Beware of an anomalous left circumflex artery when considering aortic valve or root procedures.

Anomalous coronary arteries pose an additional challenge when contemplating surgical options for a patient with aortic valve or root pathology. We demonstrate the course of an anomalous retro-aortic left circumflex coronary artery arising from the right coronary sinus in a patient with an aortic root and ascending aortic aneurysm with severe aortic regurgitation who underwent ascending aorta and aortic valve replacements.

Surgical timing in infective endocarditis complicated by intracranial hemorrhage.

Given the growing incidence of infective endocarditis (IE), understanding the risks and benefits of valvular surgery is critical. This decision is particularly complex for the 1 in 10 cases complicated by intracranial hemorrhage (ICH). While guideline recommendations currently favor early surgery in general, delayed intervention of at least 4 weeks is still recommended for patients with ICH. To date, there are no randomized controlled trials that inform management of patients with an indication for surgery but concomitant ICH, and even reported observational data are rare. This paper reviews the current literature on timing of surgery with a specific focus on cases of ICH. It emphasizes a growing body of literature challenging the current paradigm that surgery within 4 weeks is associated with neurologic deterioration and high mortality rates by demonstrating favorable outcomes for patients with pre-operative ICH who undergo early valvular surgery. Based on these data, we propose a practical management algorithm to facilitate decisions on surgical timing in these complicated cases. Since more rigorous evidence may never be available, clinicians should make patient-specific surgical timing decisions that attempt to balance the competing risks of neurologic versus cardiac complications.

Clinical Correlates and Prognostic Value of Elevated Right Atrial Pressure in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: The clinical characteristics associated with elevated right atrial pressure (RAP) in hypertrophic cardiomyopathy (HCM) are unknown. Few data exist as to whether elevated RAP has prognostic implications in patients with HCM. This study investigated the clinical correlates and prognostic value of elevated RAP in HCM.Methods and Results:This retrospective cohort study was performed on 180 patients with HCM who underwent right heart catheterization between 1997 and 2014. Elevated RAP was defined as >8 mmHg. Baseline characteristics, mean pulmonary artery pressure, and mean pulmonary capillary wedge pressure (PCWP) were assessed for association with elevated RAP. The predictive value of elevated RAP for all-cause mortality and the development of atrial fibrillation (AF), ventricular tachycardia/fibrillation (VT/VF), and stroke was evaluated. Elevated RAP was associated with higher New York Heart Association class, dyspnea on exertion, orthopnea, edema, jugular venous distention, larger left atrial size, right ventricular hypertrophy, higher pulmonary artery pressure, and higher PCWP. RAP independently predicted all-cause mortality (adjusted hazard ratio [aHR] 2.18 per 5-mmHg increase, 95% confidence interval [CI] 1.05-4.50, P=0.04) and incident AF (aHR 1.85 per 5-mmHg increase, 95% CI 1.20-2.85, P=0.005). Elevated RAP did not predict VT/VF (P=0.36) or stroke (P=0.28). CONCLUSIONS: Elevated RAP in patients with HCM is associated with left-sided heart failure and is an independent predictor of all-cause mortality and new-onset AF.

Late repair of ischemic mitral regurgitation does not prevent left ventricular remodeling: importance of timing for beneficial repair.

