Combined Value of Dimensionless Index and Transvalvular Flow Rate in Risk Stratification of Aortic Stenosis.

Aortic stenosis (AS) is difficult to phenotype. The metrics of severity are frequently discordant, making prognostication challenging. Flow state is central to accurately determining severity. We sought to evaluate the prognostic value of dimensionless index (DI) and transvalvular flow rate (Q) in AS. We evaluated 2 independent, longitudinal registries of ≥ moderate severity AS (aortic valve area ≤1.5 cm2 or mean gradient ≥20 mm Hg) with complete data follow-up. In the primary cohort (n = 1,104, 77 ± 11 years, 40% female), the DI and Q category significantly predicted mortality (p <0.001) (Figure 1), with the highest risk being low DI and low Q (DI <0.25, Q ≤210 mL/s). In the validation cohort (n = 939, 70 ± 13 years, 42% female), similar results were seen in Kaplan-Meier (p <0.001) and multivariable Cox model analyses (p <0.01). We advocate for wider combined use of DI and Q in AS assessment to augment current diagnostic and prognostic approaches.

Risk Factors for the Development of New-Onset Persistent Atrial Fibrillation: Subanalysis of the VITAL Study.

BACKGROUND: Sustained forms of atrial fibrillation (AF) are associated with lower treatment success rates and poorer prognosis compared with paroxysmal AF. Yet, little is known about risk factors that predispose to persistent AF on initial presentation. Our objective was to define risk factors associated with new-onset persistent AF. METHODS: We prospectively examined the differential associations between lifestyle, clinical, and socioeconomic risk factors and AF pattern (persistent versus paroxysmal) at the time of diagnosis among 25 119 participants without a history of cardiovascular disease, AF, or cancer in the VITAL rhythm study (Vitamin D and Omega-3). RESULTS: During a median follow-up of 5.3 years, 900 participants developed AF and 346 (38.4%) were classified as persistent at the time of diagnosis. In multivariable competing risk models, increasing age, male sex, White race, height, weight, body mass index ≥30 kg/m2, hypertension, current or past smoking, alcohol intake ≥2 drinks/day, postcollege education, and randomized treatment with vitamin D were significantly associated with incident persistent AF. Compared with paroxysmal AF, increasing age, male sex, weight, body mass index ≥30 kg/m2, and postcollege education were more strongly associated with persistent AF in multivariable models regardless of whether interim cardiovascular disease and heart failure events were censored. CONCLUSIONS: In a prospective cohort without baseline AF or cardiovascular disease, over one-third of AF at the time of diagnosis is persistent. Older age, male sex, postcollege education, and obesity were preferentially associated with persistent AF and represent a high-risk AF subset for population-based intervention.

A randomized clinical trial of omega-3 fatty acid and vitamin D supplementation on electrocardiographic risk profiles.

Beneficial and adverse associations with arrhythmias have been reported for omega-3 fatty acids (omega-3 FA) and Vitamin D. The 12 lead electrocardiogram (ECG) contains quantitative measures reflecting diverse aspects of electrophysiology that might provide insights into mechanisms underlying these associations. In a pre-specified ancillary study of the VITaminD and omegA-3 (VITAL) trial, we examined the effect of 1 g of marine omega-3 FA per day, comprised of 460 mg eicosapentanoic acid and 380 mg of docosahexaenoic acid, and 2000 IU VitaminD3 per day on ECG characteristics associated with atrial and ventricular arrhythmias among individuals age 50 years or greater. A total of 911 study participants underwent ECGs at baseline and again at 2 years after the randomization. Individuals randomized to active omega-3 FA demonstrated significant net increase in PR-interval duration (p = 0.005) and P-wave duration (p = 0.03) as well significant net decrease in P-wave amplitude (p = 0.037) as compared to placebo. RMSSD increased to a greater extent in the omega-3 FA arm compared to placebo (p = 0.040). For Vitamin D3, the Cornell voltage increased to a lesser extent in the participants assigned to active treatment as compared to placebo (p = 0.044). There were no other significant differences in QRS, QTc, Cornell voltage or heart rate. Thus, randomized treatment with omega-3 FA supplements resulted in changes on the ECG that are potentially reflective of heightened vagal tone and/or slowing of intraatrial and AV conduction. Vitamin D3 supplementation resulted in modest reductions in progressive LV voltage suggestive of a potential antihypertrophic effect.Trial registration ClinicalTrials.gov Identifiers: NCT01169259, NCT02178410 (06/26/2010 and 06/30/2014).

