Sammy Elmariah

Randomized Comparison of Percutaneous Repair and Surgery for Mitral Regurgitation: 5-Year Results of EVEREST II.

BACKGROUND In EVEREST II (Endovascular Valve Edge-to-Edge Repair Study), treatment of mitral regurgitation (MR) with a novel percutaneous device showed superior safety compared with surgery, but less effective reduction in MR at 1 year. OBJECTIVES This study sought to evaluate the final 5-year clinical outcomes and durability of percutaneous mitral valve (MV) repair with the MitraClip device compared with conventional MV surgery. METHODS Patients with grade 3+ or 4+ MR were randomly assigned to percutaneous repair with the device or conventional MV surgery in a 2:1 ratio (178:80). Patients prospectively consented to 5 years of follow-up. RESULTS At 5 years, the rate of the composite endpoint of freedom from death, surgery, or 3+ or 4+ MR in the as-treated population was 44.2% versus 64.3% in the percutaneous repair and surgical groups, respectively (p = 0.01). The difference was driven by increased rates of 3+ to 4+ MR (12.3% vs. 1.8%; p = 0.02) and surgery (27.9% vs. 8.9%; p = 0.003) with percutaneous repair. After percutaneous repair, 78% of surgeries occurred within the first 6 months. Beyond 6 months, rates of surgery and moderate-to-severe MR were comparable between groups. Five-year mortality rates were 20.8% and 26.8% (p = 0.4) for percutaneous repair and surgery, respectively. In multivariable analysis, treatment strategy was not associated with survival. CONCLUSIONS Patients treated with percutaneous repair more commonly required surgery for residual MR during the first year after treatment, but between 1- and 5-year follow-up, comparably low rates of surgery for MV dysfunction with either percutaneous or surgical therapy endorse the durability of MR reduction with both repair techniques. (EVEREST II Pivotal Study High Risk Registry; NCT00209274).

Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis

BACKGROUND Treatment with aspirin and a P2Y12 inhibitor is commonly used in patients with cardiovascular disorders. The overall effect of such treatment on all-cause mortality is unknown. In the Dual Antiplatelet Therapy (DAPT) Study, continuation of dual antiplatelet therapy beyond 12 months after coronary stenting was associated with an unexpected increase in non-cardiovascular death. In view of the potential public health importance of these findings, we aimed to assess the effect of extended duration dual antiplatelet therapy on mortality by doing a meta-analysis of all randomised, controlled trials of treatment duration in various cardiovascular disorders. METHODS We searched Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) to identify randomised controlled trials assessing the effect of extended duration versus no or short duration dual antiplatelet therapy, published before Oct 1, 2014. We did a meta-analysis to pool results with a hierarchical Bayesian random-effects model. The primary outcomes were hazard ratios comparing rates of all-cause, cardiovascular, and non-cardiovascular death. FINDINGS Including the DAPT Study, we identified 14 eligible trials that randomly assigned 69,644 participants to different durations of dual antiplatelet therapy. Compared with aspirin alone or short duration dual antiplatelet therapy (≤6 months), continued treatment was not associated with a difference in all-cause mortality (hazard ratio [HR] 1·05, 95% credible interval [CrI] 0·96-1·19; p=0·33). Similarly, cardiovascular (1·01, 0·93-1·12; p=0·81) and non-cardiovascular mortality (1·04, 0·90-1·26; p=0·66) were no different with extended duration versus short duration dual antiplatelet therapy or aspirin alone. INTERPRETATION Extended duration dual antiplatelet therapy was not associated with a difference in the risk of all-cause, cardiovascular, or non-cardiovascular death compared with aspirin alone or short duration dual antiplatelet therapy. FUNDING None.

A Combined Epidemiologic and Metabolomic Approach Improves CKD Prediction

Metabolomic approaches have begun to catalog the metabolic disturbances that accompany CKD, but whether metabolite alterations can predict future CKD is unknown. We performed liquid chromatography/mass spectrometry-based metabolite profiling on plasma from 1434 participants in the Framingham Heart Study (FHS) who did not have CKD at baseline. During the following 8 years, 123 individuals developed CKD, defined by an estimated GFR of <60 ml/min per 1.73 m(2). Numerous metabolites were associated with incident CKD, including 16 that achieved the Bonferroni-adjusted significance threshold of P≤0.00023. To explore how the human kidney modulates these metabolites, we profiled arterial and renal venous plasma from nine individuals. Nine metabolites that predicted CKD in the FHS cohort decreased more than creatinine across the renal circulation, suggesting that they may reflect non-GFR-dependent functions, such as renal metabolism and secretion. Urine isotope dilution studies identified citrulline and choline as markers of renal metabolism and kynurenic acid as a marker of renal secretion. In turn, these analytes remained associated with incident CKD in the FHS cohort, even after adjustment for eGFR, age, sex, diabetes, hypertension, and proteinuria at baseline. Addition of a multimarker metabolite panel to clinical variables significantly increased the c-statistic (0.77-0.83, P<0.0001); net reclassification improvement was 0.78 (95% confidence interval, 0.60 to 0.95; P<0.0001). Thus, the addition of metabolite profiling to clinical data may significantly improve the ability to predict whether an individual will develop CKD by identifying predictors of renal risk that are independent of estimated GFR.

