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Supplemental Digital Content is available in the text.Ventricular arrhythmias are common following left ventricular assist device implantation (LVAD), and the effects of ventricular tachycardia (VT) ablation on thrombosis and embolic events are unknown. We aimed to assess LVAD thrombosis, stroke, and embolic event rates after VT ablation. Left ventricular assist device implantation patients from two academic centers who underwent endocardial VT ablation between 2009 and 2016 were compared to a control group with VT who were not ablated and followed for one year. The primary composite outcome was confirmed or suspected LVAD thrombosis, stroke, or other embolic event. Survival analysis was conducted with Kaplan-Meier curves, log-rank tests, and Cox regression. Forty-three LVAD patients underwent VT ablation, and 73 LVAD patients had VT but were not ablated. Patients who were ablated were more likely have VT prior to LVAD (p= 0.04), monomorphic VT (p< 0.01), and to be on antiarrhythmics (p< 0.01). Fifty-eight percent of the patients in the ablation group experienced the primary composite outcome (11% had confirmed device thrombosis [DT], 41% suspected DT, 39% had a stroke or embolic event) compared to 30% in the control group (12% with confirmed DT, 11% with suspected DT, 14% with stroke or embolic event) (p= 0.002). In multivariable regression, ablation was an independent predictor of the primary composite outcome (hazard ratios, 2.24; 95% confidence interval, 1.09–4.61; p= 0.03). Patients with LVADs referred for endocardial VT ablation had elevated rates of DT and embolic events.

Left ventricular (LV) unloading with a LV assist device (LVAD) reverse remodels the heart and may lead to favorable changes in cellular architecture and LV geometry promoting myocardial recovery. Currently, there are no standardized methods for evaluating myocardial recovery. This study assesses the systolic slope of the LVAD outflow cannula as a marker for myocardial contractility. Doppler echocardiography (transthoracic echocardiogram [TTE]) of the LVAD outflow cannula and TTE of the LV cavity were prospectively collected in 57 patients with LVADs. Systolic acceleration of the LVAD outflow cannula was measured in each patient as the peak change of velocity over time (dv/dt) during systole from continuous-wave Doppler signal acquired from the LVAD outflow cannula. Ventricular volumes were concurrently measured by TTE. In a subset of 10 patients, the systolic slope was measured during each stage of a ramp study to study the properties of this parameter across a variety of loading conditions. The systolic slope of the LVAD outflow cannula was successfully measured in 53 of 57 patients (93%). Systolic slope strongly correlated with ejection fraction (EF) (R= 0.92). Analysis of systolic slope stratified by EF (EF >30%, EF 20–30%, EF 10–20%, and EF <10%) revealed systolic slopes that were significantly different between the groups (1,371 cm/s2± 324; 983 cm/s2± 122; 578 cm/s2± 139; and 495 cm/s2± 107, respectively; p< 0.001). Systolic slope did not change significantly across variable preload and afterload conditions during a ramp study. Systolic slope of the LVAD outflow cannula strongly correlates with EF and can be used to assess underlying myocardial contractility across a variety of LVAD loading conditions.

Cardiac resynchronization therapy (CRT) and left ventricular assist devices (LVADs) are common heart failure therapies; however, little is known regarding the concomitant use of these devices. We aim to evaluate unloading differences in LVAD patients with and without active biventricular pacing. Left ventricular assist device patients with and without CRT prospectively underwent ramp hemodynamic/echocardiographic testing. Patients with >95% biventricular pacing comprised the active CRT pacing group; all others (no device, implantable cardioverter defibrillator only, CRT without biventricular pacing) were categorized into the non-CRT pacing group. Invasive hemodynamics and echocardiographic characteristics (left ventricular end-diastolic/systolic diameter and valvular regurgitation) were measured at baseline and at incremental speed changes. Unloading slopes were calculated using linear regression modeling for individual hemodynamics and echocardiographic characteristics across speeds. Among 62 LVAD patients (age 59.6 ± 11.4 years, 60% male), 25 had active CRT pacing. There was no significant difference in echocardiographic or hemodynamic characteristics at baseline or final set speeds between CRT groups. Similarly, no significant differences were noted in the unloading characteristics. In LVAD patients, active biventricular pacing is unlikely to improve echocardiographic or hemodynamic characteristics.