Sex Differences in Extensive Mitral Annular Calcification With Associated Mitral Valve Dysfunction.

Mitral annular calcification (MAC)-related mitral valve (MV) dysfunction is an increasingly recognized entity, which confers a high burden of morbidity and mortality. Although more common among women, there is a paucity of data regarding how the phenotype of MAC and the associated adverse clinical implications may differ between women and men. A total of 3,524 patients with extensive MAC and significant MAC-related MV dysfunction (i.e., transmitral gradient ≥3 mm Hg) were retrospectively analyzed from a large institutional database, with the goal of defining gender differences in clinical and echocardiographic characteristics and the prognostic importance of MAC-related MV dysfunction. We stratified patients into low- (3 to 5 mm Hg), moderate- (5 to 10 mm Hg), and high- (≥10 mm Hg) gradient groups and analyzed the gender differences in phenotype and outcome. The primary outcome was all-cause mortality, assessed using adjusted Cox regression models. Women represented the majority (67%) of subjects, were older (79.3 ± 10.4 vs 75.5 ± 10.9 years, p <0.001) and had a lower burden of cardiovascular co-morbidities than men. Women had higher transmitral gradients (5.7 ± 2.7 vs 5.3 ± 2.6 mm Hg, p <0.001), more concentric hypertrophy (49% vs 33%), and more mitral regurgitation. The median survival was 3.4 years (95% confidence interval 3.0 to 3.6) among women and 3.0 years (95% confidence interval 2.6 to 4.5) among men. The adjusted survival was worse among men, and the prognostic impact of the transmitral gradient did not differ overall by gender. In conclusion, we describe important gender differences among patients with MAC-related MV dysfunction and show worse adjusted survival among men; although, the adverse prognostic impact of the transmitral gradient was similar between men and women.

Indexing Left Atrial Volumes: Alternative Indexing Methods Better Predict Outcomes in Overweight and Obese Populations.

BACKGROUND: Left atrial volume (LAV) is often adjusted for body surface area (BSA). In overweight individuals this may result in underestimation of left atrial (LA) dilation. The authors investigated whether alternative indexing techniques better predict mortality and cardiovascular (CV) events. OBJECTIVES: The purpose of this study was to evaluate the efficacy of different methods of indexing LAV in predicting mortality and CV events across a range of body sizes. METHODS: LAV was adjusted for BSA, idealized BSA (iBSA), height, and height-squared (H2) in patients aged over 50 years who underwent outpatient echocardiography and longitudinal follow-up at our institution. LA dilation was categorized using published criteria. Mortality and CV events were assessed via medical records. RESULTS: LAVs were calculated in 17,454 individuals. In this study, 71.2% were overweight or obese. Indexing using iBSA, height, and H2 resulted in reclassification of LA size in up to 28.4% (P < 0.001) compared with indexing using BSA. In severely obese individuals (body mass index [BMI] ≥40 kg/m2), LA dilation indexed for BSA no longer predicted mortality (P = 0.70). Other indexing methods remained predictive of mortality. Height, H2, and iBSA all had greater performance, compared with BSA, for prediction of mortality and CV events in all overweight patients with H2 showing the best overall performance (P < 0.001). Net reclassification index for mortality was significant for all alternative indexing techniques (P < 0.001) and patients whose LA was reclassified from normal to dilated had increased risk of mortality (P < 0.001) and CV events (P < 0.001) across all BMI categories. CONCLUSIONS: LA dilation based on standard indexing using BSA is nondiscriminatory for prediction of mortality in the severely obese. Indexing using height, H2, or iBSA to diagnose LA dilation better predicts mortality in this population and has better overall predictive performance across all overweight and obese populations. Using BSA indexing may lead to underappreciation of LA dilation and underestimation of patients at increased risk.

Effect of Marine Omega-3 Fatty Acid and Vitamin D Supplementation on Incident Atrial Fibrillation: A Randomized Clinical Trial.