Paradoxical Effects of Statins on Aortic Valve Myofibroblasts and Osteoblasts: Implications for End-Stage Valvular Heart Disease

Objectives—We evaluated the effects of statins on aortic valve myofibroblasts (AVMFs) and osteoblast calcification in vitro. Methods and Results—Cultured porcine AVMFs and M2–10B4 cells were treated with simvastatin and pravastatin. Mevalonate, a 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase metabolite, was added in parallel experiments. Manumycin A, which inhibits protein prenylation, was added to cultures in the absence of statins. Calcification was assessed by counting the number of calcific nodules formed and measuring alkaline phosphatase activity (APA). Statins inhibited calcific nodule formation (P<0.01) and APA (P<0.01) in AVMFs. Mevalonate reversed the statin effect on nodule formation (P<0.05) and APA (P<0.01). Manumycin A had no effect on either parameter. M2–10B4 cells treated with simvastatin formed more calcific nodules compared with controls (P<0.01), although pravastatin had no effect. Both statins, however, resulted in increased APA in M2–10B4 cells (P<0.01). Mevalonate had no impact on nodule numbers or APA in M2–10B4 cells. Conclusions—Statins inhibit calcification in AVMFs by inhibiting the cholesterol biosynthetic pathway, independent of protein prenylation, but paradoxically stimulate bone cell calcification. Because 15% of patients with end-stage valvular heart disease exhibit mature bone in their aortic valves, statins may differentially regulate calcification within a valve, limiting dystrophic calcification but promoting ossification of formed bone.

Differential left ventricular remodelling and longitudinal function distinguishes low flow from normal-flow preserved ejection fraction low-gradient severe aortic stenosis

AIMS There is uncertainty in identifying patients with severe aortic stenosis (AS) with preserved left ventricular (LV) ejection fraction, low flow, and low gradients (LFLG). Prior studies propose that these patients demonstrate significant concentric remodelling and decreased survival, while others suggest that they have features and survival similar to moderate AS. METHODS AND RESULTS We compared the clinical characteristics, echocardiographic features, and overall survival of LFLG AS patients (n = 38) to those with normal-flow, low-gradient (NFLG) severe AS (n = 75) and moderate AS (n = 70). Low-flow, low-gradient patients had the lowest end-diastolic volume index (43 vs. 54 vs. 54 mL/m², P < 0.001), highest relative wall thickness (RWT) (60 vs. 49 vs. 48%, P < 0.001), and lowest septal mitral annular displacement (1.0 vs. 1.5 vs. 1.5 cm, P < 0.001). New York Heart Association (NYHA) class III/IV symptoms were the most frequent in the LFLG group (29 vs. 11 vs. 3%, P < 0.001). Survival at 3 years was significantly lower in LFLG compared with NFLG (P = 0.006) and moderate AS (P = 0.002), but not different between NFLG and moderate AS (P = 0.49). Higher NYHA classification (HR 1.77, 95% CI 1.22-2.57), RWT > 50% (HR 3.28, 95% CI 1.33-8.1), and septal displacement <1.1 cm (HR 3.93, 95% CI 1.96-7.82) but not low flow were independent predictors of survival in Cox proportional hazards analysis. CONCLUSION Preserved ejection fraction, LFLG AS patients exhibit marked concentric remodelling and impaired longitudinal functional-features that predict their poor long-term survival. Normal-flow, low-gradient AS patients have outcomes similar to moderate AS.

