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Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling [Original Research Article]

Lun, 15/01/2018 - 19:40
Background:Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of the nitric oxide pathway as a therapeutic strategy.Methods:We analyzed the association of common and rare genetic variants in 2 genes that mediate nitric oxide signaling (Nitric Oxide Synthase 3 [NOS3] and Guanylate Cyclase 1, Soluble, Alpha 3 [GUCY1A3]) with a range of human phenotypes. We selected 2 common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm?Hg reduction in mean arterial pressure. Using individual-level data from 335?464 participants in the UK Biobank and summary association results from 7 large-scale genome-wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27?815).Results:A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease (odds ratio, 0.37; 95% confidence interval [CI], 0.31-0.45; P=5.5*10–26], peripheral arterial disease (odds ratio 0.42; 95% CI, 0.26-0.68; P=0.0005), and stroke (odds ratio, 0.53; 95% CI, 0.37-0.76; P=0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm?Hg higher systolic blood pressure (95% CI, 12-34; P=5.6*10–5) and a 3-fold higher risk of coronary heart disease (odds ratio, 3.03; 95% CI, 1.29-7.12; P=0.01).Conclusions:A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke. Pharmacological stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.

Association Between Urinary Sodium and Potassium Excretion and Blood Pressure Among Adults in the United States [Original Research Article]

Lun, 15/01/2018 - 19:40
Background:Higher levels of sodium and lower levels of potassium intake are associated with higher blood pressure. However, the shape and magnitude of these associations can vary by study participant characteristics or intake assessment method. Twenty-four–hour urinary excretion of sodium and potassium are unaffected by recall errors and represent all sources of intake, and were collected for the first time in a nationally representative US survey. Our objective was to assess the associations of blood pressure and hypertension with 24-hour urinary excretion of sodium and potassium among US adults.Methods:Cross-sectional data were obtained from 766 participants age 20 to 69 years with complete blood pressure and 24-hour urine collections in the 2014 National Health and Nutrition Examination Survey, a nationally representative survey of the US noninstitutionalized population. Usual 24-hour urinary electrolyte excretion (sodium, potassium, and their ratio) was estimated from ?2 collections on nonconsecutive days, adjusting for day-to-day variability in excretion. Outcomes included systolic and diastolic blood pressure from the average of 3 measures and hypertension status, based on average blood pressure ?140/90 and antihypertensive medication use.Results:After multivariable adjustment, each 1000-mg difference in usual 24-hour sodium excretion was directly associated with systolic (4.58 mm?Hg; 95% confidence interval [CI], 2.64–6.51) and diastolic (2.25 mm?Hg; 95% CI, 0.83–3.67) blood pressures. Each 1000-mg difference in potassium excretion was inversely associated with systolic blood pressure (–3.72 mm?Hg; 95% CI, –6.01 to –1.42). Each 0.5 U difference in sodium-to-potassium ratio was directly associated with systolic blood pressure (1.72 mm?Hg; 95% CI, 0.76–2.68). Hypertension was linearly associated with progressively higher sodium and lower potassium excretion; in comparison with the lowest quartile of excretion, the adjusted odds of hypertension for the highest quartile was 4.22 (95% CI, 1.36–13.15) for sodium, and 0.38 (95% CI, 0.17–0.87) for potassium (P<0.01 for trends).Conclusions:These cross-sectional results show a strong dose-response association between urinary sodium excretion and blood pressure, and an inverse association between urinary potassium excretion and blood pressure, in a nationally representative sample of US adults.

Diagnostic Accuracy of the Aortic Dissection Detection Risk Score Plus D-Dimer for Acute Aortic Syndromes [Original Research Article]