Importance: Atrial fibrillation (AF) is the most common heart rhythm disturbance, continues to increase in incidence, and results in significant morbidity and mortality. The marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D have been reported to have both benefits and risks with respect to incident AF, but large-scale, long-term randomized trial data are lacking. Objective: To test the effects of long-term administration of marine omega-3 fatty acids and vitamin D on incident AF. Design, Setting, and Participants: An ancillary study of a 2 × 2 factorial randomized clinical trial involving 25 119 women and men aged 50 years or older without prior cardiovascular disease, cancer, or AF. Participants were recruited directly by mail between November 2011 and March 2014 from all 50 US states and were followed up until December 31, 2017. Interventions: Participants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D3 (2000 IU/d) (n = 6272 analyzed); EPA-DHA and placebo (n = 6270 analyzed); vitamin D3 and placebo (n = 6281 analyzed); or 2 placebos (n = 6296 analyzed). Main Outcomes and Measures: The primary outcome was incident AF confirmed by medical record review. Results: Among the 25 119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24 127 (96.1%) completed the trial. Over a median 5.3 years of treatment and follow-up, the primary end point of incident AF occurred in 900 participants (3.6% of study population). For the EPA-DHA vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.24; P = .19). For the vitamin D3 vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.25; P = .19). There was no evidence for interaction between the 2 study agents (P = .39). Conclusions and Relevance: Among adults aged 50 years or older, treatment with EPA-DHA or vitamin D3, compared with placebo, resulted in no significant difference in the risk of incident AF over a median follow-up of more than 5 years. The findings do not support the use of either agent for the primary prevention of incident AF. Trial Registration: ClinicalTrials.gov Identifiers: NCT02178410; NCT01169259.

Transvalvular Flow Rate Determines Prognostic Value of Aortic Valve Area in Aortic Stenosis.

BACKGROUND: Aortic valve area (AVA) ≤1.0 cm2 is a defining characteristic of severe aortic stenosis (AS). AVA can be underestimated at low transvalvular flow rate. Yet, the impact of flow rate on prognostic value of AVA ≤1.0 cm2 is unknown and is not incorporated into AS assessment. OBJECTIVES: This study aimed to evaluate the effect of flow rate on prognostic value of AVA in AS. METHODS: In total, 1,131 patients with moderate or severe AS and complete clinical follow-up were included as part of a longitudinal database. The effect of flow rate (ratio of stroke volume to ejection time) on prognostic value of AVA ≤1.0 cm2 for time to death was evaluated, adjusting for confounders. Sensitivity analysis was performed to identify the optimal cutoff for prognostic threshold of AVA. The findings were validated in a separate external longitudinal cohort of 939 patients. RESULTS: Flow rate had a significant effect on prognostic value of AVA. AVA ≤1.0 cm2 was not prognostic for mortality (p = 0.15) if AVA was measured at flow rates below median (≤242 ml/s). In contrast, AVA ≤1.0 cm2 was highly prognostic for mortality (p = 0.003) if AVA was measured at flow rates above median (>242 ml/s). Findings were irrespective of multivariable adjustment for age, sex, and surgical/transcatheter aortic valve replacement (as time-dependent covariates); comorbidities; medications; and echocardiographic features. AVA ≤1.0 cm2 was also not an independent predictor of mortality below median flow rate in the validation cohort. The optimal flow rate cutoff for prognostic threshold was 210 ml/s. CONCLUSIONS: Transvalvular flow rate determines prognostic value of AVA in AS. AVA measured at low flow rate is not a good prognostic marker and therefore not a good diagnostic marker for truly severe AS. Flow rate assessment should be incorporated into clinical diagnosis, classification, and prognosis of AS.

Non-Vitamin K Antagonist Oral Anticoagulants and Antiplatelet Therapy for Stroke Prevention in Patients With Atrial Fibrillation: A Meta-Analysis of Randomized Controlled Trials.

Non-vitamin K antagonist oral anticoagulants (NOACs) are frequently used to prevent stroke in patients with atrial fibrillation. These patients are often also on aspirin or other antiplatelet agents. It is possible that treatment with both NOACs and aspirin or other antiplatelet drug may be effective in decreasing stroke, but data are sparse regarding the efficacy and safety of using both agents for stroke prevention. To address these issues, data were pooled from the 4 recent randomized, controlled trials of NOACs: apixaban, rivaroxaban, dabigatran, and edoxaban, which included 42,411 patients; 14,148 (33.4%) were also on aspirin or other antiplatelet drug. The number of thromboembolic events among participants on NOAC and aspirin/antiplatelet was compared with the number of events in patients on NOAC alone. Bleeding rates were also compared between those on NOAC + aspirin/antiplatelet and on NOAC alone. These results were compared with thromboembolic and bleeding events in the warfarin + aspirin/antiplatelet versus warfarin alone. No greater risk for thromboembolism was seen in patients on NOACs compared with patients on both NOACs and aspirin/antiplatelet drug. In this nonrandomized comparison, there was initially a signal toward higher thromboembolic rates among NOAC users also on aspirin/antiplatelet drugs (relative risk, 1.16; 95% confidence intervals, 1.05, 1.29) when compared with NOAC alone. This likely reflected the higher CHADS2 scores of those on aspirin/antiplatelet drugs. When the analysis was limited to studies that included aspirin rather than other antiplatelet drugs, no difference was seen for thromboembolic rates comparing dual therapy to NOAC alone (relative risk, 1.02; 95% confidence intervals, 0.90, 1.15). Higher rates of bleeding were seen with aspirin/antiplatelet drug in conjunction with NOAC. In this meta-analysis and nonrandomized comparison of aspirin/antiplatelet users and nonusers also on anticoagulation, there was no additional benefit seen of anticoagulation and antiplatelet therapy for stroke prevention when compared with anticoagulation alone. There was, however, an increased risk of bleeding. Careful assessment of the indications for antiplatelet drugs in patients with atrial fibrillation who are also receiving oral anticoagulants is warranted, and future randomized comparisons are needed.

