Transcatheter edge-to-edge repair for mitral regurgitation using PASCAL or MitraClip.

BACKGROUND: There is a paucity of data regarding the comparative efficacy and safety of Mitral valve transcatheter edge-to-edge repair (MTEER) using the PASCAL or MitraClip systems for patients with mitral regurgitation (MR). METHODS: An electronic search was conducted for MEDLINE, COCHRANE, and EMBASE, through February 2023, for studies comparing the clinical outcomes of MTEER using PASCAL versus MitraClip systems among patients with severe MR. The primary study outcome was residual MR ≤ 2 at discharge. Data were pooled using a random-effects model. RESULTS: The final analysis included six studies with a total of 1581 patients, with a weighted follow-up period of 3.5 months. Two studies only included patients with degenerative MR, while the remaining studies included both degenerative and functional MR. There was no significant difference in procedure duration between MTEER with the PASCAL or MitraClip systems. There was no difference in residual MR ≤ 2 at discharge (94.7% vs. 91.9%; odds ratio [OR]: 1.44; 95% confidence interval [CI]: 0.92-2.27) or residual MR ≤ 2 at the mid-term follow-up (94.6% vs. 91.0%, p = 0.05) among the PASCAL versus MitraClip systems. There was no difference between both groups in residual MR ≤ 1 at discharge (73.1% vs. 63.8%, p = 0.12), while there was greater incidence of residual MR ≤ 1 at midterm follow-up with the PASCAL system (71.3% vs. 56.2%, p < 0.001). There was no difference between the PASCAL and MitraClip MTEER systems in technical success (97.0% vs. 97.9%, p = 0.15), procedural success (89.1% vs. 87.1%, p = 0.78), single leaflet detachment (1.8% vs. 1.4%, p = 0.55), or all-cause mortality (3.6% vs. 4.6%, p = 0.71). CONCLUSION: In this meta-analysis, we demonstrated comparable efficacy and safety between the PASCAL and MitraClip MTEER systems at short- and mid-term assessments. Randomized trials are warranted to evaluate the comparative long-term outcomes between both MTEER systems.

A common Matrix metalloproteinase 8 promoter haplotype enhances the risk for hypertension via diminished interactions with nuclear factor kappa B.

OBJECTIVES: Matrix metalloproteinase 8 (MMP8) has a prominent role in collagen turnover in blood vessels and vascular remodeling. The contribution of regulatory single nucleotide polymorphisms in MMP8 to cardiovascular diseases is unclear. We aimed to delineate the influence of MMP8 promoter variations on hypertension. METHODS: A case-control study in unrelated individuals ( n  = 2565) was carried out. Resequencing of the MMP8 proximal promoter, linkage disequilibrium analysis, genotyping of variants and regression analyses were performed. MMP8 promoter-reporter constructs were generated and expressed in human vascular endothelial cells under various conditions. RESULTS: We identified four single nucleotide polymorphisms (SNPs) in the promoter region of MMP8 : -1089A/G (rs17099452), -815G/T (rs17099451), -795C/T (rs11225395), -763A/T (rs35308160); these SNPs form three major haplotypes. Hap3 (viz., GTTT haplotype) carriers showed significant associations with hypertension in two geographically distinct human populations (e.g., Chennai: odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.16-1.86, P  = 2 × 10 -3 ; Chandigarh: OR = 1.85, 95% CI = 1.21-2.81, P  = 4 × 10 -3 ). Hap3 carriers also displayed elevated systolic blood pressure, diastolic blood pressure and mean arterial pressure levels. Hap3 promoter-reporter construct showed lower promoter activity than the wild-type (Hap1) construct. In silico analysis and molecular dynamics studies predicted diminished binding of the transcription factor nuclear factor kappa B (NF-κB) to the functional -815T allele of Hap3 compared to the -815G wild-type allele; this prediction was validated by in-vitro experiments. Hap3 displayed impaired response to tumor necrosis factor-alpha treatment, possibly due to weaker binding of NF-κB. Notably, MMP8 promoter haplotypes were identified as independent predictors of plasma MMP8 and endothelial dysfunction markers (von Willebrand factor and endothelin-1) levels. CONCLUSION: MMP8 promoter GTTT haplotype has a functional role in reducing MMP8 expression during inflammation via diminished interaction with NF-κB and in enhancing the risk of hypertension.

