlled trials regarding the impact of IF and the intake of specific nutrients on inflammation and post-infection outcomes in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The current review of recent literature was performed to explore the immunomodulatory roles of IF regimens and supplements involving the intake of specific nutrients including vitamins (A, B, C, D, and E), zinc, and nutraceuticals (n-3 polyunsaturated fatty acids, quercetin, and probiotics) on inflammatory and oxidative stress markers, with consideration of how they may be related to SARS-CoV-2.

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-ß signalling molecules and spectrin ß. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

Association of periodic fasting with lower severity of COVID-19 outcomes in the SARS-CoV-2 prevaccine era: an observational cohort from the INSPIRE registry.

Objectives: Intermittent fasting boosts some host defence mechanisms while modulating the inflammatory response. Lower-frequency fasting is associated with greater survival and lower risk from COVID-19-related comorbidities. This study evaluated associations of periodic fasting with COVID-19 severity and, secondarily, initial infection by SARS-CoV-2. Design: Prospective longitudinal observational cohort study. Setting: Single-centre secondary care facility in Salt Lake City, Utah, USA with follow-up across a 24-hospital integrated healthcare system. Participants: Patients enrolled in the INSPIRE registry in 2013-2020 were studied for the primary outcome if they tested positive for SARS-CoV-2 during March 2020 to February 2021 (n=205) or, for the secondary outcome, if they had any SARS-CoV-2 test result (n=1524). Interventions: No treatment assignments were made; individuals reported their personal history of routine periodic fasting across their life span. Main outcome measures: A composite of mortality or hospitalisation was the primary outcome and evaluated by Cox regression through February 2021 with multivariable analyses considering 36 covariables. The secondary outcome was whether a patient tested positive for SARS-CoV-2. Results: Subjects engaging in periodic fasting (n=73, 35.6%) did so for 40.4±20.6 years (max: 81.9 years) prior to COVID-19 diagnosis. The composite outcome occurred in 11.0% of periodic fasters and 28.8% of non-fasters (p=0.013), with HR=0.61 (95% CI 0.42 to 0.90) favouring fasting. Multivariable analyses confirmed this association. Other predictors of hospitalisation/mortality were age, Hispanic ethnicity, prior MI, prior TIA and renal failure, with trends for race, smoking, hyperlipidaemia, coronary disease, diabetes, heart failure and anxiety, but not alcohol use. In secondary analysis, COVID-19 was diagnosed in 14.3% of fasters and 13.0% of non-fasters (p=0.51). Conclusions: Routine periodic fasting was associated with a lower risk of hospitalisation or mortality in patients with COVID-19. Fasting may be a complementary therapy to vaccination that could provide immune support and hyperinflammation control during and beyond the pandemic. Trial registration: Clinicaltrials.gov, NCT02450006 (the INSPIRE registry).

Simplifying the ISCHEMIA trial algorithm for clinical practice: Identifying left main coronary artery disease using coronary artery calcium scans.

BACKGROUND: Several recent trials have evaluated invasive versus medical therapy for stable ischemic heart disease. Importantly, patients with significant left main coronary stenosis (LMCS) were excluded from these trials. In the ISCHEMIA trial, these patients were identified by a coronary CT angiogram (CCTA), which adds time, expense, and contrast exposure. We tested whether a coronary artery calcium scan (CACS), a simpler, less expensive test, could replace CCTA to exclude significant LMCS. METHODS: We hypothesized that patients with ≥50% LMCS would have a LM CACS score > 0. As a corollary, we postulated that a LM CACS = 0 would exclude patients with LMCS. To test this, we searched Intermountain Healthcare's electronic medical records database for all adult patients who had undergone non-contrast cardiac CT for quantitative CACS scoring prior to invasive coronary angiography (ICA). Patients aged <50 and those with a heart transplant were excluded. Cases with incomplete (qualitative) angiographic reports for LMCS and those with incomplete or discrepant LM CACS results were reviewed and reassessed blinded to CACS or ICA findings, respectively. RESULTS: Among 669 candidate patients with CACS followed by ICA, 36 qualifying patients were identified who had a quantitative CACS score and LMCS ≥ 50%. Their age averaged 71.8 years, and 81% were men. Angiographic LMCS averaged 72% (range 50%-99%). Median time between CACS and ICA was 6 days. Total CACS score averaged 2,383 Agatston Units (AU), range 571-6,636. LM CACS score averaged 197 AU, range 31-610. Importantly, no LMCS patient had a LM CACS score of 0 vs 57% (362/633) of non-LMCS controls (P < .00001). CONCLUSIONS: Our results support the hypothesis that an easily administered, inexpensive, low radiation CACS can identify a large subset of patients with a very low risk of LMCS who would not have the need for routine CCTA. Using CACS to exclude LMCS may efficiently allow for safe implementation of an initial medical therapy strategy of patients with stable ischemic heart disease in clinical practice. These promising results deserve validation in larger data sets.

