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Long-Term Potassium Monitoring and Dynamics in Heart Failure and Risk of Mortality [Original Research Article]

Lun, 26/03/2018 - 19:40
Background:The prognostic value of long-term potassium monitoring and dynamics in heart failure has not been characterized completely. We sought to determine the association between serum potassium values collected at follow-up with all-cause mortality in a prospective and consecutive cohort of patients discharged from a previous acute heart failure admission.Methods:Serum potassium was measured at every physician-patient encounter, including hospital admissions and ambulatory settings. The multivariable-adjusted association of serum potassium with mortality was assessed by using comprehensive state-of-the-art regression methods that can accommodate time-dependent exposure modeling.Results:The study sample included 2164 patients with a total of 16?116 potassium observations. Mean potassium at discharge was 4.3±0.48 mEq/L. Hypokalemia (<3.5 mEq/L), normokalemia (3.5–5.0 mEq/L), and hyperkalemia (>5 mEq/L) were observed at the index admission in 77 (3.6%), 1965 (90.8%), and 122 (5.6%) patients, respectively. At a median follow-up of 2.8 years (range, 0.03–12.8 years), 1090 patients died (50.4%). On a continuous scale, the multivariable-adjusted association of potassium values and mortality revealed a nonlinear association (U-shaped) with higher risk at both ends of its distribution (omnibus P=0.001). Likewise, the adjusted hazard ratios for hypokalemia and hyperkalemia, normokalemia as reference, were 2.35 (95% confidence interval, 1.40–3.93; P=0.001) and 1.55 (95% confidence interval, 1.11–2.16; P=0.011), respectively (omnibus P=0.0003). Furthermore, dynamic changes in potassium were independently associated with substantial differences in mortality risk. Potassium normalization was independently associated with lower mortality risk (P=0.001).Conclusions:Either modeled continuously or categorically, serum potassium levels during long-term monitoring were independently associated with mortality in patients with heart failure. Likewise, persistence of abnormal potassium levels was linked to a higher risk of death in comparison with patients who maintained or returned to normal values.

Exposure to Low-Dose Ionizing Radiation From Cardiac Procedures and Malignancy Risk in Adults With Congenital Heart Disease [Original Research Article]

Lun, 26/03/2018 - 19:40
Background:Adults with congenital heart disease (CHD) are exposed to increasing amounts of low-dose ionizing radiation (LDIR) from cardiac procedures. Cancer prevalence in this population is higher than in the general population. This study estimates the association between LDIR exposure from cardiac procedures and incident cancer in adult patients with CHD.Methods:The study population derived from the Quebec Congenital Heart Disease Database. We measured cumulative numbers of LDIR-related cardiac procedures for each patient until 1 year before the time of cancer diagnosis or administrative censoring. To assess the association between LDIR exposure and cancer risk, we conducted a nested case-control study and matched cancer cases with controls on sex, CHD severity, birth year, and age.Results:The study included 24?833 adult patients with CHD aged 18 to 64 years from 1995 to 2009. In >250?791 person-years of follow-up, 602 cancer cases were observed (median age, 55.4 years). The cumulative incidence of cancer estimated up to 64 years of age was 15.3% (95% confidence interval [CI], 14.2–16.5). Cases had more LDIR-related cardiac procedures than controls (1410 versus 921 per 1000 adult patients with CHD, P<0.0001). Cumulative LDIR exposure was independently associated with cancer (odds ratio [OR], 1.08 per procedure; 95% CI, 1.04–1.13). Similar results were obtained by using dose estimates for LDIR exposure (OR, 1.10 per 10 mSv; 95% CI, 1.05–1.15) with a possible dose-related response. The effect measure was in the same direction, and the association was persistent for exposure from ?6 procedures in all sensitivity analyses: after excluding most smoking-related cancer cases (OR, 1.10 per procedure; 95% CI, 1.05–1.16 and OR when exposure from ?6 procedures, 3.08; 95% CI, 1.77–5.37), and after applying a 3-year lag period (OR, 1.09 per procedure; 95% CI, 1.03–1.14 and OR when exposure from ?6 procedures: 2.58; 95% CI, 1.43–4.69).Conclusions:To our knowledge, this is the first large population-based study to analyze and document the association between LDIR-related cardiac procedures and incident cancer in the population of adults with CHD. Confirmations of these findings by prospective studies are needed to reinforce policy recommendations for radiation surveillance in patients with CHD where no regulation currently exists. Physicians ordering and performing cardiac imaging should ensure that exposure is as low as reasonably achievable without sacrificing quality of care.

