Clavell, Alfredo L.

Abstract Background Heart transplant (HTx) patients can develop graft dysfunction (GD) without biopsy evidence of cell or antibody mediated rejection. Cardiac MRI (CMR) can detect inflammatory or infiltrative causes of cardiomyopathy however CMR findings in HTx recipients with GD have not been previously described. Purpose We sought to identify CMR characteristics of HTx patients with GD, and evaluate its additive value in its diagnosis and prognosis. Methods CMR has been performed routinely to evaluate GD at our institutions. There were 37 HTx recipients who presented with acute decline in left ventricular ejection fraction (LVEF) of <50% and >10% from baseline, with no biopsy evidence of rejection between 2007 and 2018. Coronary angiogram with IVUS was done to rule out allograft vasculopathy. Treatment of GD was per discretion of the treating clinician. Responders were defined as those with LVEF improvement >10% at 180 days or greater post-presentation. LV and RV indices, the presence and pattern of late gadolinium enhancement (LGE) were determined by CMR. Results There were 34% females and mean age at transplant was 49±13 years. Median time from HTx to GD was 1.2 years. Presenting symptoms were heart failure (n=25), cardiogenic shock (n=1) and 11 patients were asymptomatic. Mean LVEF at presentation was 37±12% and donor specific antibodies were detected in 38% patients. Most patients were treated with steroid bolus (n=29), and/or plasmapheresis (n=23). There were no major changes made in immunosuppression in 6 patients. Delayed enhancement MRI was performed with standard inversion-recovery (IR) gradient echo sequences, between 5 and 20 minutes after institutional-standard protocol administration of IV gadolinium contrast. Biventricular LGE was present in 18/37 (49%) patients with GD and was more prevalent in responders (57%, 13 of 23) than non-responders (35%, 5 of 14), although not statistically significant (p=0.21). There were two patterns of LGE noted: 1) Diffuse epicardial (10 patients out which 9 were responders) and 2) Patchy pattern with non-specific distribution (8 patients out of which 4 were responders). Myocardial edema by triple IR sequencing was seen in 6 patients, all having diffuse epicardial pattern of enhancement matching the delayed enhancement pattern. When comparing different treatment groups, among those treated for GD (n=31), 12 of 21 (57%) responders had LGE and 4 of 10 (40%) non-responders had LGE (p=0.37), a pattern similar to the broader population. Among those not treated for GD (n=6), 1 of 2 responders had LGE and 1 of 4 non-responders had LGE (p=0.5). Conclusion CMR identified inflammation as a potential cause of GD in approximately 50% of HTx patients. There are 2 distinct patterns of LGE observed in GD, diffuse epicardial (56%) and patchy (44%). Although the presence of LGE in itself is not associated with myocardial recovery, 90% of patients with a diffuse epicardial pattern have recovery of GD. Funding Acknowledgement Type of funding source: None

Abstract Objectives Right ventricular (RV) failure occurring after left ventricular assist device (LVAD) implantation is associated with increased mortality. Purpose We sought to determine whether RV strain by echocardiography predicts outcomes following LVAD. Methods Consecutive patients who underwent continuous flow LVAD placement at our clinic between February 2007 and October 2018 were included. Patients with complex congenital heart disease and arrhythmogenic right ventricular cardiomyopathy were excluded. Baseline characteristics, pre-operative hemodynamic catheterization (1 week) transthoracic echocardiography (1 month) measurements were obtained from the medical record. Speckle tracking RV free wall longitudinal 2D strain was measured using TomTec Imaging System. Univariate and multivariable analysis performed to identify predictors of mortality following LVAD. Results The study group was comprised of 323 patients (mean age 60.8±11.5, 79.9% male) of which 256 had adequate image quality for RV strain. RV strain was impaired in most patients (mean −11.7±3.47). RV strain of −8.1% was identified as predictive of poor outcomes. RV strain did not correlate with other measures of RV dysfunction including pulmonary artery pulsatility index (PAPi) and RVFAC. After adjusting for PAPi, RA pressure, and clinical cumulative risk scores (Matthews, Kormos and Lietz-Miller) impaired RV free wall longitudinal strain (OR: 1.14; 95% CI: 1.01–1.29, p=0.025), tricuspid regurgitation (by vena contracta width (TRvc) (OR: 1.19; 95% CI: 1.05–1.36, p=:0.0021) and smaller LVEDD (OR: 0.95; 95% CI: 0.92–0.99, p:0.023) predicted 30-day all-cause mortality and RV failure. Decreased RV free wall strain also predicted peri-operative mortality (22.58% vs. 4.89%, p=0.0003) and prolonged inotropic support (247.0.±277.4 vs. 122.8±139.3, p=0.024). Conclusions RV free wall strain is a non-invasive independent predictor of 30-day adverse outcomes (RV failure or all-cause mortality) Routine measurement of RV free strain may identify those patients at highest risk for early and long term mortality following LVAD. Funding Acknowledgement Type of funding source: None