Background:Fascia-wrapped diced cartilage grafts have become a useful tool in modern rhinoplasty surgery. Unfortunately, fascial harvest is associated with donor site morbidity; therefore, a nonautologous alternative to fascia would be ideal. Decellularized porcine mesothelium (PM), Meso BioMatrix™, is an acellular scaffold that could potentially fill this need. To determine if PM could serve as an acceptable alternative, we histologically compared diced cartilage grafts wrapped in fascia versus PM.Methods:Human rib cartilage and temporoparietal fascia were obtained under an IRB-approved protocol. Cartilage was diced into 0.5 mm pieces and implanted in subcutaneous pockets in nude rats. Implanted materials included cartilage alone, cartilage wrapped in fascia, cartilage wrapped in PM, fascia alone, or PM alone. Specimens were harvested at 8 weeks and stained with hematoxylin and eosin, Masson's trichrome, Safranin-O, and Verhoeff's stain to assess cartilage viability, architecture, and regenerative potential.Results:Unwrapped diced cartilage showed the highest cartilage viability, but was associated with loss of contour and dispersion of the cartilage pieces. Meso BioMatrix-wrapped grafts maintained contour and cartilage pieces had not dispersed; however, there was a significantly lower number of nucleated lacunae and a greater amount of basophilia than both fascia-wrapped cartilage and unwrapped cartilage. There was no significant difference in cartilage resorption between fascia-wrapped cartilage and Meso BioMatrix-wrapped cartilage or in the proteoglycan or collagen content between all groups.Conclusion:Off-the-shelf decellularized PM was associated with lower cartilage viability than unprocessed fascial allograft. No cartilage piece dispersion, fibrosis, resorption, or a foreign body reaction to Meso BioMatrix was observed. PM, although not equivalent to autologous tissue, may be utilized to achieve acceptable clinical results and be a viable alternative that limits donor side morbidity. This experimental study supports further clinical investigation of this material in rhinoplasty procedures.

Reverse remodelling is the process by which failing myocardium demonstrates normative changes in chamber geometry and function, and might also include correction of molecular and transcriptional abnormalitiesAdvances in sequencing technologies have allowed for detailed analysis of transcriptome changes in the setting of reverse remodelling, including non-coding RNAs such as microRNAs and long non-coding RNAsDespite evidence of reverse remodelling, numerous abnormalities in myocardial transcriptome, metabolism, and extracellular matrix persist, supporting the concept that myocardial remission is distinct from myocardial recoveryThe newly proposed phenotype of 'heart failure with improved ejection fraction' highlights the clinical course of 'remission' with relapses in heart failure symptoms despite improvement in ventricular structure and function

Background: MicroRNAs are small noncoding RNA molecules that play a critical role in regulating physiological and disease processes. Recent studies have now recognized microRNAs as an important player in cardiac arrhythmogenesis. Molecular insight into arrhythmogenic cardiomyopathy (AC) has primarily focused on mutations in desmosome proteins. To our knowledge, models of AC due to microRNA dysregulation have not been reported. Previously, we reported on miR-130a mediated down-regulation of Connexin43. Objective: Here, we investigate miR-130a-mediated translational repression of Desmocollin2 (DSC2), as it has a predicted target site for miR-130a. DSC2 is an important protein for cell adhesion, which has been shown to be dysregulated in human AC. Method & Results: After induction of miR-130a, transgenic mice demonstrated right ventricular dilation. Surface ECG revealed spontaneous premature ventricular complexes confirming an arrhythmogenic phenotype in αMHC-miR130a mice. Using total protein from whole ventricular lysate, western blot analysis demonstrated an 80% reduction in DSC2 levels in transgenic myocardium. Furthermore, immunofluorescent staining confirmed downregulation of DSC2 in transgenic compared with littermate control myocardium. In transgenic hearts, histologic findings revealed fibrosis and lipid accumulation within both ventricles. To validate DSC2 as a direct target of miR-130a, we performed in vitro target assays in 3T3 fibroblasts, known to express miR-130a. Using a luciferase reporter fused to the 3UTR of DSC2 compared with a control, we found a 42% reduction in luciferase activity with the DSC2 3UTR. This reduction was reversed upon selective inhibition of miR-130a. Conclusion: Overexpression of miR-130a results in a disease phenotype characteristic of AC and therefore, may serve as potential model for microRNA-induced AC.