Bisphosphonate Use and Prevalence of Valvular and Vascular Calcification in Women: MESA (The Multi-Ethnic Study of Atherosclerosis)

OBJECTIVES the aim of this study was to determine whether nitrogen-containing bisphosphonate (NCBP) therapy is associated with the prevalence of cardiovascular calcification. BACKGROUND cardiovascular calcification correlates with atherosclerotic disease burden. Experimental data suggest that NCBP might limit cardiovascular calcification, which has implications for disease prevention. METHODS the relationship of NCBP use to the prevalence of aortic valve, aortic valve ring, mitral annulus, thoracic aorta, and coronary artery calcification (AVC, AVRC, MAC, TAC, and CAC, respectively) detected by computed tomography was assessed in 3,710 women within the MESA (Multi-Ethnic Study of Atherosclerosis) with regression modeling. RESULTS Analyses were age-stratified, because of a significant interaction between age and NCBP use (interaction p values: AVC p < 0.0001; AVRC p < 0.0001; MAC p = 0.002; TAC p < 0.0001; CAC p = 0.046). After adjusting for age; body mass index; demographic data; diabetes; smoking; blood pressure; cholesterol levels; and statin, hormone replacement, and renin-angiotensin inhibitor therapy, NCBP use was associated with a lower prevalence of cardiovascular calcification in women ≥ 65 years of age (prevalence ratio: AVC 0.68 [95% confidence interval (CI): 0.41 to 1.13]; AVRC 0.65 [95% CI: 0.51 to 0.84]; MAC 0.54 [95% CI: 0.33 to 0.93]; TAC 0.69 [95% CI: 0.54 to 0.88]; CAC 0.89 [95% CI: 0.78 to 1.02]), whereas calcification was more prevalent in NCBP users among the 2,181 women <65 years of age (AVC 4.00 [95% CI: 2.33 to 6.89]; AVRC 1.92 [95% CI: 1.42 to 2.61]; MAC 2.35 [95% CI: 1.12 to 4.84]; TAC 2.17 [95% CI: 1.49 to 3.15]; CAC 1.23 [95% CI: 0.97 to 1.57]). CONCLUSIONS among women in the diverse MESA cohort, NCBPs were associated with decreased prevalence of cardiovascular calcification in older subjects but more prevalent cardiovascular calcification in younger ones. Further study is warranted to clarify these age-dependent NCBP effects.

Outcomes of Transcatheter and Surgical Aortic Valve Replacement in High-Risk Patients With Aortic Stenosis and Left Ventricular Dysfunction Results From the Placement of Aortic Transcatheter Valves (PARTNER) Trial (Cohort A)

Background—The Placement of Aortic Transcatheter Valves (PARTNER) trial demonstrated similar survival after transcatheter and surgical aortic valve replacement (TAVR and SAVR, respectively) in high-risk patients with symptomatic, severe aortic stenosis. The aim of this study was to evaluate the effect of left ventricular (LV) dysfunction on clinical outcomes after TAVR and SAVR and the impact of aortic valve replacement technique on LV function. Methods and Results—The PARTNER trial randomized high-risk patients with severe aortic stenosis to TAVR or SAVR. Patients were stratified by the presence of LV ejection fraction (LVEF) <50%. All-cause mortality was similar for TAVR and SAVR at 30-days and 1 year regardless of baseline LV function and valve replacement technique. In patients with LV dysfunction, mean LVEF increased from 35.7±8.5% to 48.6±11.3% (P<0.0001) 1 year after TAVR and from 38.0±8.0% to 50.1±10.8% after SAVR (P<0.0001). Higher baseline LVEF (odds ratio, 0.90 [95% confidence interval, 0.86, 0.95]; P<0.0001) and previous permanent pacemaker (odds ratio, 0.34 [95% confidence interval, 0.15, 0.81]) were independently associated with reduced likelihood of ≥10% absolute LVEF improvement by 30 days; higher mean aortic valve gradient was associated with increased odds of LVEF improvement (odds ratio, 1.04 per 1 mm Hg [95% confidence interval, 1.01, 1.08]). Failure to improve LVEF by 30 days was associated with adverse 1-year outcomes after TAVR but not SAVR. Conclusions—In high-risk patients with severe aortic stenosis and LV dysfunction, mortality rates and LV functional recovery were comparable between valve replacement techniques. TAVR is a feasible alternative for patients with symptomatic severe aortic stenosis and LV dysfunction who are at high risk for SAVR. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894.