Effect of vitamin D supplementation alone or with calcium on adiposity measures: a systematic review and meta-analysis of randomized controlled trials.

CONTEXT: The independent or interactive effects of vitamin D and calcium on adiposity remain inconclusive. OBJECTIVE: The objective of this systematic review and meta-analysis was to assess whether vitamin D and calcium supplements cause changes in adiposity. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases were searched for literature published from 1966 to March 2014. STUDY SELECTION: A systematic search was conducted for randomized clinical trials with ≥ 50 participants aged ≥ 18 years at baseline who had received at least 12 weeks of treatment. Among the inclusion criteria were supplementation with vitamin D with or without calcium and measurement of adiposity (weight, body mass index [BMI], and/or fat mass). DATA EXTRACTION: The primary endpoints assessed were changes in weight, BMI, or fat mass. DATA SYNTHESIS: Of 953 trials identified, 26 randomized clinical trials (n = 12, vitamin D alone; n = 10, vitamin D plus calcium versus calcium control; n = 4, vitamin D plus calcium versus placebo) with a total of 42,430 participants (median duration, 12 months) met the inclusion criteria. When compared with placebo, vitamin D supplementation had no significant effect on BMI (weighted mean difference [WMD], -0.06 kg/m(2); 95% confidence interval [95%CI], -0.14 to 0.03), weight (WMD, -0.05 kg; 95%CI, -0.32 to 0.23), or fat mass (WMD, -0.43 kg; 95%CI, -1.69 to 0.84). Likewise, no significant reduction in BMI (WMD, 0.02 kg/m(2); 95%CI, -0.11 to 0.14), weight (WMD, 0.12 kg; 95%CI, -0.24 to 0.49), or fat mass (WMD, 0.12 kg; 95%CI, -0.22 to 0.45) was observed in participants who received vitamin D plus calcium compared with those who received calcium control. CONCLUSIONS: Supplementation with vitamin D showed no effect on adiposity measures in adults.

Lack of association between SLCO1B1 polymorphisms and clinical myalgia following rosuvastatin therapy.

BACKGROUND: Carriers of the rs4363657C and rs4149056C alleles in SLCO1B1 have increased myopathic complaints when taking simvastatin. Whether rosuvastatin has a similar effect is uncertain. This study assesses whether SLCO1B1 polymorphisms relate to clinical myalgia after rosuvastatin therapy. METHODS: In the JUPITER trial, participants without prior cardiovascular disease or diabetes who had low-density lipoprotein cholesterol <130 mg/dL and C-reactive protein ≥2 mg/L were randomly allocated to rosuvastatin 20 mg or placebo and followed for the first cardiovascular disease events and adverse effects. We evaluated the effect of rs4363657 and rs4149056 in SLCO1B1, which encodes organic anion-transporting polypeptide OATP1B1, a regulator of hepatic statin uptake, on clinically reported myalgia. RESULTS: Among 4,404 participants allocated to rosuvastatin, clinical myalgia occurred with a rate of 4.1 events per 100 person-years as compared with 3.7 events per 100 person-years among 4,378 participants allocated to placebo (hazard ratio [HR] 1.13, 95% CI 0.98-1.30). Among those on rosuvastatin, there were no differences in the rate of myalgia among those with the rs4363657C (HR 0.95, 95% CI 0.79-1.14 per allele) or the rs4149056C allele (HR 0.95, 95% CI 0.79-1.15 per allele) compared with those without the C allele. Similar null data were observed when the myalgia definition was broadened to include muscle weakness, stiffness, or pain. None of the 3 participants on rosuvastatin or the 3 participants on placebo with frank myopathy had the minor allele at either polymorphism. CONCLUSION: There appears to be no increased risk of myalgia among users of rosuvastatin who carry the rs4363657C or the rs4149056C allele in SLCO1B1.