BACKGROUND: Ischemic mitral regurgitation (MR) is a frequent complication of myocardial infarction associated with left ventricular (LV) dilatation and dysfunction, which doubles mortality. At the molecular level, moderate ischemic MR is characterized by a biphasic response, with initial compensatory rise in prohypertrophic and antiapoptotic signals, followed by their exhaustion. We have shown that early MR repair 30 days after myocardial infarction is associated with LV reverse remodeling. It is not known whether MR repair performed after the exhaustion of compensatory mechanisms is also beneficial. We hypothesized that late repair will not result in LV reverse remodeling. METHODS AND RESULTS: Twelve sheep underwent distal left anterior descending coronary artery ligation to create apical myocardial infarction and implantation of an LV-to-left atrium shunt to create standardized moderate volume overload. At 90 days, animals were randomized to shunt closure (late repair) versus sham (no repair). LV remodeling was assessed by 3-dimensional echocardiography, dP/dt, preload-recruitable stroke work, and myocardial biopsies. At 90 days, animals had moderate volume overload, LV dilatation, and reduced ejection fraction (all P<0.01 versus baseline, P=NS between groups). Shunt closure at 90 days corrected the volume overload (regurgitant fraction 6 ± 5% versus 27 ± 16% for late repair versus sham, P<0.01) but was not associated with changes in LV volumes (end-diastolic volume 106 ± 15 versus 110 ± 22 mL; end-systolic volume 35 ± 6 versus 36 ± 6 mL) or increases in preload-recruitable stroke work (41 ± 7 versus 39 ± 13 mL mm Hg) or dP/dt (803 ± 210 versus 732 ± 194 mm Hg/s) at 135 days (all P=NS). Activated Akt, central in the hypertrophic process, and signal transducer and activator of transcription 3 (STAT3), a critical node in the hypertrophic stimulus by cytokines, were equally depressed in both groups. CONCLUSIONS: Late correction of moderate volume overload after myocardial infarction did not improve LV volume or contractility. Upregulation of prohypertrophic intracellular pathways was not observed. This contrasts with previously reported study in which early repair (30 days) reversed LV remodeling. This suggests a window of opportunity to repair ischemic MR after which no beneficial effect on LV is observed, despite successful repair.

Localization of coronary bypass targets in hard-to-see coronary arteries.

BACKGROUND: Precise identification of coronary arteries and selection of anastomotic sites are critical stages of coronary bypass surgery. Visualization of coronary arteries is occasionally challenging when the heart is covered with a thick layer of fat or scar tissue. In this paper, we review the methods to localize the coronary arteries during coronary surgery. METHODS: Prior publications were searched to summarize all available methods for localization of coronary arteries during coronary surgery. RESULTS: Five clinically recognized and three experimental techniques from the literature review are reviewed and summarized. CONCLUSIONS: Knowledge of various techniques of coronary artery identification in hard-to-see coronary arteries is an important asset in coronary surgery and especially useful during the most critical option of the most common heart surgery.

The Role of Angiogenesis and Arteriogenesis in Myocardial Infarction and Coronary Revascularization.

Surgical myocardial revascularization is associated with long-term survival benefit in patients with multivessel coronary artery disease. However, the exact biological mechanisms underlying the clinical benefits of myocardial revascularization have not been elucidated yet. Angiogenesis and arteriogenesis biologically leading to vascular collateralization are considered one of the endogenous mechanisms to preserve myocardial viability during ischemia, and the presence of coronary collateralization has been regarded as one of the predictors of long-term survival in patients with coronary artery disease (CAD). Some experimental studies and indirect clinical evidence on chronic CAD confirmed an angiogenetic response induced by myocardial revascularization and suggested that revascularization procedures could constitute an angiogenetic trigger per se. In this review, the clinical and basic science evidence regarding arteriogenesis and angiogenesis in both CAD and coronary revascularization is analyzed with the aim to better elucidate their significance in the clinical arena and potential therapeutic use.

Relation of Subacute Kidney Injury to Mortality After Transcatheter Aortic Valve Implantation.

Acute kidney injury after transcatheter aortic valve implantation (TAVI) has been associated with adverse outcomes; however, data are limited on the subacute changes in renal function that occur after discharge and their impact on clinical outcomes. This study investigates the relation between subacute changes in kidney function at 30 days after TAVI and survival. Patients from 2 centers who underwent TAVI and survived beyond 30 days with baseline, in-hospital, and 30-day measures of renal function were retrospectively analyzed. Patients were stratified based on change in estimated glomerular filtration rate (eGFR) from baseline to 30 days as follows: improved (≥15% higher than baseline), worsened (≤15% lower), or unchanged (values in between). Univariable and multivariable models were constructed to identify predictors of subacute changes in renal function and of 2-year mortality. Of the 492 patients who met inclusion criteria, eGFR worsened in 102 (22%), improved in 110 (22%), and was unchanged in 280 (56%). AKI occurred in 90 patients (18%) and in only 27% of patients with worsened eGFR at 30 days. After statistical adjustment, worsened eGFR at 30 days (hazard ratio vs unchanged eGFR 2.09, 95% CI 1.37 to 3.19, p <0.001) was associated with worse survival, whereas improvement in renal function was not associated with survival (hazard ratio vs unchanged eGFR 1.30, 95% CI 0.79 to 2.11, p = 0.30). Worsened renal function at 30 days after TAVI is associated with increased mortality after TAVI. In conclusion, monitoring renal function after discharge may identify patients at high risk of adverse outcomes.