Evaluation of TReatment With Angiotensin Converting Enzyme Inhibitors and the Risk of Lung Cancer: ERACER-An Observational Cohort Study.

INTRODUCTION: Angiotensin converting enzyme inhibitors (ACEIs) are widely prescribed medications. A recent British study reported a 14% increased risk of lung cancer with ACEI versus angiotensin receptor blocker (ARB) prescriptions, and risk increased with longer use. We sought to validate this observation. METHODS: We searched the Intermountain Enterprise Data Warehouse from 1996 to 2018 for patients newly treated with an ACEI or an ARB and with ≥1 year's follow-up or to incident lung cancer or death. Unadjusted and adjusted hazard ratios (HRs) for lung cancer and for lung cancer or all-cause mortality were calculated for ACEIs compared to ARBs. RESULTS: A total of 187,060 patients met entry criteria (age 60.2 ± 15.1 y; 51% women). During a mean of 7.1 years follow-up (max: 20.0 years), 3,039 lung cancers and 43,505 deaths occurred. Absolute lung cancer rates were 2.16 and 2.31 per 1000 patient-years in the ARB and ACEI groups, respectively. The HR of lung cancer was modestly increased with ACEIs (unadjusted HR = 1.11, CI: 1.02, 1.22, P = .014; adjusted HR = 1.18, CI: 1.06, 1.31, P = .002; number needed to harm [NNH] 6,667). Rates of the composite of lung cancer or death over time also favored ARBs. Lung cancer event curves separated gradually over longitudinal follow-up beginning at 10-12 years. CONCLUSIONS: We noted a small long-term increase in lung cancer risk with ACEIs compared with ARBs. Separation of survival curves was delayed until 10-12 years after treatment initiation. Although the observed increases in lung cancer risk are small, implications are potentially important because of the broad use of ACEIs. Thus, additional work to validate these findings is needed.

Transcatheter mitral valve in ring, hazards of long anterior mitral leaflet and 3-dimensional rings.

OBJECTIVES: The purpose of this study was to define anterior mitral leaflet (AML) length and mitral ring characteristics associated with LVOT obstruction and PVL following MViR. BACKGROUND: Transcatheter Mitral Valve in Ring (MViR) procedural complications including parvalvular leak (PVL) and left ventricular outflow tract (LVOT) obstruction are frequent. METHODS: Clinical records, computer tomographic scans (CTs) and echocardiograms of consecutive MViR patients were retrospectively reviewed for anterior mitral leaflet length, CT-simulated neoLVOT, and aortomitral angle among patients with and without MViR-induced LVOT obstruction. Acute and 1-year outcomes are described. RESULTS: Twenty-two patients underwent MViR. Technical success was achieved in 13/22 (57.1%) patients, limited by paravalvular regurgitation requiring second transcatheter heart valves (THVs) in seven patients. Second valves were needed in 6/11 (54.5%) patients with 3-dimensional rings but 1/11 (9.1%, p = .06) of patients with planar rings. Procedure success at 30 days was achieved in 20/22 (90.9%) patients. There were no procedural, in-hospital, or 30-day deaths. Two patients developed significant LVOT obstruction, one managed with urgent surgery and one with elective alcohol septal ablation. Anterior mitral leaflets were longer among the two patients with LVOT obstruction than the 20 patients who did not develop LVOT obstruction when measured by TEE (30 mm vs. 21 mm, p = .009) or by CT (29 mm vs. 22 mm, p = .026). CONCLUSIONS: AML >25 mm increases the risk of MViR induced LVOT obstruction. PVL is common, particularly in 3-dimensional rings which can be managed with a second THV.