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This study tested whether combined invasive hemodynamic and echocardiographic ramp tests can help optimize patient management.

We aim to evaluate the echocardiographic/hemodynamic effects of left ventricular assist devices in African American (AA) versusnon-AA patients undergoing ramp speed optimization and its subsequent effect on readmissions. In 65 patients (26 AA), no differences in baseline echocardiographic/hemodynamic parameters were noted. During ramp testing, there was a significantly greater increase in cardiac output (slope: 0.29 ± 0.24 vs. 0.15 ± 0.12, p< 0.01) with more rapid decrease in left ventricular end-diastolic diameter (slope: −0.21 ± 0.14 vs. −0.13 ± 0.07 L/min, p< 0.01) in the AA group. AAs had higher all-cause, but similar heart failure readmission rate as compared with the non-AA group.

Epigenetics refers to changes in phenotype and gene expression that occur without alterations in DNA sequence. Epigenetic modifications of the genome can be acquired de novo and are potentially heritable. This review focuses on the emerging recognition of a role for epigenetics in the development of pulmonary arterial hypertension (PAH). Lessons learned from the epigenetics in cancer and neurodevelopmental diseases, such as Prader-Willi syndrome, can be applied to PAH. These syndromes suggest that there is substantial genetic and epigenetic cross-talk such that a single phenotype can result from a genetic cause, an epigenetic cause, or a combined abnormality. There are three major mechanisms of epigenetic regulation, including methylation of CpG islands, mediated by DNA methyltransferases, modification of histone proteins, and microRNAs. There is substantial interaction between these epigenetic mechanisms. Recently, it was discovered that there may be an epigenetic component to PAH. In PAH there is downregulation of superoxide dismutase 2 (SOD2) and normoxic activation of hypoxia inducible factor (HIF-1α). This decrease in SOD2 results from methylation of CpG islands in SOD2 by lung DNA methyltransferases. The partial silencing of SOD2 alters redox signaling, activates HIF-1α) and leads to excessive cell proliferation. The same hyperproliferative epigenetic abnormality occurs in cancer. These epigenetic abnormalities can be therapeutically reversed. Epigenetic mechanisms may mediate gene-environment interactions in PAH and explain the great variability in susceptibility to stimuli such as anorexigens, virus, and shunts. Epigenetics may be relevant to the female predisposition to PAH and the incomplete penetrance of BMPR2 mutations in familial PAH.

Vitamin D inhibits renin expression and blocks the compensatory induction of renin associated with the use of renin-angiotensin system inhibitors. Here we test the therapeutic effects of two commonly used vitamin D analogs and their combination with losartan on the development of left ventricular hypertrophy. One-month-old male spontaneously hypertensive rats were treated with vehicle, losartan, paricalcitol, doxercalciferol, a combination of losartan and paricalcitol, or a combination of losartan and doxercalciferol for 2 months. Blood pressure was markedly reduced by losartan, but not by paricalcitol or doxercalciferol alone. Echocardiograpy demonstrated a 65 to 80% reduction in left ventricular wall thickness with losartan, paricalcitol, or doxercalciferol monotherapy and almost complete prevention of left ventricular hypertrophy with the combination therapies. Attenuation of cardiac and cardiomyocyte hypertrophy, and suppression of atrial and brain natriuretic peptides, were most marked in the combination therapy groups. These changes were well correlated with left ventricular gene and microRNA expression profiles in the different treatment groups. Renal and cardiac renin expression was markedly increased in losartan-treated animals, but nearly normalized with combination therapy. The same vitamin D analogs suppressed plasma renin activity in patients receiving chronic hemodialysis. These data demonstrate that vitamin D analogs have potent antihypertrophic activity in part via suppression of renin in the kidney and heart, and combination of these analogs with losartan achieves much better therapeutic effects because of the blockade of the compensatory renin increase.

