Edwards, Brooks S.

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.

Congestive heart failure (CHF) is a pathophysiological condition associated with increased plasma levels of atrial natriuretic factor (ANF), a peptide hormone of cardiac origin that participates in the homeostatic control of intravascular volume and vascular tone. Atrial myocytes serve as the principal source of ANF under physiological conditions, although recent studies have demonstrated that ventricular myocardium may also synthesize ANF in models of CHF associated with ventricular hypertrophy. The current study was designed to investigate the roles of atrial and ventricular myocardium to synthesize, store, and release ANF during the evolution of tachycardia-induced CHF in the dog. The present study demonstrates a persistent elevation of plasma ANF during the evolution of CHF. In acute CHF (3 h), plasma ANF increased independent of cardiac ANF synthesis. In chronic CHF (15 and 30 days), plasma ANF is maintained by an increase in atrial synthesis and release of the peptide, without recruitment of ventricular ANF synthesis. The present study demonstrates that in acute CHF the increase in plasma ANF is regulated by release of stored peptide, and in chronic CHF the persistent elevation of plasma ANF is maintained by an increase in atrial synthesis of ANF.

Background Diabetes mellitus (DM) is a risk factor for morbidity and mortality in patients with heart failure. The effect of DM on post–left ventricular assist device (LVAD) implantation outcomes is unclear. This study sought to investigate whether patients with DM had worse outcomes than patients without DM after LVAD implantation and whether LVAD support resulted in a better control of DM. Methods and Results We retrospectively reviewed 341 consecutive adults who underwent implantation of LVAD from 2007 to 2016. Patient characteristics and adverse events were studied and compared between patients with and without DM. One hundred thirty-one patients (38%) had DM. Compared with patients without DM, those with DM had higher rates of ischemic cardiomyopathy, LVAD implantation as destination therapy, and increased baseline body mass index. In a proportional hazards (Cox) model with adjustment for relevant covariates and median follow-up of 16.1 months, DM was associated with increased risk of all-cause mortality (hazard ratio, 1.73; 95% confidence interval: 1.18–2.53; P =0.005) and increased risk of nonfatal LVAD-related complications, including a composite of stroke, pump thrombosis, and device infection (hazard ratio, 2.1; 95% confidence interval: 1.35–3.18; P =0.001). Preoperative hemoglobin A1c was not significantly associated with mortality or adverse events among patients with DM. LVAD implantation resulted in a remarkable decrease in hemoglobin A1c levels (7.4±1.9 pre-LVAD versus 6.0±1.5 and 6.3±1.4 after 3 and 12 months post-LVAD, respectively; P <0.0001) and a significant reduction in requirements of DM medications. Conclusions DM is associated with increased rates of all-cause mortality and major adverse events despite favorable glycemic control after LVAD implantation.

Background: Familial transthyretin amyloidosis is a disease caused by misfolded transthyretin aggregates that can impair multiple organ systems. Liver transplantation is the first-line treatment for familial transthyretin amyloidosis. Research Question: Our objective is to study outcomes and survival among patients with familial transthyretin amyloidosis after transplantation. Design: All patients undergoing orthotopic liver transplant for familial transthyretin amyloidosis at Mayo Clinic between 1997 and 2012 were reviewed. Baseline clinical characteristics, organs transplanted, and posttransplant clinical course were assessed. Results: Of the 40 patients, 7 patients had the V30M mutation and 33 had other mutations. Nineteen patients received liver only, 19 liver and heart, and 2 combined liver, heart, and kidney transplants. The 5-year overall survival was 85% for those receiving multiple organ transplant and 52% for those receiving liver transplant only ( P = .057). There was no difference in overall survival based on mutation (V30M vs other mutations), but survival was confounded by varied disease involvement and organs transplanted. Those who had early death (≤24 months from liver transplant) had a higher incidence of baseline peripheral neuropathy, autonomic neuropathy, lower modified BMI, and higher alkaline phosphatase. Discussion: Outcomes of orthotopic liver transplant in familial transthyretin amyloidosis are variable due to heterogeneity in mutations and patient status at the time of transplant. Familial transthyretin amyloidosis can progress, despite liver transplantation. Patients receiving combined liver, heart/kidney transplant demonstrated improved survival compared to liver transplant alone.

Renal function improves early after left ventricular assist device (LVAD) implantation but later decline has been observed. We sought to determine the occurrence and evaluate possible causes for this decline. In 62 consecutive patients with HeartMateII LVAD with available calculated glomerular filtration rate (GFR, ml/min/1.73 m2) 1 year after implant, GFR was assessed repeatedly and possible predictors for decline from 3 to 12 months were investigated. Post-mortem renal specimens for patients supported with an LVAD were evaluated. GFR 54.5 ± 19.5 at admission increased to 66.4 ± 22.3 preoperatively and to 79.2 ± 30.1 ~1 month after implantation. Subsequently at ~3 months GFR declined to 74.7 ± 25.4, at ~6 months to 68.8 ± 23.1, and ~1 year after implant to 63.9 ± 17.7. Glomerular filtration rate at 1 year was significantly lower (p < 0.0001, p < 0.0001, p = 0.005) than GFR 1, 3, and 6 months after implant. Early rise in GFR after surgery was not associated with late decline. Shorter bypass time (β = −0.09, p = 0.048) and higher albumin 3 months after LVAD (β = 14.4, p = 0.025) were significantly associated with less later decline in GFR. Arteriosclerosis was identified in autopsy renal specimens. In conclusion, early gains in renal function after LVAD implant are not sustained in many patients. Patient, device, and operative factors may influence long-term renal function in these patients.