The Summit Score Stratifies Mortality and Morbidity in Chronic Obstructive Pulmonary Disease.

Introduction: Tobacco use and other cardiovascular risk factors often accompany chronic obstructive pulmonary disease (COPD). This study derived and validated the Summit Score to predict mortality in people with COPD and cardiovascular risks. Methods: SUMMIT trial subjects (N=16,485) ages 40-80 years with COPD were randomly assigned 50%/50% to derivation (N=8181) and internal validation (N=8304). Three external COPD validations from Intermountain Healthcare included outpatients with cardiovascular risks (N=9251), outpatients without cardiovascular risks (N=8551), and inpatients (N=26,170). Cox regression evaluated 40 predictors of all-cause mortality. SUMMIT treatments including combined fluticasone furoate (FF) 100µg/vilanterol 25µg (VI) were not included in the score. Results: Mortality predictors were FEV1, heart rate, systolic blood pressure, body mass index, age, smoking pack-years, prior COPD hospitalizations, myocardial infarction, heart failure, diabetes, anti-thrombotics, anti-arrhythmics, and xanthines. Combined in the Summit Score (derivation: c=0.668), quartile 4 vs 1 had HR=4.43 in SUMMIT validation (p<0.001, 95% CI=3.27, 6.01, c=0.662) and HR=8.15 in Intermountain cardiovascular risk COPD outpatients (p<0.001, 95% CI=5.86, 11.34, c=0.736), and strongly predicted mortality in the other Intermountain COPD populations. Among all SUMMIT subjects with scores 14-19, FF 100µg/VI 25µg vs placebo had HR=0.76 (p=0.0158, 95% CI=0.61, 0.95), but FF 100µg/VI 25µg was not different from placebo for scores <14 or >19. Conclusion: In this post hoc analysis of SUMMIT trial data, the Summit Score was derived and validated in multiple Intermountain COPD populations. The score was used to identify a subpopulation in which mortality risk was lower for FF 100µg/VI 25µg treatment. Trial Registration: The SUMMIT trial is registered at ClinicalTrials.gov as number NCT01313676.

Absence of Coronary Artery Calcium During Positron Emission Tomography Stress Testing in Patients Without Known Coronary Artery Disease Identifies Individuals With Very Low Risk of Cardiac Events.

BACKGROUND: Myocardial perfusion imaging, including positron emission tomography/computed tomography (PET/CT), is often used to assess for high-grade coronary artery disease (CAD) requiring revascularization. The use of coronary artery calcium (CAC) to predict risk of major adverse cardiovascular events in asymptomatic patients is accepted. However, little is known regarding the use of CAC in PET/CT patients without known CAD in identifying patients unlikely to need revascularization. Here, we determined whether the absence of CAC, using low-dose attenuation correction CT obtained during the PET/CT, identifies patients unlikely to undergo coronary revascularization within 90 days of a PET/CT. METHODS: Patients, without a history of CAD and no elevation in troponin, referred for PET/CT at Intermountain Medical Center were studied (n=5528). The presence of CAC was visually assessed using low-dose attenuation correction CT. The association between CAC and 90-day high-grade CAD and revascularization were assessed. Longer-term (up to 4 years) major adverse cardiovascular events, including all-cause death, myocardial infarction, and late revascularization (>90 days), were examined. RESULTS: There were 2510 (45.4%) patients in CAC-present group and 3018 (54.6%) patients in CAC-absent group. The CAC-absent group, compared with the CAC-present group, was less likely to undergo coronary angiography (3.4% versus 10.2%, P<0.0001), have high-grade CAD (0.5% versus 6.5%, P<0.0001), and receive revascularization (0.4% versus 5.8%, [adjusted odds ratio =0.09; 95% CI, 0.05-0.16]; P<0.0001). In patients with an ischemic burden >10%, the CAC-absent group was associated with reduced revascularization (P<0.0001). Longer-term major adverse cardiovascular events were lower in the CAC-absent (2.4%) compared with the CAC-present (6.9%) group (adjusted hazard ratio, 0.45 [95% CI, 0.34-0.60]; P<0.0001). CONCLUSIONS: The absence of CAC on low-dose attenuation correction CT identifies PET/CT patients unlikely to have high-grade CAD or require revascularization within 90 days and unlikely to experience longer-term major adverse cardiovascular events. The prognostic value of CAC, beyond ischemic burden, suggests its potential as a first-step screening tool in intermediate-risk patients to identify those who do not need coronary revascularization.