Introduction:Both invasive hemodynamics as measured by right heart catheterization (RHC) and cardiopulmonary exercise testing (CPET) are used for prognostication in advanced heart failure patients. We aimed to compare the prognostic performance of these variables in patients with advanced heart failure with a particular focus on defining the incremental prognostication of advanced hemodynamic metrics compared to CPET variables.Methods:We retrospectively analyzed patients who underwent both a RHC and CPET within one year of each other from January 2013 to January 2019 at our institution. The CPET variables of peak oxygen consumption (VO2), minute ventilation/carbon dioxide production (VE/VCO2), oxygen pulse (VO2/HR), and the RHC variables of left ventricular stroke work index (LVSWI), cardiac power output (CPO), and aortic pulsatility index (API) were used. The primary outcome was death, left ventricular assist device, or heart transplant at one year following the RHC.Results:A total of 55 patients were included in the analysis: 35% women, 51% Black, and 27% ischemic cardiomyopathy. Overall, using Spearman’s analysis, there were no significant correlations between the RHC and CPET variables. On Kaplan-Meier analysis, lower LVSWI was significantly associated with the primary outcome when compared to lower VO2/HR, HR 5.3 (95% CI 1.2-23, p = 0.02.), lower VE/VCO2, HR 3.7 (95% CI 1.3-10.4, p = 0.014), and lower peak VO2, HR 7.0 (95% CI 0.9-56, p = 0.06).Conclusion:LVSWI is more associated with one-year outcomes in patients with advanced heart failure than other prognostic hemodynamic or CPET variables. Furthermore, advanced hemodynamic metrics are more prognostic than CPET measurements when these values are discordant.

Introduction:Hyponatremia is associated with increased morbidity and mortality in heart failure (HF) patients. The implication of hyponatremia post-left ventricular assist device (LVAD) remains unknown.Hypothesis:We hypothesized that LVAD patients with hyponatremia would have increased morbidity and mortality.Methods:A retrospective study of VAD patients between 4/2014-3/2018. Patients with LVAD exchange or right VAD implantation were excluded. Patients were stratified by the presence of hyponatremia (Na<135) at 30 days post-LVAD. Clinical variables included Na levels pre-LVAD and up through 1-year post-LVAD. HF readmissions and survival during 1-year follow-up were compared between the groups.Results:Of 204 patients identified, 170 with LVAD implantation were included in the study. Mean age was 55, 31% were male, and 29% had ischemic cardiomyopathy. Na levels improved from pre-LVAD to 1-year (135.9 ? 4.5 mEq/L to 138.9 ? 3.7 mEq/L, P<0.001). At 30 days, 35 patients were in the hyponatremia group and 135 patients were in the control group. No significant difference was observed for 1-year survival between the groups (81% vs. 77%, P=0.66; Figure 1A). The control group had significantly better 1-year freedom from HF readmission compared to the hyponatremia group (85% vs. 56%, P=0.001; Figure 1B). Among patients with normonatremia (N=110), those who developed de novo hyponatremia (N=17) had lower freedom from HF readmission than those who remained normonatremic (55% vs. 84%, P=0.022; Figure 1C). Among patients with hyponatremia (N=60), those who had persistent hyponatremia (N=18) had decreased freedom from HF readmission than those who improved to normonatremia (56% vs. 88%, P=0.008; Figure 1D).Conclusions:Hyponatremia in LVAD patients is associated with increased HF readmissions but not increased mortality. Further studies need to elucidate whether therapies directed at hyponatremia (tolvaptan) would improve outcomes in LVAD patients.

J Am Acad Dermatol 2003;48:600-1.