Association Between Early Left Ventricular Ejection Fraction Improvement After Transcatheter Aortic Valve Replacement and 5-Year Clinical Outcomes.

Importance: In patients with severe aortic stenosis and left ventricular ejection fraction (LVEF) less than 50%, early LVEF improvement after transcatheter aortic valve replacement (TAVR) is associated with improved 1-year mortality; however, its association with long-term clinical outcomes is not known. Objective: To examine the association between early LVEF improvement after TAVR and 5-year outcomes. Design, Setting, and Participants: This cohort study analyzed patients enrolled in the Placement of Aortic Transcatheter Valves (PARTNER) 1, 2, and S3 trials and registries between July 2007 and April 2015. High- and intermediate-risk patients with baseline LVEF less than 50% who underwent transfemoral TAVR were included in the current study. Data were analyzed from August 2020 to May 2021. Exposures: Early LVEF improvement, defined as increase of 10 percentage points or more at 30 days and also as a continuous variable (ΔLVEF between baseline and 30 days). Main Outcomes and Measures: All-cause death at 5 years. Results: Among 659 included patients with LVEF less than 50%, 468 (71.0%) were male, and the mean (SD) age was 82.4 (7.7) years. LVEF improvement within 30 days following transfemoral TAVR occurred in 216 patients (32.8%) (mean [SD] ΔLVEF, 16.4 [5.7%]). Prior myocardial infarction, diabetes, cancer, higher baseline LVEF, larger left ventricular end-diastolic diameter, and larger aortic valve area were independently associated with lower likelihood of LVEF improvement. Patients with vs without early LVEF improvement after TAVR had lower 5-year all-cause death (102 [50.0%; 95% CI, 43.3-57.1] vs 246 [58.4%; 95% CI, 53.6-63.2]; P = .04) and cardiac death (52 [29.5%; 95% CI, 23.2-37.1] vs 135 [38.1%; 95% CI, 33.1-43.6]; P = .05). In multivariable analyses, early improvement in LVEF (modeled as a continuous variable) was associated with lower 5-year all-cause death (adjusted hazard ratio per 5% increase in LVEF, 0.94 [95% CI, 0.88-1.00]; P = .04) and cardiac death (adjusted hazard ratio per 5% increase in LVEF, 0.90 [95% CI, 0.82-0.98]; P = .02) after TAVR. Restricted cubic spline analysis demonstrated a visual inflection point at ΔLVEF of 10% beyond which there was a steep decline in all-cause mortality with increasing degree of LVEF improvement. There were no statistically significant differences in rehospitalization, New York Heart Association functional class, or Kansas City Cardiomyopathy Questionnaire Overall Summary score at 5 years in patients with vs without early LVEF improvement. In subgroup analysis, the association between early LVEF improvement and 5-year all-cause death was consistent regardless of the presence or absence of coronary artery disease or prior myocardial infarction. Conclusions and Relevance: In patients with severe aortic stenosis and LVEF less than 50%, 1 in 3 experience LVEF improvement within 1 month after TAVR. Early LVEF improvement is associated with lower 5-year all-cause and cardiac death.

Mitral leaflet adaptation to ventricular remodeling: prospective changes in a model of ischemic mitral regurgitation.