Recombinant apolipoprotein A-I Milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model

AIMS Aortic stenosis (AS) is associated with significant morbidity and mortality. Recombinant apolipoprotein A-I Milano (rApoA-I(M)) induces atherosclerotic plaque regression. The aims of this study were to determine the effects of rApoA-I(M) on experimental aortic valve degeneration and its mechanisms of action. METHODS AND RESULTS New Zealand White rabbits (n = 20) were fed an atherogenic diet for 9 months and then randomized to either placebo or rApoA-I(M). Echocardiography was used to assess the effect of the treatments on AS. Porcine aortic valve myofibroblasts (PAVMF) treated with oxidized low-density lipoprotein served to define the effects of rApoA-I(M) on the expression of monocyte chemoattractant protein-1 (MCP-1), nuclear factor (NF)-kappaB, and alkaline phosphatase (AP). Recombinant apolipoprotein A-I Milano increased aortic valve area (AVA) by 32% (0.25 +/- 0.05 to 0.34 +/- 0.07 cm(2), P < 0.01); whereas AVA remained unchanged in the placebo group (0.24 +/- 0.05 to 0.26 +/- 0.04 cm(2), P = 0.58). Histopathological examination of aortic valves in the rApoA-I(M) animals showed significantly less leaflet thickening, inflammation, and calcification vs. the placebo group. In vitro, rApoA-I(M) significantly inhibited MCP-1, AP, and NF-kappaB and decreased intracellular cholesterol content in PAVMF. CONCLUSION Recombinant apolipoprotein A-I Milano treatment reverses AS in this experimental rabbit model. The beneficial effects seem to be mediated by enhanced cholesterol removal and by reduced inflammation and calcification.

A Plasma Long-Chain Acylcarnitine Predicts Cardiovascular Mortality in Incident Dialysis Patients

Background The marked excess in cardiovascular mortality that results from uremia remains poorly understood. Methods and Results In 2 independent, nested case‐control studies, we applied liquid chromatography‐mass spectrometry‐based metabolite profiling to plasma obtained from participants of a large cohort of incident hemodialysis patients. First, 100 individuals who died of a cardiovascular cause within 1 year of initiating hemodialysis (cases) were randomly selected along with 100 individuals who survived for at least 1 year (controls), matched for age, sex, and race. Four highly intercorrelated long‐chain acylcarnitines achieved the significance threshold adjusted for multiple testing (P<0.0003). Oleoylcarnitine, the long‐chain acylcarnitine with the strongest association with cardiovascular mortality in unadjusted analysis, remained associated with 1‐year cardiovascular death after multivariable adjustment (odds ratio per SD 2.3 [95% confidence interval, 1.4 to 3.8]; P=0.001). The association between oleoylcarnitine and 1‐year cardiovascular death was then replicated in an independent sample (n=300, odds ratio per SD 1.4 [95% confidence interval, 1.1 to 1.9]; P=0.008). Addition of oleoylcarnitine to clinical variables improved cardiovascular risk prediction using net reclassification (NRI, 0.38 [95% confidence interval, 0.20 to 0.56]; P<0.0001). In physiologic profiling studies, we demonstrate that the fold change in plasma acylcarnitine levels from the aorta to renal vein and from pre‐ to post hemodialysis samples exclude renal or dialytic clearance of long‐chain acylcarnitines as confounders in our analysis. Conclusions Our data highlight clinically meaningful alterations in acylcarnitine homeostasis at the time of dialysis initiation, which may represent an early marker, effector, or both of uremic cardiovascular risk.

Platelet function normalization after a prasugrel loading‐dose: time‐dependent effect of platelet supplementation

Summary.  Background: Hemostatic benefits of platelet transfusions in thienopyridine‐treated acute coronary syndrome (ACS) patients may be compromised by residual metabolite in circulation.Objectives: To estimate the earliest time after a prasugrel loading‐dose when added platelets are no longer inhibited by prasugrels active metabolite.Methods: Baseline platelet reactivity of healthy subjects (n = 25, 30 ± 5 years, 68% male) on ASA 325 mg was tested using maximum platelet aggregation (MPA, ADP 20 μm) and VerifyNow® P2Y12 and was followed by a 60 mg prasugrel loading‐dose. At 2, 6, 12 and 24 h post‐dose, fresh concentrated platelets from untreated donors were added ex‐vivo to subjects’ blood, raising platelet counts by 0% (control), 40%, 60% and 80%. To estimate the earliest time when prasugrels active metabolites inhibitory effect on the added platelets ceases, platelet function in supplemented samples was compared across time‐points to identify the time when effect of supplementation on platelet function stabilized (i.e. the increase in platelet reactivity was statistically similar to that at the next time‐point).Results: Supplemented samples showed concentration‐dependent increases in platelet reactivity vs. respective controls by both MPA and VerifyNow® at all assessment time‐points. For each supplementation level, platelet reactivity showed a sharp increase from 2 to 6 h but was stable (P = NS) between 6 and 12 h.Conclusions: The earliest measured time when supplemented platelets were not inhibited by circulating active metabolite of prasugrel was 6 h after a prasugrel loading‐dose. These findings may have important implications for prasugrel‐treated ACS patients requiring platelet transfusions during surgery.