Case-Only Survival Analysis Reveals Unique Effects of Genotype, Sex, and Coronary Disease Severity on Survivorship.

Survival bias may unduly impact genetic association with complex diseases; gene-specific survival effects may further complicate such investigations. Coronary artery disease (CAD) is a complex phenotype for which little is understood about gene-specific survival effects; yet, such information can offer insight into refining genetic associations, improving replications, and can provide candidate genes for both mortality risk and improved survivorship in CAD. Building on our previous work, the purpose of this current study was to: evaluate LSAMP SNP-specific hazards for all-cause mortality post-catheterization in a larger cohort of our CAD cases; and, perform additional replication in an independent dataset. We examined two LSAMP SNPs-rs1462845 and rs6788787-using CAD case-only Cox proportional hazards regression for additive genetic effects, censored on time-to-all-cause mortality or last follow-up among Caucasian subjects from the Catheterization Genetics Study (CATHGEN; n = 2,224) and the Intermountain Heart Collaborative Study (IMHC; n = 3,008). Only after controlling for age, sex, body mass index, histories of smoking, type 2 diabetes, hyperlipidemia and hypertension (HR = 1.11, 95%CI = 1.01-1.22, p = 0.032), rs1462845 conferred significantly increased hazards of all-cause mortality among CAD cases. Even after controlling for multiple covariates, but in only the primary cohort, rs6788787 conferred significantly improved survival (HR = 0.80, 95% CI = 0.69-0.92, p = 0.002). Post-hoc analyses further stratifying by sex and disease severity revealed replicated effects for rs1462845: even after adjusting for aforementioned covariates and coronary interventional procedures, males with severe burden of CAD had significantly amplified hazards of death with the minor variant of rs1462845 in both cohorts (HR = 1.29, 95% CI = 1.08-1.55, p = 0.00456; replication HR = 1.25, 95% CI = 1.05-1.49, p = 0.013). Kaplan-Meier curves revealed unique cohort-specific genotype effects on survival. Additional analyses demonstrated that the homozygous risk genotype ('A/A') fully explained the increased hazard in both cohorts. None of the post-hoc analyses in control subjects were significant for any model. This suggests that genetic effects of rs1462845 on survival are unique to CAD presence. This represents formal, replicated evidence of genetic contribution of rs1462845 to increased risk for all-cause mortality; the contribution is unique to CAD case status and specific to males with severe burden of CAD.

Ultraviolet Radiation Affects Thoratec HeartMate II Driveline Mechanical Properties: A Pilot Experiment.

Longevity and quality of life for left ventricular assist device (LVAD) patients are plagued by driveline exit site infections. Ultraviolet (UV) radiation, a current treatment in wound healing clinics, could potentially treat LVAD exit site infections. However, the effect of UV radiation on the tensile properties of HeartMate II (HMII) driveline material is unknown. The sleeve of a single HMII driveline was distributed into six exposure groups (n = 10/group). The six groups were further divided into two treatment cohorts designed to replicate wound treatment schedules of postimplant LVAD patients. Strip biaxial tensile tests were performed on both unexposed and exposed samples to analyze changes in material elasticity (Young's modulus), point of deformation (yield strength), and breaking point. Our data suggest that UV exposure changes the elasticity of the HMII driveline. However, the material endured aberrantly large forces and the properties remained within the safety threshold of device performance. This study warrants further examination of the effect of UV light on driveline material, to determine safety, reliability, and efficacy of UV treatment on exit site infections.

Gene-smoking interactions in multiple Rho-GTPase pathway genes in an early-onset coronary artery disease cohort.