Background Pregnancies may result in antibodies against HLA, a risk factor for antibody-mediated rejection (AMR) and subsequent cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). The aim of this study was to evaluate sex differences in the incidence of AMR events and subsequent risk of CAV among HTx recipients. Methods The study comprised 160 patients (51 [32%] women) who underwent HTx in 2008 to 2014. The cumulative effect of AMR events was calculated by AMR score (sum of myocardial biopsy grading divided by number of biopsies taken during 3 years post-HTx). Results Females had higher levels of anti-HLA I antibodies pre-HTx compared to males which was associated with a history of pregnancies, total number of children and with a higher AMR score at 6 months post-HTx (P < 0.05). Women demonstrated a significant increase in the total incidence of AMR events (27 vs. 7%, P = 0.001) and in AMR scores at 6, 12, 24 and 36 months post-HTx compared to men (P < 0.05). There were no differences in cellular rejection between the groups. A history of AMR events was associated with a significantly increased risk of severe CAV onset (hazard ratio, 7.0; 95% confidence interval, 1.5-31.5; P = 0.012). Conclusions Women are at higher risk for AMR post-HTx which subsequently increases their risk for CAV. Females recipients may benefit from closer surveillance to identify AMR at an earlier stage post-HTx, and targeted immunosuppressive therapy to attenuate the development of CAV.

BackgroundEndocardial ablation approaches targeting the retroatrial cardiac ganglia to treat atrial fibrillation (AF) have been proposed. However, the potential value using this approach is unknown. Disruption of the autonomic inputs with orthotropic heart transplant (OHT) provides a unique opportunity to study the effects of autonomic innervation on AF genesis and maintenance. We hypothesized that due to denervation, the risk of postoperative AF would be lower following OHT compared to surgical maze even though both groups get isolation of the pulmonary veins.Methods and ResultsWe reviewed 155 OHTs (mean age 52 ± 11 years, 72% males) and used 1:1 age‐, sex‐, and date‐of‐surgery‐matched two control groups from patients undergoing surgical maze or only coronary artery bypass grafting (CABG). Using conditional logistic regression we compared the odds of AF within 2 weeks following OHT versus controls. Postoperative AF occurred in 10/155 (6.5%) OHT patients. The conditional odds of postoperative AF were lower for OHT as compared to controls (vs maze: odds ratio [OR] 0.27 [95% confidence interval (CI) 0.13–0.57], vs CABG: OR 0.38 [0.17–0.81], P = 0.003; and on additional adjustment for left atrial enlargement, vs maze: OR 0.28 [0.13–0.60], vs CABG: OR 0.14 [0.04–0.47], P = 0.0009).ConclusionsRisk of postoperative AF is significantly lower with OHT as in comparison to surgical maze. As both surgeries entail isolation of the pulmonary veins but only OHT causes disruption of autonomic innervation, this observation supports a mechanistic role of autonomic nervous system in AF. The benefit of targeting the cardiac autonomic system to treat AF needs further investigation.

BACKGROUND Cardiac glycosides have traditionally been used as inotropic agents in the treatment of congestive heart failure (CHF). The renal actions of cardiac glycosides independent of inotropic effects are not characterized. The presence of endogenous digitalis-like factors (EDLFs) with characteristic Na+,K(+)-ATPase activity has been postulated in volume-expanded states such as CHF, and recent studies have demonstrated that at least one EDLF shares structural homology with ouabain. This study was undertaken to evaluate the renal actions of ouabain in normal dogs and those with CHF. METHODS AND RESULTS After surgical preparation, normal dogs (n = 6) and dogs in pacing-induced CHF (n = 6) received intrarenal ouabain in sequential doses of 0.167 micrograms/kg/min, 0.334 micrograms/kg/min, and 0.668 micrograms/kg/min. Hemodynamics and renal function were evaluated during the infusion. There was no change in heart rate or mean arterial pressure during the infusion compared with baseline in both groups. Sodium excretion and urine volume significantly increased in both groups. Plasma renin activity, activated by the onset of pacing in the CHF group, was inhibited by the administration of intrarenal ouabain in this group only. CONCLUSIONS These studies demonstrate that ouabain has diuretic and natriuretic actions independent of cardiac hemodynamics that are preserved in CHF. Furthermore, intrarenal ouabain suppresses activation of renin in CHF.