Multimodality imaging assessment of bicuspid aortic valve disease, thoracic aortic ectasia, and thoracic aortic aneurysmal disease.

Acute aortic syndromes have extremely high mortality rates and those with aortic dilation are at increased risk for these often catastrophic events. Serial monitoring of patients with aortic dilation is critical to determine the appropriate timing of preventative interventions. The thoracic aorta can be imaged and measured using multiple imaging modalities including transthoracic echocardiography, transesophageal echocardiography, multidetector cardiac computed tomography, and magnetic resonance imaging. There has not been agreement on the specific techniques that should be used to measure thoracic aortic dimensions with each imaging modality, leading to potential errors and challenges in comparing changes in measurements over time. It is critical to understand the current recommendations on thoracic aortic measurements for each imaging modality and cardiovascular imaging specialists need to be explicit about the methods that they have used to derive the thoracic aortic measurements. In those at high risk for aortic pathology, such as those with connective tissue diseases or bicuspid aortic valve, a multimodality imaging strategy incorporating echocardiography including three-dimensional measurements along with cardiac computed tomography or magnetic resonance imaging should be used to establish aortic dimensions and for continued monitoring to avoid progression to acute aortic syndromes.

Dual Antiplatelet Therapy After Percutaneous Coronary Intervention and Drug-Eluting Stents: A Systematic Review and Network Meta-Analysis.

BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with drug-eluting stents remains uncertain. We compared short-term (<6-month) DAPT followed by aspirin or P2Y12 inhibitor monotherapy; midterm (6-month) DAPT; 12-month DAPT; and extended-term (>12-month) DAPT after percutaneous coronary intervention with drug-eluting stents. METHODS: Twenty-four randomized, controlled trials were selected using Medline, Embase, Cochrane library, and online databases through September 2019. The coprimary end points were myocardial infarction and major bleeding, which constituted the net clinical benefit. A frequentist network meta-analysis was conducted with a random-effects model. RESULTS: In 79 073 patients, at a median follow-up of 18 months, extended-term DAPT was associated with a reduced risk of myocardial infarction in comparison with 12-month DAPT (absolute risk difference, -3.8 incident cases per 1000 person-years; relative risk, 0.68 [95% CI, 0.54-0.87]), midterm DAPT (absolute risk difference, -4.6 incident cases per 1000 person-years; relative risk, 0.61 [0.45-0.83]), and short-term DAPT followed by aspirin monotherapy (absolute risk difference, -6.1 incident cases per 1000 person-years; relative risk, 0.55 [0.37-0.83]), or P2Y12 inhibitor monotherapy (absolute risk difference, -3.7 incident cases per 1000 person-years; relative risk, 0.69 [0.51-0.95]). Conversely, extended-term DAPT was associated with a higher risk of major bleeding than all other DAPT groups. In comparison with 12-month DAPT, no significant differences in the risks of ischemic end points or major bleeding were observed with midterm or short-term DAPT followed by aspirin monotherapy, with the exception that short-term DAPT followed by P2Y12 inhibitor monotherapy was associated with a reduced risk of major bleeding. There were no significant differences with respect to mortality between the different DAPT strategies. In acute coronary syndrome, extended-term in comparison with 12-month DAPT was associated with a reduced risk of myocardial infarction without a significant increase in the risk of major bleeding. CONCLUSIONS: The present network meta-analysis suggests that, in comparison with 12-month DAPT, short-term DAPT followed by P2Y12 inhibitor monotherapy reduces major bleeding after percutaneous coronary intervention with drug-eluting stents, whereas extended-term DAPT reduces myocardial infarction at the expense of more bleeding events.

Remnant cholesterol, coronary atheroma progression and clinical events in statin-treated patients with coronary artery disease.