AbstractA combined right and left‐sided heart catheterization (RHC/LHC) protocol was recently reported to optimize patients supported by left ventricular assist device (LVAD). Using this platform, we sought to evaluate the prognostic significance of several hemodynamic indices, including left ventricular end‐diastolic pressure (LVEDP) and transaortic gradient (peak aortic pressure ‐ peak left ventricular pressure in systole, TAG). We evaluated all patients undergoing RHC/LHC at our institution from 2015 through 2018, and comprehensive clinical data were obtained. Primary end points were (1) a composite outcome that included hospitalization or death and (2) 1‐year overall survival after catheterization. Forty‐two patients were included in the analysis. Optimization resulted in normalization of hemodynamic parameters; all variables were significantly improved from baseline (P ≤ .05). On univariate modeling, final LVEDP was associated with the primary end point (hazard ratio [HR], 1.2 per 1‐mm Hg increase; 95% CI, 1.1‐1.3; P = .002). After adjusting for LVAD speed, TAG, and cardiac index in a multivariate model, the association between LVEDP and the composite end point remained significant (HR, 1.2 per 1‐mm Hg increase; 95% CI, 1.1‐1.4; P = .001). In the setting of LVAD support, inadequate LV unloading was a significant marker of poor outcomes with time, suggesting that LVEDP is a central prognostic marker in this population.

There is a paucity of data describing the invasive assessment of afterload and influence on cardiac output in patients supported on left ventricular assist device (LVAD) therapy. From 2015 to 2018, patients on LVAD therapy were evaluated with simultaneous left/right heart catheterization ramp study for speed optimization. Hemodynamic parameters from 31 patients without significant aortic insufficiency were analyzed. Mean central aortic pressure (MAP) was elevated at 87 ± 13 mm Hg at baseline. No direct association between MAP and cardiac index (CI) was found (r = 0.11, p = 0.20). However, variable MAP provided vastly different patterns of cardiac output response to speed increments (positive correlation, p = 0.047 for MAP <80 mm Hg; negative trend, p = 0.25 for MAP > 100 mm Hg). Patients noted to be hypertensive (MAP > 90, n = 8) received nitrate therapy and experienced both improvement in biventricular filling pressures and a mean increase in CI from 2.4 to 2.9 L/min/m2 (+22%, p = 0.04) at a fixed revolutions per minute. High afterload is common in patients on LVAD therapy, is associated with poor response to ramp, and is ameliorated by nitrates. These findings serve as a foundation to evaluate the dynamic effects of high afterload and chronic vasodilator therapy in patients with durable LVADs.

Background The presence of a durable left ventricular assist device ( LVAD ) is associated with increased risk of vasoplegia in the early postoperative period following heart transplantation ( HT ). However, preoperative predictors of vasoplegia and its impact on survival after HT are unknown. We sought to examine predictors and outcomes of patients who develop vasoplegia after HT following bridging therapy with an LVAD . Methods and Results We identified 94 patients who underwent HT after bridging with continuous‐flow LVAD from 2008 to 2018 at a single institution. Vasoplegia was defined as persistent low vascular resistance requiring ≥2 intravenous vasopressors within 48 hours after HT for >24 hours to maintain mean arterial pressure >70 mm Hg. Overall, 44 patients (46.8%) developed vasoplegia after HT . Patients with and without vasoplegia had similar preoperative LVAD , echocardiographic, and hemodynamic parameters. Patients with vasoplegia were significantly older; had longer LVAD support, higher preoperative creatinine, longer cardiopulmonary bypass time, and higher Charlson comorbidity index; and more often underwent combined organ transplantation. In a multivariate logistic regression model, older age (odds ratio: 1.08 per year; P =0.010), longer LVAD support (odds ratio: 1.06 per month; P =0.007), higher creatinine (odds ratio: 3.9 per 1 mg/dL; P =0.039), and longer cardiopulmonary bypass time (odds ratio: 1.83 per hour; P =0.044) were independent predictors of vasoplegia. After mean follow‐up of 4.0 years after HT , vasoplegia was associated with increased risk of all‐cause mortality (hazard ratio: 5.20; 95% CI, 1.71–19.28; P =0.003). Conclusions Older age, longer LVAD support, impaired renal function, and prolonged intraoperative CPB time are independent predictors of vasoplegia in patients undergoing HT after LVAD bridging. Vasoplegia is associated with worse prognosis; therefore, detailed assessment of these predictors can be clinically important.