BACKGROUND: Ischemic mitral regurgitation is caused by systolic traction on the mitral leaflets related to ventricular distortion. Little is known about how chronic tethering affects leaflet area, in part because it cannot be measured repeatedly in situ. Recently, a new method for 3D echocardiographic measurement of mitral leaflet area was developed and validated in vivo against sheep valves, later excised. Clinical studies (n=80) showed that mitral leaflet area increased by >30% in patients with inferior myocardial infarction and dilated cardiomyopathy versus normal; greater adaptation independently predicted less mitral regurgitation. This study explored whether mitral valve area changes over time within the same heart with ischemic mitral regurgitation. METHODS AND RESULTS: Twelve sheep were studied at baseline and 3 months after inferior myocardial infarction by 3D echocardiography; 6 were untreated and 6 were treated initially with an epicardial patch to limit left ventricular dilation and mitral regurgitation. Untreated sheep developed left ventricular dilation at 3 months, with global dysfunction (mean+/-SD ejection fraction, 24+/-10% versus 44+/-10% with patching, P=0.02) and moderate mitral regurgitation (vena contracta, 5.0+/-1.0 versus 0.8+/-1.0 mm, P<0.0002). In untreated sheep, total diastolic leaflet area increased from 13.1+/-1.3 to 18.1+/-2.5 cm(2) (P=0.0001). In patched sheep, leaflet area at 3 months was not significantly different from baseline sheep values (13.0+/-1.1 versus baseline, 12.1+/-1.8 cm(2), P=0.31). CONCLUSIONS: Mitral valve area, independent of systolic stretch, increases over time as the left ventricular remodels after inferior myocardial infarction. This increase, however, fails to compensate adequately for tethering to prevent mitral regurgitation. Understanding the mechanism of valve adaptation can potentially suggest new biological and surgical therapeutic targets.

Association of Pulmonary Hypertension With Clinical Outcomes of Transcatheter Mitral Valve Repair.

Importance: Pulmonary hypertension (pHTN) is associated with increased risk of mortality after mitral valve surgery for mitral regurgitation. However, its association with clinical outcomes in patients undergoing transcatheter mitral valve repair (TMVr) with a commercially available system (MitraClip) is unknown. Objective: To assess the association of pHTN with readmissions for heart failure and 1-year all-cause mortality after TMVr. Design, Setting, and Participants: This retrospective cohort study analyzed 4071 patients who underwent TMVr with the MitraClip system from November 4, 2013, through March 31, 2017, across 232 US sites in the Society of Thoracic Surgery/American College of Cardiology Transcatheter Valve Therapy registry. Patients were stratified into the following 4 groups based on invasive mean pulmonary arterial pressure (mPAP): 1103 with no pHTN (mPAP, <25 mm Hg [group 1]); 1399 with mild pHTN (mPAP, 25-34 mm Hg [group 2]); 1011 with moderate pHTN (mPAP, 35-44 mm Hg [group 3]); and 558 with severe pHTN (mPAP, ≥45 mm Hg [group 4]). Data were analyzed from November 4, 2013, through March 31, 2017. Interventions: Patients were stratified into groups before TMVr, and clinical outcomes were assessed at 1 year after intervention. Main Outcomes and Measures: Primary end point was a composite of 1-year mortality and readmissions for heart failure. Secondary end points were 30-day and 1-year mortality and readmissions for heart failure. Linkage to Centers for Medicare & Medicaid Services administrative claims was performed to assess 1-year outcomes in 2381 patients. Results: Among the 4071 patients included in the analysis, the median age was 81 years (interquartile range, 73-86 years); 1885 (46.3%) were women and 2186 (53.7%) were men. The composite rate of 1-year mortality and readmissions for heart failure was 33.6% (95% CI, 31.6%-35.7%), which was higher in those with pHTN (27.8% [95% CI, 24.2%-31.5%] in group 1, 32.4% [95% CI, 29.0%-35.8%] in group 2, 36.0% [95% CI, 31.8%-40.2%] in group 3, and 45.2% [95% CI, 39.1%-51.0%] in group 4; P < .001). Similarly, 1-year mortality (16.3% [95% CI, 13.4%-19.5%] in group 1, 19.8% [95% CI, 17.0%-22.8%] in group 2, 22.4% [95% CI, 18.8%-26.1%] in group 3, and 27.8% [95% CI, 22.6%-33.3%] in group 4; P < .001) increased across pHTN groups. The association of pHTN with mortality persisted despite multivariable adjustment (hazard ratio per 5-mm Hg mPAP increase, 1.05; 95% CI, 1.01-1.09; P = .02). Conclusions and Relevance: These findings suggest that pHTN is associated with increased mortality and readmission for heart failure in patients undergoing TMVr using the MitraClip system for severe mitral regurgitation. Further efforts are needed to determine whether earlier intervention before pHTN develops will improve clinical outcomes.