Lun, 15/01/2018 - 19:40
Background:Acute aortic syndromes (AASs) are rare and severe cardiovascular emergencies with unspecific symptoms. For AASs, both misdiagnosis and overtesting are key concerns, and standardized diagnostic strategies may help physicians to balance these risks. D-dimer (DD) is highly sensitive for AAS but is inadequate as a stand-alone test. Integration of pretest probability assessment with DD testing is feasible, but the safety and efficiency of such a diagnostic strategy are currently unknown.Methods:In a multicenter prospective observational study involving 6 hospitals in 4 countries from 2014 to 2016, consecutive outpatients were eligible if they had ?1 of the following: chest/abdominal/back pain, syncope, perfusion deficit, and if AAS was in the differential diagnosis. The tool for pretest probability assessment was the aortic dissection detection risk score (ADD-RS, 0–3) per current guidelines. DD was considered negative (DD?) if <500 ng/mL. Final case adjudication was based on conclusive diagnostic imaging, autopsy, surgery, or 14-day follow-up. Outcomes were the failure rate and efficiency of a diagnostic strategy for ruling out AAS in patients with ADD-RS=0/DD? or ADD-RS ?1/DD?.Results:A total of 1850 patients were analyzed. Of these, 438 patients (24%) had ADD-RS=0, 1071 patients (58%) had ADD-RS=1, and 341 patients (18%) had ADD-RS >1. Two hundred forty-one patients (13%) had AAS: 125 had type A aortic dissection, 53 had type B aortic dissection, 35 had intramural aortic hematoma, 18 had aortic rupture, and 10 had penetrating aortic ulcer. A positive DD test result had an overall sensitivity of 96.7% (95% confidence interval [CI], 93.6–98.6) and a specificity of 64% (95% CI, 61.6–66.4) for the diagnosis of AAS; 8 patients with AAS had DD?. In 294 patients with ADD-RS=0/DD?, 1 case of AAS was observed. This yielded a failure rate of 0.3% (95% CI, 0.1–1.9) and an efficiency of 15.9% (95% CI, 14.3–17.6) for the ADD-RS=0/DD? strategy. In 924 patients with ADD-RS ?1/DD?, 3 cases of AAS were observed. This yielded a failure rate of 0.3% (95% CI, 0.1–1) and an efficiency of 49.9% (95% CI, 47.7–52.2) for the ADD-RS ?1/DD? strategy.Conclusions:Integration of ADD-RS (either ADD-RS=0 or ADD-RS ?1) with DD may be considered to standardize diagnostic rule out of AAS.Clinical Trial Registration:URL: https://www.clinicaltrials.gov. Unique identifier: NCT02086136.

Magnitude of Soluble ST2 as a Novel Biomarker for Acute Aortic Dissection [Original Research Article]

Lun, 15/01/2018 - 19:40
Background:Misdiagnosis of acute aortic dissection (AAD) can lead to significant morbidity and death. Soluble ST2 (sST2) is a cardiovascular injury–related biomarker. The extent to which sST2 is elevated in AAD and whether sST2 can discriminate AAD from other causes of sudden-onset severe chest pain are unknown.Methods:We measured plasma concentrations of sST2 (R&D Systems assay) in 1360 patients, including 1027 participants in the retrospective discovery set and 333 patients with initial suspicion of AAD enrolled in the prospective validation cohort. Measures of discrimination for differentiating AAD from other causes of chest pain were calculated.Results:In the acute phase, sST2 levels were higher in patients with AAD than those with either acute myocardial infarction in the first case-control discovery set within 24 hours of symptom onset or with patients with pulmonary embolism in the second discovery set (medians of 129.2 ng/mL versus 14.7 with P<0.001 for AAD versus acute myocardial infarction and 88.6 versus 9.3 with P<0.001 for AAD versus pulmonary embolism). In the prospective validation set, sST2 was most elevated in patients with AAD (median [25th, 75th percentile]: 76.4 [49.6, 130.3]) and modestly elevated in acute myocardial infarction (25.0 [15.5, 37.2]), pulmonary embolism (14.9 [10.2, 30.1]), and angina patients (21.5 [13.1, 27.6], all P<0.001 versus AAD). The area under receiver operating characteristic curve for patients with AAD versus all control patients within 24 hours of presenting at the emergency department was 0.97 (0.95, 0.98) for sST2, 0.91 (0.88, 0.94) for D-dimer, and 0.50 (0.44, 0.56) for cardiac troponin I, respectively. At a cutoff level of 34.6 ng/mL, sST2 had a sensitivity of 99.1%, specificity of 84.9%, positive predictive value of 68.7%, negative predictive value of 99.7%, positive likelihood ratio of 6.6, and negative likelihood ratio of 0.01.Conclusions:Among patients with suspected aortic dissection in the emergency department, sST2 showed superior overall diagnostic performance to D-dimer or cardiac troponin I. Additional study is needed to determine whether sST2 might be a useful rule-out marker for AAD in the emergency room.