AIM: Remnant cholesterol has been proposed to promote atherosclerotic cardiovascular disease independent of low-density lipoprotein cholesterol, yet the underlying mechanisms are not well understood. We aimed to study the association of remnant cholesterol with coronary atheroma progression and clinical events. METHODS: We analyzed data from 5754 patients with coronary artery disease undergoing serial intravascular ultrasonography who were enrolled in 10 trials examining various medical therapies. Remnant cholesterol was calculated as (non-high-density lipoprotein cholesterol - low-density lipoprotein cholesterol (estimated using the Hopkins-Martin equation)). Changes in percentage atheroma volume and 2-year major adverse cardiovascular events were compared across various levels of remnant cholesterol, and multivariable models were used to assess the independent relationship of remnant cholesterol with changes in percentage atheroma volume. RESULTS: The mean age was 58.1 ± 9.2 years, 28% were women and 96% received a statin. Percentage atheroma volume progression (changes in percentage atheroma volume > 0) occurred in a linear fashion at on-treatment remnant cholesterol levels of 25 mg/dL or greater. The highest on-treatment remnant cholesterol quartile demonstrated greater percentage atheroma volume progression (+0.53 ± 0.26 vs. -0.15 ± 0.25%, P < 0.001) and 2-year major adverse cardiovascular events (23% vs. 14%, log-rank P < 0.001) compared with the lowest. In multivariable analyses, changes in percentage atheroma volume significantly correlated with on-treatment remnant cholesterol (P < 0.001] independent of low-density lipoprotein cholesterol, apolipoprotein B, C-reactive protein, high-density lipoprotein cholesterol levels and clinical risk factors. Changes in percentage atheroma volume also significantly correlated with changes in remnant cholesterol following multivariable adjustment. CONCLUSIONS: In statin-treated patients with atherosclerotic cardiovascular disease, remnant cholesterol was associated with coronary atheroma progression regardless of conventional lipid parameters, C-reactive protein or clinical risk factors. Higher remnant cholesterol levels also correlated with higher major adverse cardiovascular events. These data support further investigations into remnant cholesterol-lowering interventions in statin-treated patients harboring residual atherosclerotic cardiovascular disease risk.

Cardiovascular complications of systemic sclerosis: What to look for.

Systemic sclerosis, an autoimmune disease characterized by fibrosis of the skin and various internal organs, is associated with cardiovascular abnormalities including pulmonary hypertension, atherosclerosis, right and left ventricular dysfunction, arrhythmias, conduction defects, pericardial disease, and valvular heart disease. Clinicians caring for patients with this disease should regularly screen for cardiac symptoms, and patients with abnormal findings should be managed in conjunction with a cardiologist to optimally modify cardiovascular risks.

Association of Initial and Serial C-Reactive Protein Levels With Adverse Cardiovascular Events and Death After Acute Coronary Syndrome: A Secondary Analysis of the VISTA-16 Trial.

Importance: Higher baseline high-sensitivity C-reactive protein (hsCRP) levels after an acute coronary syndrome (ACS) are associated with adverse cardiovascular outcomes. The usefulness of serial hsCRP measurements for risk stratifying patients after ACS is not well characterized. Objective: To assess whether longitudinal increases in hsCRP measurements during the 16 weeks after ACS are independently associated with a greater risk of a major adverse cardiac event (MACE), all-cause death, and cardiovascular death. Design, Setting, and Participants: Secondary analysis of the double-blind, multicenter, randomized clinical Vascular Inflammation Suppression to Treat Acute Coronary Syndromes for 16 Weeks (VISTA-16) trial conducted between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012), which included 5145 patients from 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America assigned to receive varespladib or placebo on a background of atorvastatin treatment beginning within 96 hours of presentation with an ACS. The present study evaluated data from patients with available baseline and longitudinal hsCRP levels measured at weeks 1, 2, 4, 8, and 16 after randomization to treatment or placebo. Statistical analysis was performed from June 15, 2018, through September 15, 2018. Main Outcomes and Measures: Outcomes were MACE (composite of cardiovascular death, myocardial infarction, nonfatal stroke, or unstable angina with documented ischemia requiring hospitalization), cardiovascular death, and all-cause death after adjustment for baseline clinical, treatment, and laboratory characteristics, including baseline hsCRP levels. Results: Among 4257 patients in this study, 3141 (73.8%) were men and the mean age was 60.3 years (interquartile range [IQR], 53.5-67.8 years). The median 16-week low-density lipoprotein cholesterol level was 64.9 mg/dL (IQR, 50.3-82.3 mg/dL), and the median hsCRP level was 2.4 mg/L (IQR, 1.1-5.2 mg/L). On multivariable analysis, higher baseline hsCRP level (hazard ratio [HR], 1.36 [95% CI, 1.13-1.63]; P = .001) and higher longitudinal hsCRP level (HR, 1.15 [95% CI, 1.09-1.21]; P < .001) were independently associated with MACE. Similar significant and independent associations were shown between baseline and longitudinal hsCRP levels and cardiovascular death (baseline: HR, 1.61 per SD [95% CI, 1.07-2.41], P = .02; longitudinal: HR, 1.26 per SD [95% CI, 1.19-1.34], P < .001) and between baseline and longitudinal hsCRP levels and all-cause death (baseline: HR, 1.58 per SD [95% CI, 1.07-2.35], P = .02; longitudinal: HR, 1.25 per SD [95% CI, 1.18-1.32], P < .001). Conclusions and Relevance: Initial and subsequent increases in hsCRP levels during 16 weeks after ACS were associated with a greater risk of the combined MACE end point, cardiovascular death, and all-cause death despite established background therapies. Serial measurements of hsCRP during clinical follow-up after ACS may help to identify patients at higher risk for mortality and morbidity.