Prognostic Implications of Magnetic Resonance-Derived Quantification in Asymptomatic Patients With Organic Mitral Regurgitation [Original Research Article]

Lun, 26/03/2018 - 19:40
Background:Magnetic resonance imaging (MRI) is an accurate method for the quantitative assessment of organic mitral regurgitation (OMR). The aim of the present study was to compare the discriminative power of MRI quantification and the recommended Doppler echocardiography (ECHO)–derived integrative approach to identify asymptomatic patients with OMR and adverse outcome.Methods:The study population consisted of 258 asymptomatic patients (63±14 years, 60% men) with preserved left ventricular ejection fraction (>60%) and chronic moderate and severe OMR (flail 25%, prolapse 75%) defined by using the ECHO-derived integrative approach. All patients underwent MRI to quantify regurgitant volume (RV) of OMR by subtracting the aortic forward flow volume from the total left ventricular stroke volume. Severe OMR was defined as RV?60 mL.Results:Mean ECHO-derived RV was on average 17.1 mL larger than the MRI-derived RV (P<0.05). Concordant grading of OMR severity with both techniques was observed in 197 (76%) individuals with 62 (31%) patients having severe OMR (MRI SEV-ECHO SEV) and 135 (69%) patients having moderate OMR (MRI MOD-ECHO MOD). The remaining 61 (24%) individuals had discordant findings (MRI SEV-ECHO MOD or MRI MOD-ECHO SEV) between the 2 techniques. The majority of these differences in OMR classification were observed in patients with late systolic or multiple jets (both ?<0.2). Patients with eccentric jets showed moderate agreement (?=0.53; 95% confidence interval, 0.41–0.64). In contrast, a very good agreement (?=0.90; 95% confidence interval, 0.82–0.98) was observed in a combination of holosystolic, central, and single jet. During a median follow-up of 5.0 years (interquartile range, 3.5–6.0 years), 38 (15%) patients died and 106 (41%) either died or developed indication for mitral valve surgery. In separate Cox regression analyses, the MRI-derived left ventricular end-systolic volume index, RV, and OMR category (severe versus moderate), and the ECHO-derived OMR category were independent predictors of all-cause mortality (all P<0.05). The MRI-derived RV showed the largest area under the curve to predict mortality (0.72) or its combination with the development of indication for mitral valve surgery (0.83).Conclusions:The findings of the present study suggest that the MRI-derived assessment of OMR can better identify patients with severe OMR and adverse outcome than ECHO-derived integrative approach warranting close follow-up and perhaps, early mitral valve surgery.

High-Density Lipoprotein Subspecies Defined by Presence of Apolipoprotein C-III and Incident Coronary Heart Disease in Four Cohorts [Original Research Article]

Lun, 26/03/2018 - 19:40
Background:The causal role of high-density lipoprotein (HDL) cholesterol in cardioprotection has been questioned by genetic and randomized studies. Novel measures that relate to HDL function may contribute new information to the prediction of cardiovascular risk. Apolipoprotein C-III (apoC-III) is a key regulator of lipoprotein metabolism. We investigated whether subspecies of HDL defined by apoC-III are associated with coronary heart disease (CHD).Methods:We used immunoaffinity chromatography to measure the apoA-I concentrations of HDL that contains and lacks apoC-III in 2 prospective studies of adults free of CHD. In MESA (Multi-Ethnic Study of Atherosclerosis), 5657 participants (52% women, 52–72 years of age) were followed for risk of CHD from 2000 to 2002 through 2013. In a case-cohort study nested within the DCH study (Danish Diet, Cancer, and Health), 3642 participants (47% women, 51–64 years of age) were followed from 1994 to 1997 through 2010. Subsequently, we conducted a meta-analysis that combined these results with the previously published findings from 2 cohort studies that used similar laboratory methodology to measure lipoproteins, totaling 2997 incident cases.Results:ApoC-III was found on 6% to 8% of apoA-I. The 2 HDL subspecies showed opposing associations, with risk of CHD in each of the individual cohorts and in the meta-analysis (P heterogeneity between the 2 subspecies <0.01). HDL that contains apoC-III was associated with a higher risk of CHD (pooled relative risk per standard deviation, 1.09; 95% confidence interval, 1.01–1.18), whereas HDL that lacks apoC-III was associated with lower risk (relative risk, 0.76; 95% confidence interval, 0.70–0.83). The relative risk for HDL lacking apoC-III was even more negative than the relative risk for total HDL (relative risk, 0.80; 95% confidence interval, 0.74–0.87).Conclusions:Our findings from 4 prospective studies support the hypothesis that apoC-III may mark a subfraction of HDL that is associated with higher risk of CHD. New measures reflecting HDL structure and function may provide novel insights for cardiovascular risk that extend beyond traditional plasma HDL cholesterol concentrations.