Derivation and Validation of the CREST Model for Very Early Prediction of Circulatory Etiology Death in Patients Without ST-Segment-Elevation Myocardial Infarction After Cardiac Arrest [Original Research Article]

Lun, 15/01/2018 - 19:40
Background:No practical tool quantitates the risk of circulatory-etiology death (CED) immediately after successful cardiopulmonary resuscitation in patients without ST-segment–elevation myocardial infarction. We developed and validated a prediction model to rapidly determine that risk and facilitate triage to individualized treatment pathways.Methods:With the use of INTCAR (International Cardiac Arrest Registry), an 87-question data set representing 44 centers in the United States and Europe, patients were classified as having had CED or a combined end point of neurological-etiology death or survival. Demographics and clinical factors were modeled in a derivation cohort, and backward stepwise logistic regression was used to identify factors independently associated with CED. We demonstrated model performance using area under the curve and the Hosmer-Lemeshow test in the derivation and validation cohorts, and assigned a simplified point-scoring system.Results:Among 638 patients in the derivation cohort, 121 (18.9%) had CED. The final model included preexisting coronary artery disease (odds ratio [OR], 2.86; confidence interval [CI], 1.83–4.49; P?0.001), nonshockable rhythm (OR, 1.75; CI, 1.10–2.77; P=0.017), initial ejection fraction<30% (OR, 2.11; CI, 1.32–3.37; P=0.002), shock at presentation (OR, 2.27; CI, 1.42–3.62; P<0.001), and ischemic time >25 minutes (OR, 1.42; CI, 0.90–2.23; P=0.13). The derivation model area under the curve was 0.73, and Hosmer-Lemeshow test P=0.47. Outcomes were similar in the 318-patient validation cohort (area under the curve 0.68, Hosmer-Lemeshow test P=0.41). When assigned a point for each associated factor in the derivation model, the average predicted versus observed probability of CED with a CREST score (coronary artery disease, initial heart rhythm, low ejection fraction, shock at the time of admission, and ischemic time >25 minutes) of 0 to 5 was: 7.1% versus 10.2%, 9.5% versus 11%, 22.5% versus 19.6%, 32.4% versus 29.6%, 38.5% versus 30%, and 55.7% versus 50%.Conclusions:The CREST model stratified patients immediately after resuscitation according to risk of a circulatory-etiology death. The tool may allow for estimation of circulatory risk and improve the triage of survivors of cardiac arrest without ST-segment–elevation myocardial infarction at the point of care.

Prognostic Value of High-Sensitivity Troponin T in Chronic Heart Failure [Systematic Review]

Lun, 15/01/2018 - 19:40
Background:Most patients with chronic heart failure have detectable troponin concentrations when evaluated by high-sensitivity assays. The prognostic relevance of this finding has not been clearly established so far. We aimed to assess high-sensitivity troponin assay for risk stratification in chronic heart failure through a meta-analysis approach.Methods:Medline, EMBASE, Cochrane Library, and Scopus were searched in April 2017 by 2 independent authors. The terms were “troponin” AND “heart failure” OR “cardiac failure” OR “cardiac dysfunction” OR “cardiac insufficiency” OR “left ventricular dysfunction.” Inclusion criteria were English language, clinical stability, use of a high-sensitivity troponin assay, follow-up studies, and availability of individual patient data after request to authors. Data retrieved from articles and provided by authors were used in agreement with the PRISMA statement. The end points were all-cause death, cardiovascular death, and hospitalization for cardiovascular cause.Results:Ten studies were included, reporting data on 11 cohorts and 9289 patients (age 66±12 years, 77% men, 60% ischemic heart failure, 85% with left ventricular ejection fraction <40%). High-sensitivity troponin T data were available for all patients, whereas only 209 patients also had high-sensitivity troponin I assayed. When added to a prognostic model including established risk markers (sex, age, ischemic versus nonischemic etiology, left ventricular ejection fraction, estimated glomerular filtration rate, and N-terminal fraction of pro-B-type natriuretic peptide), high-sensitivity troponin T remained independently associated with all-cause mortality (hazard ratio, 1.48; 95% confidence interval, 1.41–1.55), cardiovascular mortality (hazard ratio, 1.40; 95% confidence interval, 1.33–1.48), and cardiovascular hospitalization (hazard ratio, 1.42; 95% confidence interval, 1.36–1.49), over a median 2.4-year follow-up (all P<0.001). High-sensitivity troponin T significantly improved risk prediction when added to a prognostic model including the variables above. It also displayed an independent prognostic value for all outcomes in almost all population subgroups. The area under the curve–derived 18 ng/L cutoff yielded independent prognostic value for the 3 end points in both men and women, patients with either ischemic or nonischemic etiology, and across categories of renal dysfunction.Conclusions:In chronic heart failure, high-sensitivity troponin T is a strong and independent predictor of all-cause and cardiovascular mortality, and of hospitalization for cardiovascular causes, as well. This biomarker then represents an additional tool for prognostic stratification.

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