We performed a gene-smoking interaction analysis using families from an early-onset coronary artery disease cohort (GENECARD). This analysis was focused on validating and expanding results from previous studies implicating single nucleotide polymorphisms (SNPs) on chromosome 3 in smoking-mediated coronary artery disease. We analyzed 430 SNPs on chromosome 3 and identified 16 SNPs that showed a gene-smoking interaction at P < 0.05 using association in the presence of linkage--ordered subset analysis, a method that uses permutations of the data to empirically estimate the strength of the association signal. Seven of the 16 SNPs were in the Rho-GTPase pathway indicating a 1.87-fold enrichment for this pathway. A meta-analysis of gene-smoking interactions in three independent studies revealed that rs9289231 in KALRN had a Fisher's combined P value of 0.0017 for the interaction with smoking. In a gene-based meta-analysis KALRN had a P value of 0.026. Finally, a pathway-based analysis of the association results using WebGestalt revealed several enriched pathways including the regulation of the actin cytoskeleton pathway as defined by the Kyoto Encyclopedia of Genes and Genomes.

Red cell distribution width is predictive of mortality in trauma patients.

BACKGROUND: Red blood cell distribution width (RDW) is a component of the complete blood count (CBC) that is traditionally used to identify iron-deficiency anemia. RDW has been shown to predict mortality in patients with multiple different medical conditions and in general populations. It is unknown whether RDW predicts outcomes in trauma patients. This study tested whether RDW predicts mortality in a trauma population at a Level I trauma center. METHODS: Trauma patients with a CBC from October 2005 to December 2011 were evaluated. Sex-specific 30-day and 1-year all-cause mortality and RDW were studied using Cox regression adjusted for age, Injury Severity Score (ISS), hospital length of stay, blunt versus penetrating trauma, and other CBC parameters. RESULTS: A total of 3,637 females and 5,901 males were evaluated at 30 days and 1 year. With full adjustment, RDW predicted 30-day mortality in males (for RDW quintiles 1-5: 2.2%, 1.8%, 3.6%, 4.8%, 10.1%, respectively; p < 0.001) but not in females (3.4%, 1.9%, 3.0%, 3.9%, 6.2%; p = 0.036). At 1 year, RDW predicted mortality in both males (p < 0.001; 0.5%, 0.4%, 0.8%, 1.7%, and 8.3%) and females (p < 0.001; 0.5%, 2.1%, 3.0%, 4.2%, and 8.8%). Receiver operating characteristic analysis found c = 0.705 in males and c = 0.625 in females at 30 days and c = 0.820 in males and c = 0.723 in females at 1 year. CONCLUSION: RDW independently predicted mortality in trauma patients at this single Level I trauma center. RDW may reveal underlying health status and be clinically useful for prognostication. The mechanistic relationship between RDW and mortality in trauma remains unknown and should be further evaluated. LEVEL OF EVIDENCE: Prognostic and epidemiological study, level III.

Panoptic total cardiovascular risk prediction using all predictors versus optimized risk assessment using variable subsets.

Cardiovascular disease remains the primary cause of mortality and morbidity in the developed world. Risk scores can provide clinical risk stratification and many exist for use in cardiovascular disease prevention and treatment. Cardiovascular risk scores predict mortality, coronary heart disease and other vascular disease using risk predictors such as patient age, sex, BMI, smoking history, cholesterol level, blood pressure, glucose level or diabetes diagnosis, family history of cardiovascular disease and creatinine. While the risk scores in existence are excellent for risk stratification, actual use in a clinical environment is lagging behind the rate of new risk score creation. Future research should focus on how to utilize risk scores most effectively and efficiently in clinical practice.

Genome-wide significance and replication of the chromosome 12p11.22 locus near the PTHLH gene for peripartum cardiomyopathy.