Functional Metabolomics Characterizes a Key Role for N-Acetylneuraminic Acid in Coronary Artery Diseases [Original Research Article]

Lun, 26/03/2018 - 19:40
Background:As new biomarkers of coronary artery diseases (CAD) emerge via metabolomics, the underlying functional mechanisms remain to be elucidated. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms.Methods:A cohort of 2324 patients who underwent coronary angiography from 4 independent centers was studied. A combination of ultra–performance liquid chromatography and quadrupole time-of-flight mass spectrometry in the negative ion mode was used for untargeted analysis of metabolites in plasma. Significant differential metabolites were identified by cross-comparisons with and within CAD types, including normal coronary artery, nonobstructvie coronary atherosclerosis, stable angina, unstable angina, and acute myocardial infarction. A tandem liquid chromatography-mass spectrometry–based approach using isotope-labeled standard addition was subsequently performed for targeted analysis of the metabolic marker N-acetylneuraminic acid (Neu5Ac). A functional metabolomics strategy was proposed to investigate the role of Neu5Ac in the progression of CAD by using in vitro and in vivo models.Results:We identified a total of 36 differential metabolites, 35 of which were confirmed with reference compounds. Elevation of Neu5Ac was observed in plasma during CAD progression in center 1 (P=4.0e-64, n=2019) and replicated in 3 independent centers (n=305). The increased level of Neu5Ac in plasma was confirmed by accurate targeted quantification. Mechanistically, Neu5Ac was able to trigger myocardial injury in vitro and in vivo by activation of the Rho/Rho-associated coiled-coil containing protein kinase signaling pathway through binding to RhoA and Cdc42, but not Rac1. Silencing neuraminidase-1, the enzyme that regulates Neu5Ac generation, ameliorated oxygen-glucose deprivation–induced injury in cardiomyocytes and ligation/isoprenaline-induced myocardial ischemia injury in rats. Pharmacological inhibition of neuraminidase by anti-influenza drugs, oseltamivir and zanamivir, also protected cardiomyocytes and the heart from myocardial injury.Conclusions:Functional metabolomics identified a key role for Neu5Ac in acute myocardial infarction, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for CAD.

Cardiovascular and Metabolic Heterogeneity of Obesity [In Depth]

Lun, 26/03/2018 - 19:40
The prevalence of obesity has increased globally over the last 2 decades. Although the body mass index has been a convenient and simple index of obesity at the population level, studies have shown that obesity defined by body mass index alone is a remarkably heterogeneous condition with varying cardiovascular and metabolic manifestations across individuals. Adipose tissue is an exquisitely active metabolic organ engaged in cross-talk between various systems; perturbation of adipose tissue results in a pathological response to positive caloric balance in susceptible individuals that directly and indirectly contributes to cardiovascular and metabolic disease. Inadequate subcutaneous adipose tissue expansion in the face of dietary triglycerides leads to visceral and ectopic fat deposition, inflammatory/adipokine dysregulation, and insulin resistance. Conversely, preferential fat storage in the lower body depot may act as a metabolic buffer and protect other tissues from lipotoxicity caused by lipid overflow and ectopic fat. Translational, epidemiological, and clinical studies over the past 30 years have clearly demonstrated a strong link between visceral and ectopic fat and the development of a clinical syndrome characterized by atherogenic dyslipidemia, hyperinsulinemia/glucose intolerance, hypertension, atherosclerosis, and adverse cardiac remodeling/heart failure. This relationship is even more nuanced when clinical entities such as metabolically healthy obesity phenotype and the obesity paradox are considered. Although it is clear that the accumulation of visceral/ectopic fat is a major contributor to cardiovascular and metabolic risk above and beyond the body mass index, implementation of fat distribution assessment into clinical practice remains a challenge. Anthropometric indexes of obesity are easily implemented, but newer imaging-based methods offer improved sensitivity and specificity for measuring specific depots. Lifestyle, pharmacological, and surgical interventions allow a multidisciplinary approach to overweight/obesity that may improve outcomes and align with a public health message to combat the growing epidemic of obesity worldwide and to build healthier lives free of cardiovascular diseases.

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