Mitral leaflet adaptation to ventricular remodeling: occurrence and adequacy in patients with functional mitral regurgitation.

BACKGROUND: Functional mitral regurgitation (MR) is caused by systolic traction on the mitral leaflets related to ventricular distortion. Little is known about whether chronic tethering causes the mitral leaflet area to adapt to the geometric needs imposed by tethering, in part because of inability to reconstruct leaflet area in vivo. Our aim was to explore whether adaptive increases in leaflet area occur in patients with functional MR compared with normal subjects and to test the hypothesis that leaflet area influences MR severity. METHODS AND RESULTS: A new method for 3-dimensional echocardiographic measurement of mitral leaflet area was developed and validated in vivo against 15 sheep heart valves, later excised. This method was then applied in 80 consecutive patients from 3 groups: patients with normal hearts by echocardiography (n=20), patients with functional MR caused by isolated inferior wall-motion abnormality or dilated cardiomyopathy (n=29), and patients with inferior wall-motion abnormality or dilated cardiomyopathy but no MR (n=31). Leaflet area was increased by 35+/-20% in patients with LV dysfunction compared with normal subjects. The ratio of leaflet to annular area was 1.95+/-0.40 and was not different among groups, which indicates a surplus leaflet area that adapts to left-heart changes. In contrast, the ratio of total leaflet area to the area required to close the orifice in midsystole was decreased in patients with functional MR compared with those with normal hearts (1.29+/-0.15 versus 1.78+/-0.39, P=0.001) and compared with patients with inferior wall-motion abnormality or dilated cardiomyopathy but no MR (1.81+/-0.38, P=0.001). After adjustment for measures of LV remodeling and tethering, a leaflet-to-closure area ratio <1.7 was associated with significant MR (odds ratio 23.2, 95% confidence interval 2.0 to 49.1, P=0.02). CONCLUSIONS: Mitral leaflet area increases in response to chronic tethering in patients with inferior wall-motion abnormality and dilated cardiomyopathy, but the development of significant MR is associated with insufficient leaflet area relative to that demanded by tethering geometry. The varying adequacy of leaflet adaptation may explain in part the heterogeneity of this disease among patients. The results suggest the need to understand the mechanisms that underlie leaflet adaptation and whether leaflet area can potentially be modified as part of the therapeutic approach.

A novel approach for reducing ischemic mitral regurgitation by injection of a polymer to reverse remodel and reposition displaced papillary muscles.