BACKGROUND: Peripartum (PP) cardiomyopathy (CM) is a rare condition of unknown etiology that occurs in late pregnancy or early postpartum. Initial evidence suggests that genetic factors may influence PPCM. This study evaluated and replicated genome-wide association of single nucleotide polymorphisms with PPCM. METHODS AND RESULTS: Genome-wide single nucleotide polymorphisms in women with verified PPCM diagnosis (n=41) were compared separately with local control subjects (n=49 postmenopausal age-discordant women with parity ≥1 and no heart failure) and iControls (n=654 women ages 30 to 84 years with unknown phenotypes). A replication study of independent population samples used new cases (PPCM2, n=30) compared with new age-discordant control subjects (local2, n=124) and with younger control subjects (n=89) and obstetric control subjects (n=90). A third case set of pregnancy-associated CM cases not meeting strict PPCM definitions (n=29) was also studied. In the genome-wide association study, 1 single nucleotide polymorphism (rs258415) met genome-wide significance for PPCM versus local control subjects (P=2.06×10(-8); odds ratio [OR], 5.96). This was verified versus iControls (P=7.92×10(-19); OR, 8.52). In the replication study for PPCM2 cases, rs258415 (ORs are per C allele) replicated at P=0.009 versus local2 control subjects (OR, 2.26). This replication was verified for PPCM2 versus younger control subjects (P=0.029; OR, 2.15) and versus obstetric control subjects (P=0.013; OR, 2.44). In pregnancy-associated cardiomyopathy cases, rs258415 had a similar effect versus local2 control subjects (P=0.06; OR, 1.79), younger control subjects (P=0.14; OR, 1.65), and obstetric control subjects (P=0.038; OR, 1.99). CONCLUSIONS: Genome-wide association with PPCM was discovered and replicated for rs258415 at chromosome 12p11.22 near PTHLH. This study indicates a role of genetic factors in PPCM and provides a new locus for further pathophysiological and clinical investigation.

Relation of elevated plasma renin activity at baseline to cardiac events in patients with angiographically proven coronary artery disease.

Plasma renin activity (PRA) is a measure of renin-angiotensin system activity and is associated with cardiovascular outcomes in patients with heart failure (HF). We conducted a prospective analysis to assess whether elevated baseline PRA is associated with cardiovascular outcomes in 1,165 patients with coronary artery disease (> or =70% stenosis on the coronary angiogram) enrolled in the Intermountain Heart Collaborative Study. The exclusion criteria included previous myocardial infarction (MI) or HF, ejection fraction < or =45%, and a discharge diagnosis of MI/beta-blocker treatment. Baseline PRA measurements were evaluated as risk categories (< or =0.50, 0.51 to 2.30, and >2.30 ng/ml/h) and as tertiles (< or =0.40, 0.41 to 1.90, and > or =1.90 ng/ml/h). Predefined cardiovascular outcomes were assessed for a minimum follow-up of 3 years (mean 6.4 +/- 3.2, maximum 14.6) using Cox regression analysis to adjust for the baseline characteristics. The mean patient age was 64.4 years; most patients were men (73.1%) and hypertensive (63.2%). Elevated baseline PRA (high vs low category; >2.30 vs < or =0.50 ng/ml/h) was associated with a significantly increased risk of 3-year cardiac morbidity/mortality (hazard ratio 1.96; p = 0.004), MI (hazard ratio 2.41; p = 0.02), HF hospitalization (hazard ratio 4.39; p = 0.03), and all-cause death (hazard ratio 1.80; p = 0.01). Elevated baseline PRA was also associated with longer-term HF hospitalization (hazard ratio 2.12; p = 0.004) and all-cause death (hazard ratio 1.56; p = 0.002). Similar results were observed for the PRA tertiles. The association of PRA with outcomes was observed after correction for hypertension, hyperlipidemia, diabetes, a family history of cardiovascular events, smoking, renal failure, and the use of statins. In conclusion, elevated baseline PRA is associated with cardiac morbidity and mortality in patients with coronary artery disease but normal left ventricular function and no previous MI or HF.

Antilipidemic adherence post-coronary artery disease diagnosis among those with and without an ICD-9 diagnosis of depression.