The association between HDL particle concentration and incident metabolic syndrome in the multi-ethnic Dallas Heart Study.

AIMS: Metabolic syndrome (MetS) increases atherosclerotic cardiovascular disease (ASCVD) risk. Low HDL cholesterol (HDL-C) is a diagnostic criterion of MetS and a major ASCVD risk factor. HDL particle concentration (HDL-P) associates with incident ASCVD independent of HDL-C, but its association with incident MetS has not been studied. We hypothesized that HDL-P would be inversely associated with incident metabolic syndrome independent of HDL-C and markers of adiposity and insulin resistance. MATERIALS AND METHODS: HDL-P was measured by NMR and visceral fat by MRI in participants of the Dallas Heart Study, a probability-based population sample of adults age 30-65. Participants with prevalent MetS, DM, CVD, and any systemic illlness were excluded. Incident MetS as defined by NCEP ATPIII criteria was determined in all participants after median follow-up period of 7.0 years. RESULTS: Among 1120 participants without DM or MetS at baseline (57% women, 45% Black, mean age 43), 22.8% had incident MetS at follow-up. HDL-P and HDL-C were modestly correlated (r=0.54, p<0.0001). In models adjusted for traditional risk factors and MetS risk factors including visceral fat, HS-CRP, triglyceride to HDL-C ratio, and HOMA-IR, the lowest quartile of HDL-P was associated with a 2-fold increased risk of incident MetS (OR 2.1, 95%CI 1.4-3.1; p=0.0003). CONCLUSIONS: Low HDL-P is independently associated with incident MetS after adjustment for traditional risk factors, lipid parameters, adiposity, inflammation, and markers of insulin resistance. Further studies are warranted to validate these findings and elucidate the mechanisms underpinning this association.

Premature coronary heart disease and autosomal dominant hypercholesterolemia: Increased risk in women with LDLR mutations.

BACKGROUND: For patients with autosomal dominant hypercholesterolemia (ADH), it remains unclear whether differences exist in the risk of premature coronary heart disease (CHD) between patients with confirmed mutations in low-density lipoprotein receptor (LDLR) vs those without detectable mutations. OBJECTIVE: This study sought to assess the risk of premature CHD in ADH patients with mutations in LDLR (referred to as familial hypercholesterolemia [FH]) vs those without detectable mutations (unexplained ADH), stratified by sex. METHODS: Comparative study of premature CHD in a multiethnic cohort of 111 men and 165 women meeting adult Simon-Broome criteria for ADH. RESULTS: Women with FH (n = 51) had an increased risk of premature CHD compared with unexplained ADH women (n = 111; hazard ratio [HR], 2.74; 95% confidence interval, 1.40-5.34; P = .003) even after adjustment for lipid levels and traditional CHD risk factors (HR, 2.53 [1.10-5.83]; P = .005). Men with FH (n = 42), in contrast, had a similar risk of premature CHD when compared with unexplained ADH men (n = 66; unadjusted: HR, 1.48 [0.84-2.63]; P = .18; adjusted: HR, 1.04 [0.46-2.37]; P = .72). To address whether mutation status provides additional information beyond LDL-cholesterol level, we analyzed premature CHD risk for FH vs unexplained ADH at various percentiles of LDL-cholesterol: the risk ratios were significant for women at 25th percentile (HR, 4.90 [1.69-14.19]) and 50th percentile (HR, 3.44 [1.42-8.32]) but not at 75th percentile (HR, 1.99 [0.95-4.17]), and were not significant for men at any percentile. CONCLUSIONS: Our findings suggest that genetic confirmation of ADH may be important to identify patient's risk of CHD, especially for female LDLR mutation carriers.