Vitamin d and cardiovascular disease.

OPINION STATEMENT: Vitamin D has received widespread attention for its potential role in preventing cardiovascular disease (CVD) and type 2 diabetes mellitus. Several epidemiological studies have suggested that individuals with low blood levels of vitamin D have increased risks of heart disease, stroke, hypertension, and diabetes. Yet, the revised 2011 Institute of Medicine report for intake of calcium and vitamin D, which was guided by skeletal health alone, concluded that the evidence that vitamin D prevents CVD, diabetes, or other cardiometabolic outcomes was inconsistent and inconclusive and did not meet criteria for establishing a cause and effect relationship [1•, 2]. This finding was consistent with an earlier systematic review conducted by the Agency for Healthcare Research and Quality (AHRQ) in 2009 [3•]. Ongoing clinical trials seek to address the effects of vitamin D supplementation on CVD and other nonskeletal outcomes.

Novel loci, including those related to Crohn disease, psoriasis, and inflammation, identified in a genome-wide association study of fibrinogen in 17 686 women: the Women's Genome Health Study.

BACKGROUND: Fibrinogen is a multifunctional circulating glycoprotein involved in wound healing, thrombosis, platelet aggregation, and inflammation, and elevated levels predict vascular disease. Despite evidence of crucial biological function and moderate heritability, comprehensive analysis of the influence of genetic variation on fibrinogen is not available. METHODS AND RESULTS: To address this issue, we undertook a genome-wide association study evaluating the potential relationships between 337 343 single-nucleotide polymorphisms (SNPs) and plasma fibrinogen levels among 17 686 apparently healthy women participating in the Women's Genome Health Study. As C-reactive protein is also an inflammatory marker known to predict cardiovascular diseases, we compared the determinants of fibrinogen levels with those of C-reactive protein. Four novel loci were identified, in addition to the fibrinogen gene cluster, which were associated with fibrinogen levels at genome-wide levels of significance (range of probability values from 8.82 x 10(-09) to 8.04 x 10(-39)). Two of the loci are related to common chronic inflammatory diseases: the first, at locus 5q31.1 (SLC22A5, SLC22A4, IRF1), lies immediately adjacent to a locus linked to Crohn disease (P value for lead SNP, 1.24 x 10(-12)) and the second, at locus 17q25.1 (CD300LF, SLC9A3R1, NAT9), has been associated with psoriasis (P value for lead SNP, 7.72 x 10(-11)). A third locus at 1q21.3 (IL6R) lies within the interleukin 6 receptor gene, a critical component of the inflammatory cascade (P value for lead SNP, 1.80 x 10(-11)). A novel locus at 2q34 (CPSI) participates in the urea cycle (P=8.82 x 10(-09)). The majority of implicated SNPs showed little evidence of dual association with C-reactive protein levels. CONCLUSIONS: A genome-wide survey of the human genome identifies novel loci related to common chronic inflammatory diseases as genetic determinants of fibrinogen levels, in addition to loci that relate to the inflammatory cascade, the urea cycle, and the fibrinogen gene cluster.

Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study.

Although elevated levels of C-reactive protein (CRP) independently predict increased risk of development of metabolic syndrome, diabetes, myocardial infarction, and stroke, comprehensive analysis of the influence of genetic variation on CRP is not available. To address this issue, we performed a genome-wide association study among 6345 apparently healthy women in which we evaluated 336,108 SNPs as potential determinants of plasma CRP concentration. Overall, seven loci that associate with plasma CRP at levels achieving genome-wide statistical significance were found (range of p values for lead SNPs within the seven loci: 1.9 x 10(-)(8) to 6.2 x 10(-)(28)). Two of these loci (GCKR and HNF1A) are suspected or known to be associated with maturity-onset diabetes of the young, one is a gene-desert region on 12q23.2, and the remaining four loci are in or near the leptin receptor protein gene, the apolipoprotein E gene, the interleukin-6 receptor protein gene, or the CRP gene itself. The protein products of six of these seven loci are directly involved in metabolic syndrome, insulin resistance, beta cell function, weight homeostasis, and/or premature atherothrombosis. Thus, common variation in several genes involved in metabolic and inflammatory regulation have significant effects on CRP levels, consistent with CRP's identification as a useful biomarker of risk for incident vascular disease and diabetes.