BACKGROUND: Ischemic mitral regurgitation (MR) relates to displacement of the papillary muscles from ischemic ventricular distortion. We tested the hypothesis that repositioning of the papillary muscles can be achieved by injection of polyvinyl-alcohol (PVA) polymer, a biologically inert biomaterial that has been specially formulated to produce an encapsulated, stable, resilient gel once injected into the myocardium. The purpose is to materially support the infarcted myocardium while at the same time repositioning the papillary muscles that become apically tethered in MR. METHODS AND RESULTS: Nine sheep underwent ligation of circumflex branches to produce acute ischemic MR. PVA polymer was then injected by echo guidance into the myocardium underlying the infarcted papillary muscle. Hemodynamic data, left ventricular ejection fraction, elastance, tau (relaxation constant), left ventricular stiffness coefficient, and 2-dimensional and 3-dimensional echocardiograms were obtained post-MR and post-PVA injection. One animal died after coronary ligation and 2 did not develop MR. In the remaining 6, moderate MR developed. With PVA injection, the MR decreased significantly from moderate to trace-mild (vena contracta: 5+/-0.4 mm versus 2+/-0.7 mm, post-MR versus post-PVA injection; P<0.0001). This was associated with a decrease in infarcted papillary muscle-to-mitral annulus tethering distance (27+/-4 to 24+/-4 mm, post-MR versus post-PVA, P<0.001). Importantly, PVA injection was not associated with significant decreases in left ventricular ejection fraction (43+/-6% versus 37+/-4%, post-MR versus post-PVA, P=nonsignificant), elastance (3.5+/-1.4 versus 2.9+/-1.3; post-MR versus post-PVA injection, P=nonsignificant). Measures of left ventricular diastolic function, tau (100+/-51 ms to 84+/-37 ms, post-MR versus post-PVA; P=nonsignificant), and left ventricular stiffness coefficient (0.18+/-0.12 versus 0.14+/-0.08, post-MR versus post-PVA; P=nonsignificant) did not increase post-PVA. CONCLUSIONS: PVA polymer injection resulted in acute reverse remodeling of the ventricle with papillary muscle repositioning to decrease MR. This was not associated with an adverse effect on left ventricular systolic and diastolic function. This new approach to alter pathological anatomy after infarction may offer an alternative strategy for relieving ischemic MR by correcting the position of the affected papillary muscle, thus relieving apical tethering.

Transcatheter Versus Surgical Aortic Valve Replacement in Low-Risk Patients.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has emerged as a safe and effective therapeutic option for patients with severe aortic stenosis (AS) who are at prohibitive, high, or intermediate risk for surgical aortic valve replacement (SAVR). However, in low-risk patients, SAVR remains the standard therapy in current clinical practice. OBJECTIVES: This study sought to perform a meta-analysis of randomized controlled trials (RCTs) comparing TAVR versus SAVR in low-risk patients. METHODS: Electronic databases were searched from inception to March 20, 2019. RCTs comparing TAVR versus SAVR in low-risk patients (Society of Thoracic Surgeons Predicted Risk of Mortality [STS-PROM] score <4%) were included. Primary outcome was all-cause death at 1 year. Random-effects models were used to calculate pooled risk ratio (RR) and corresponding 95% confidence interval (CI). RESULTS: The meta-analysis included 4 RCTs that randomized 2,887 patients (1,497 to TAVR and 1,390 to SAVR). The mean age of patients was 75.4 years, and the mean STS-PROM score was 2.3%. Compared with SAVR, TAVR was associated with significantly lower risk of all-cause death (2.1% vs. 3.5%; RR: 0.61; 95% CI: 0.39 to 0.96; p = 0.03; I2 = 0%) and cardiovascular death (1.6% vs. 2.9%; RR: 0.55; 95% CI: 0.33 to 0.90; p = 0.02; I2 = 0%) at 1 year. Rates of new/worsening atrial fibrillation, life-threatening/disabling bleeding, and acute kidney injury stage 2/3 were lower, whereas those of permanent pacemaker implantation and moderate/severe paravalvular leak were higher after TAVR versus SAVR. There were no significant differences between TAVR versus SAVR for major vascular complications, endocarditis, aortic valve re-intervention, and New York Heart Association functional class ≥II. CONCLUSIONS: In this meta-analysis of RCTs comparing TAVR versus SAVR in low-risk patients, TAVR was associated with significantly lower risk of all-cause death and cardiovascular death at 1 year. These findings suggest that TAVR may be the preferred option over SAVR in low-risk patients with severe AS who are candidates for bioprosthetic AVR.

Early repair of moderate ischemic mitral regurgitation reverses left ventricular remodeling: a functional and molecular study.