Background Diastolic pulmonary gradient ( DPG ) was proposed as a better marker of pulmonary vascular remodeling compared with pulmonary vascular resistance ( PVR ) and transpulmonary gradient ( TPG ). The prognostic significance of DPG in patients requiring a left ventricular assist device ( LVAD ) remains unclear. We sought to investigate whether pre‐ LVAD DPG is a predictor of survival or right ventricular ( RV ) failure post‐ LVAD . Methods and Results We retrospectively reviewed 268 patients who underwent right heart catheterization before LVAD implantation from 2007 to 2017 and had pulmonary hypertension because of left heart disease. Patients were dichotomized using DPG ≥7 mm Hg, PVR ≥3 mm Hg, or TPG ≥12 mm Hg. The associations between these parameters and all‐cause mortality or RV failure post LVAD were assessed with Cox proportional hazards regression and Kaplan–Meier analyses. After a mean follow‐up time of 35 months, elevated DPG was associated with increased risk of RV failure (hazard ratio [ HR ]: 3.30; P =0.004, for DPG ≥7 versus DPG <7), whereas elevated PVR ( HR 1.85, P =0.13 for PVR ≥3 versus PVR <3) or TPG ( HR 1.47, P =0.35, for TPG ≥12 versus TPG <12) were not associated with the development of RV failure. Elevated DPG was not associated with mortality risk ( HR 1.16, P =0.54, for DPG ≥7 versus DPG <7), whereas elevated PVR , but not TPG , was associated with higher mortality risk ( HR 1.55; P =0.026, for PVR ≥3 versus PVR <3). Conclusions Among patients with pulmonary hypertension because of left heart disease requiring LVAD support, elevated DPG was associated with RV failure but not survival, while elevated PVR predicted mortality post LVAD implantation.

Background The true prevalence of heart failure due to wild type transthyretin amyloidosis (ATTRwt) is likely underestimated. There is a paucity of data with regard to the management of ATTRwt-related advanced heart failure and the natural history of extracardiac ATTRwt. Methods We conducted a retrospective cohort study of patients undergoing cardiac transplant (HTx) for ATTRwt at a single institution. Comprehensive clinical data, including baseline hemodynamic and echocardiographic characteristics, and posttransplant outcomes, were obtained. Results Seven patients with ATTRwt underwent HTx between 2007 and 2015. All patients were male with a mean age of 66 ± 9. Patients had a reduced ejection fraction (mean, 37 ± 14%) and elevated filling pressures pre-HTx (mean pulmonary capillary wedge pressure 22 ± 7 mm Hg) before HTx. Three-year survival was 100%; 1 patient died of pancreatic cancer 45 months post-HTx (1 death per 30.8 patient-years). Oxygen consumption (Δ +6.8 ± 4.9 mL·kg−1·min−1) and 6-minute walk distances (Δ +189 ± 60 m) improved. Symptomatic gastrointestinal involvement (n = 2) and peripheral nerve involvement (n = 4) by ATTRwt developed late. Conclusions This is the first report of a series of ATTRwt patients receiving HTx in which excellent outcomes are demonstrated. Although cardiac death is averted, systemic manifestations of ATTRwt may develop posttransplantation.

C-type natriuretic peptide (CNP) is a vasoactive and antimitogenic peptide that is structurally similar but genetically distinct from atrial natriuretic peptide. While first discovered in the brain, CNP has been shown to be produced by endothelial cells and may function in a paracrine and autocrine fashion in the control of vascular tone. Recently, CNP immunoreactivity and B-type natriuretic peptide receptors (NPR-B), for which CNP is a specific ligand, have been identified in the kidney. The present study was designed to determine whether renal epithelial cells produce and secrete CNP and whether CNP immunoreactivity is present in canine kidney. Opossum kidney (OK) cells that express proximal tubular cell characteristics were incubated for 6 h in fetal calf serum-free Dulbecco's modified Eagle's medium (DMEM). CNP immunoreactivity was measured in the preincubation and 6-h conditioned media by radioimmunoassay (RIA) using a specific antibody to CNP-22. Furthermore the molecular form of this CNP-like protein was determined by reverse-phase high-performance liquid chromatography (HPLC), and intracellular localization of the CNP immunoreactivity was determined by immunohistochemical staining. CNP immunoreactivity was also determined in renal tissue from dogs subjected to saline or endothelin infusion. Six-hour incubation in DMEM resulted in accumulation of CNP immunoreactivity (baseline below detection level vs. 6 h = 117.3 +/- 8.3 pg/ml, P < 0.001). Intracellular CNP concentration determined after sonication was 1.9 +/- 0.2 micrograms/g protein, and immunohistochemical staining for CNP was markedly positive in the cytoplasm.(ABSTRACT TRUNCATED AT 250 WORDS)