OBJECTIVES: An association between depression and coronary artery disease (CAD) is well established. Poor adherence to cardiac treatments may be one way depression could contribute to the increased risk of coronary events among depressed patients. We sought to evaluate whether adherence to antilipid medication, a therapy shown to be beneficial in secondary prevention of coronary events, differs among CAD patients with and without an ICD-9 depression diagnosis. METHODS: Patients were included if, at angiography, they were determined to have CAD (stenosis >or=70%), were discharged on an antilipid medication, and re-filled their prescriptions at a participating pharmacy. A patient was determined to have depression (ICD-9 codes 296.2-296.36, 311) if the diagnosis occurred prior to angiography or within 6 months of the CAD diagnosis. Adherence and long-term outcomes were evaluated at 6 months, 1 year, 18 months and 2 years. RESULTS: A total of 585 patients were included, with 73 (12.5%) having a diagnosis of depression prior to or within 6 months of CAD diagnosis. At all time-points, those with depression had a lower mean adherence compared to those without depression. Differences in adherence rates after adjustment were 7% (P=.001), 6% (P=.02), 13% (P<.0001) and 5% (P=.18) at 6 months, 1 year, 18 months, and 2 years, respectively. Though not statistically significant, there were clinically important associations between adherence and depression on the combined outcome of death, myocardial infarction, and revascularization. CONCLUSION: Depression was the strongest predictor of antilipidemic medication adherence after 2 years of follow-up among CAD patients. Such results suggest that poor antilipid adherence may be one mechanism by which depression contributes to CAD events.

Warfarin knowledge in patients with atrial fibrillation: implications for safety, efficacy, and education strategies.

BACKGROUND: Multiple factors influence warfarin metabolism and can significantly affect the risk of adverse events. The extent to which patients understand the modifiable factors that impact on warfarin safety and efficacy is unclear. METHODS: A 52-item questionnaire related to knowledge of warfarin was administered to patients with atrial fibrillation in a face-to-face interview with a dietitian. Results were compiled based on five categories: general warfarin knowledge, compliance, drug interactions, herbal or vitamin interactions, and diet. RESULTS: 100 patients were surveyed. Stroke risk factors included hypertension (57%), heart failure (36%), age >75 years (33%), diabetes (22%), and prior stroke/transient ischemic attack (29%). The majority were either high-school (49%) or college graduates (27%). Ten (10%) had a stroke while on warfarin, 11 (11%) had a blood transfusion, and 26 (26%) had at least one fall. The percentages correct for questionnaire items in the five categories were as follows: general knowledge (62%), compliance (71%), drug interactions (17%), herbal or vitamin interactions (7%), and diet (23%). Neither education level nor duration of therapy correlated with warfarin knowledge. Patients at highest risk of stroke had very low knowledge scores in general. DISCUSSION: Patients on warfarin have a poor general understanding of the medication, particularly those at highest risk of stroke.

Validation study of genetic associations with coronary artery disease on chromosome 3q13-21 and potential effect modification by smoking.

The CATHGEN study reported associations of chromosome 3q13-21 genes (KALRN, MYLK, CDGAP, and GATA2) with early-onset coronary artery disease (CAD). This study attempted to independently validate those associations. Eleven single nucleotide polymorphisms (SNPs) were examined (rs10934490, rs16834817, rs6810298, rs9289231, rs12637456, rs1444768, rs1444754, rs4234218, rs2335052, rs3803, rs2713604) in patients (N = 1618) from the Intermountain Heart Collaborative Study (IHCS). Given the higher smoking prevalence in CATHGEN than IHCS (41% vs. 11% in controls, 74% vs. 29% in cases), smoking stratification and genotype-smoking interactions were evaluated. Suggestive association was found for GATA2 (rs2713604, p = 0.057, OR = 1.2). Among smokers, associations were found in CDGAP (rs10934490, p = 0.019, OR = 1.6) and KALRN (rs12637456, p = 0.011, OR = 2.0) and suggestive association was found in MYLK (rs16834871, p = 0.051, OR = 1.8, adjusting for gender). No SNP association was found among non-smokers, but smoking/SNP interactions were detected for CDGAP (rs10934491, p = 0.017) and KALRN (rs12637456, p = 0.010). Similar differences in SNP effects by smoking status were observed on re-analysis of CATHGEN. CAD associations were suggestive for GATA2 and among smokers significant post hoc associations were found in KALRN, MYLK, and CDGAP. Genetic risk conferred by some of these genes may be modified by smoking. Future CAD association studies of these and other genes should evaluate effect modification by smoking.