BACKGROUND: Mitral regurgitation (MR) doubles postmyocardial infarction (MI) mortality. We have shown that moderate MR augments remodeling in an apical MI model (no intrinsic MR) with independent left ventricle-to-left atrial MR-type flow. We hypothesized that repairing moderate MR 1 month after MI reverses this remodeling. METHODS AND RESULTS: Anteroapical MIs were created in 18 sheep, and a left ventricle-to-left atrial shunt implanted in 12 (regurgitant fraction, 30%). Six sheep had the shunt closed at 1 month (repair group). Sheep were compared at baseline, and at 1 and 3 months. Sheep in the MI+MR (unrepaired) and repaired groups remodeled during the first month (120% increased left ventricular end-systolic volume [ESV; P<0.01]), but shunt closure reversed remodeling at 3 months, with end-diastolic volume (EDV) and ESV 135% and 128% of baseline versus 220% and 280% without repair (P<0.001). At 3 months, dP/dt and preload-recruitable stroke work were relatively maintained in the repaired and MI-only groups versus nearly 50% decreases without repair. Prohypertrophic gp130 and antiapoptotic pAkt increased followed by exhaustion below baseline without repair, but remained elevated at 3 months with repair or MI only. With repair, matrix metalloproteinase-2 decreased to < or = 50% that without repair in remote and border zones at 3 months, and the matrix metalloproteinase inhibitor TIMP-4 increased dramatically. CONCLUSIONS: Early repair of moderate MR in the setting of apical MI substantially reverses the otherwise progressive remodeling process, with reduced left ventricular volumes, relatively maintained contractility, persistently activated intracellular signals promoting hypertrophy and opposing apoptosis, and reduced matrix proteolytic activity. These findings are of interest for the current controversy regarding potential benefits of repair of MR after MI.

Application of polymer-mesh device to remodel left ventricular-mitral valve apparatus in ischemic mitral regurgitation.

OBJECTIVES: Ischemic mitral regurgitation (IMR) results from ischemic left ventricular (LV) distortion and remodeling, which displaces the papillary muscles and tethers the mitral valve leaflets apically. The aim of this experimental study was to examine efficacy of an adjustable novel polymer filled mesh (poly-mesh) device to reverse LV remodeling and reduce IMR. METHODS: Acute (N = 8) and chronic (8 weeks; N = 5) sheep models of IMR were studied. IMR was produced by ligation of circumflex branches to create myocardial infarction. An adjustable poly-mesh device was attached to infarcted myocardium in acute and chronic IMR models and compared with untreated sham sheep. Two- and 3-dimensional echocardiography and hemodynamic measurements were performed at baseline, post IMR, and post poly-mesh (humanely killed). RESULTS: In acute models, moderate IMR developed in all sheep and decreased to trace/mild (vena contracta: 0.50 ± 0.09 cm to 0.26 ± 0.12 cm; P < .01) after poly-mesh. In chronic models, IMR decreased in all sheep after poly-mesh, and this reduction persisted over 8 weeks (vena contracta: 0.42 ± 0.09 cm to 0.08 ± 0.12 cm; P < .01) with significant increase in the slope of end-systolic pressure-volume relationship (1.1 ± 0.5 mm Hg/mL to 2.9 ± 0.7 mm Hg/mL; P < .05). There was a significant reduction in LV volumes from chronic IMR to euthanasia stage with poly-mesh compared with sham group (%end-diastolic volume change -20 ± 11 vs 15% ± 16%, P < .01; %end-systolic volume change -14% ± 19% vs 22% ± 22%, P < .05; poly-mesh vs sham group) consistent with reverse remodeling. CONCLUSIONS: An adjustable polymer filled mesh device reduces IMR and prevents continued LV remodeling during chronic follow-up.

Common Coding Variants in SCN10A Are Associated With the Nav1.8 Late Current and Cardiac Conduction.

BACKGROUND: Genetic variants at the SCN5A/SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. METHODS: We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology. RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium (r 2=0.86) with each other to be the strongest signals for PR (rs10428132, ß=-4.74, P=1.52×10-14) and QRS intervals (rs6599251, QRS ß=-0.73; P=1.2×10-4), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium (r 2≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P=0.03, and I962V+V1073A, 22.4±0.8%, P=0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P=0.03). CONCLUSIONS: Our findings suggest an association between genetic variation in SCN10A, the late sodium current, and alterations in cardiac conduction.