HDL function and subclinical atherosclerosis in juvenile idiopathic arthritis.

BACKGROUND: Increasing evidence suggests that inflammation adversely impacts the protective properties of high-density lipoproteins (HDL) and progression of atherosclerosis. The impact of early chronic inflammatory conditions on HDL function and vascular risk has not been well investigated. METHODS: We compared measures of HDL particle distribution and functionality, in addition to measures of carotid intima-medial thickness (cIMT) in patients with juvenile idiopathic arthritis (JIA) and age matched controls. RESULTS: JIA patients demonstrated lower levels of HDL cholesterol [47.0 (40.0, 56.0) vs. 56.0 (53.0, 61.0) mg/dL, P=0.04], total HDL [29.5 (27.9, 32.3) vs. 32.9 (31.6, 36.3) mg/dL, P=0.05] and large HDL [5.1 (3.7, 7.3) vs. 8.0 (6.7, 9.7) mg/dL, P=0.04] particles. In association JIA patients demonstrated greater cholesterol efflux mediated via ATP binding cassette A1 (ABCA1) [17.3% (12.8, 19.7) vs. 10.0% (5.8, 16.0), P=0.05] and less efflux mediated via ATP binding cassette G-1 (ABCG1) [3.2% (2.0, 3.9) vs. 4.8% (3.5, 5.8), P=0.01] and SR-B1 [6.9% (6.0, 8.4) vs. 9.1% (8.6, 10.2), P=0.002] compared with controls. Exposure of macrophages to serum from JIA patients resulted in a smaller increase in mRNA expression of ABCA1 (2.0±0.95 vs. 7.1±5.7 fold increase, P=0.01) and greater increases in expression of ABCG1 [1.4 (0.9, 1.5) vs. 0.8 (0.7, 1.1) fold increase, P=0.04] and SR-B1 (1.3±0.47 vs. 0.7±0.3 fold increase, P=0.001) compared with controls. Arylesterase (128.9±27.6 vs. 152.0±45.2 umoles/min/mL, P=0.04) activity and endothelial cell migration (491.2±68.9 vs. 634.2±227.4 cells/field, P=0.01) were less in JIA patients. No differences in cIMT were observed between JIA patients and controls. CONCLUSIONS: The presence of JIA was associated with alterations in HDL particle distribution, cholesterol efflux and non-lipid transporting activities. The ultimate implication of these findings for cardiovascular risk requires further investigation.

Niacin Therapy, HDL Cholesterol, and Cardiovascular Disease: Is the HDL Hypothesis Defunct?

High-density lipoprotein cholesterol (HDL-C) has been shown in epidemiologic studies to be associated with cardiovascular (CV) risk and thus significant efforts have been focused on HDL-C modulation. Multiple pharmaceutical agents have been developed with the goal of increasing HDL-C. Niacin, the most widely used medication to raise HDL-C, increases HDL-C by up to 25 % and was shown in multiple surrogate end point studies to reduce CV risk. However, two large randomized controlled trials of niacin, AIM-HIGH and HPS2-THRIVE, have shown that despite its effects on HDL-C, niacin does not decrease the incidence of CV events and may have significant adverse effects. Studies of other classes of agents such as cholesteryl ester transfer protein (CETP) inhibitors have also shown that even dramatic increases in HDL-C do not necessarily translate to reduction in clinical events. While these findings have cast doubt upon the importance of HDL-C modulation on CV risk, it is becoming increasingly clear that HDL function-related measures may be better targets for CV risk reduction. Increasing ApoA-I, the primary apolipoprotein associated with HDL, correlates with reduced risk of events, and HDL particle concentration (HDL-P) inversely associates with incident CV events adjusted for HDL-C and LDL particle measures. Cholesterol efflux, the mechanism by which macrophages in vessel walls secrete cholesterol outside cells, correlates with both surrogate end points and clinical events. The effects of niacin on these alternate measures of HDL have been conflicting. Further studies should determine if modulation of these HDL function markers translates to clinical benefits. Although the HDL cholesterol hypothesis may be defunct, the HDL function hypothesis is now poised to be rigorously tested.

Relation of high-density lipoprotein cholesterol:apolipoprotein a-I ratio to progression of coronary atherosclerosis in statin-treated patients.

High-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels are inversely associated with adverse cardiovascular outcomes. Associations between these HDL-C-related measurements and coronary plaque progression have not been studied. We performed a retrospective analysis of 2,566 statin-treated patients with angiographic coronary artery disease who underwent serial evaluation of atheroma burden with intravascular ultrasound. Relations between achieved levels of HDL-related measurements with clinical characteristics and changes in plaque burden were determined. A strong correlation between HDL-C and apoA-I (r = 0.80, p <0.001) was observed. HDL-C, apoA-I, and the HDL-C:apoA-I ratio demonstrated negative correlations with the change in percent atheroma volume and total atheroma volume (all p ≤0.001). Increasing levels of achieved HDL-C:apoA-I (p = 0.04), but not HDL-C (p = 0.18) or apoA-I (p = 0.67), were associated with less progression of percent atheroma volume. Similar results were seen for change in total atheroma volume, with less progression seen with increased HDL-C:apoA-I (p = 0.002) but not with increases in HDL-C (p = 0.09) or apoA-I (p = 0.19). In conclusion, increasing levels of HDL-C:apoA-I associated with less progression of coronary atherosclerosis. This suggests that interventions increasing the cholesterol content of HDL particles may be of cardiovascular benefit.

YouTube and inflammatory bowel disease.

UNLABELLED: Background and aims Nearly half of all patients with inflammatory bowel disease (IBD) use the Internet as a source of information for their disease. We analyzed the source, content and accuracy of IBD videos found on YouTube - one of the most popular websites in the United States - and assessed the demographic variables of the viewers. METHODS: The 100 most viewed videos with relevant information on IBD were analyzed. We included only English language videos that were less than 20 min in length and primarily focused on IBD. Those with no sound/poor sound quality were excluded. More than 30 variables were analyzed. RESULTS: Adults of 45-54 years old (95.1%) comprised the most common age group of viewers. Forty-eight percent of videos focused on Crohn's disease (CD), 32.0% on ulcerative colitis (UC), and 20.0% on both. Overall content for patient education was poor. Videos discussing alternative treatment options were more likely to depict patients' personal experience (73.9% vs. 2.4%) (p<0.001) and be an advertisement compared to patient education videos (78.3% vs. 0) (p<0.001). Videos discussing patient education had a higher number of favorites (mean 25.0 vs. 5.5) (p<0.001), comments (mean 22.0 vs. 5.0) (p<0.022) and "likes" (mean 19.0 vs. 9.0) (p=0.025) than the ones discussing alternative treatment options. CONCLUSIONS: YouTube videos on IBD are popular but a poor source of patient education. Healthcare providers and professional societies should provide more educational materials using this powerful Internet tool to counteract the misleading information, especially for the targeted age group (45-54 years).

Visualizing canonical Wnt signaling during mouse craniofacial development.

Wnt signaling is critical for proper development of the head and face in the mouse embryo, playing important roles in various aspects of craniofacial development ranging from axis formation to survival of cranial neural crest cells to patterning of the brain. The signaling requirements for the development of different cell lineages in the head and face are active areas of investigation. In this study, we use a recently developed TCF/Lef-LacZ transgenic reporter mouse to characterize the expression of canonical Wnt signaling activity during craniofacial development. We present an atlas of representative sections to show embryonic craniofacial development. Our results demonstrate a pattern of sustained Wnt signaling reporter activity in most tissues which suggests sequential roles in craniofacial development.