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There is limited experience in management of orthotopic heart transplant (OHT) patients with COVID-19. In this study, we present our initial experience using a standardized management algorithm. Data collection was performed on OHT patients with COVID-19 after March 10, 2020 (declaration of state of emergency in Massachusetts). Among the 358 OHT patients currently followed at our program, 5 patients (1.4%) tested positive for COVID-19 (median age 50 years [IQR, 49-58], duration post-OHT 21 years [IQR, 6-25], and 4 of 5 [80%] were men). Among the 5 OHT patients, 2 of 5 (20%) had mild disease and had no change in baseline immunosuppression therapy. Two of 5 (20%) had moderate disease and received remdesivir as part of a clinical trial and reduced immunosuppression therapy. One patient (20%) died prior to presenting to the hospital, consistent with 20% case fatality rate. Four patients (80%) are doing well 4 weeks post-discharge. In this small cohort of OHT patients with COVID-19, we report a 1.4% COVID-19 infection rate and 20% case fatality rate. All OHT patients managed under our clinical management algorithm had good short-term outcomes. Further study to estimate the true risk profile of OHT patients and validate the proposed management strategy is warranted., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: It is increasingly recognized that pump thrombosis most likely represents the end stage of a complex interaction between the patient-pump interface. We hypothesized that early patient/pump mismatch, as manifested by suboptimal left ventricular (LV) unloading early after left ventricular assist device (LVAD) implantation, may be a harbinger of increased risk for later LVAD thrombosis., Methods: In 64 patients (59 ± 11 years old, 78% men, 44% destination therapy) discharged alive without thrombosis or other device malfunction after first HeartMate II LVAD implantation (between January 2011 and June 2014), LV dimensions in end diastole (LVIDd) and end systole (LVIDs) were compared between pre-implant and optimal set speed pre-discharge echocardiography. LV dimension decrement indices (pre-implant dimension - optimal set speed dimension ÷ pre-implant dimension × 100) for LVIDd [LVIDdDI] and LVIDs [LVIDsDI] were calculated., Results: The incidence of pump thrombosis was 0.06 per patient year (n = 18, median time 8 [interquartile range 2, 17] months). Baseline characteristics including pre-operative LVIDd and LVIDs were similar between LVAD thrombosis and no thrombosis groups. After ventricular assist device implantation, set speed and other ramp parameters did not differ between groups. However, LVIDdDI (19 ± 13% vs 25 ± 11%, p = 0.04) and LVIDsDI (16 ± 16% vs 27 ± 13%, p = 0.008) were significantly lower in patients with later pump thrombosis. A cutoff value of ≤15% using receiver operating characteristic curve analysis was 83% sensitive for LVIDdDI and LVIDsDI for predicting pump thrombosis. Patients with LVIDdDI of >15% vs ≤15% were significantly more likely to be free of pump thrombosis over a median follow-up period of 15 (interquartile range 9, 26) months (log-rank test, p = 0.045)., Conclusions: LV dimension decrement index at optimized speed setting on pre-discharge echocardiography is associated with LVAD thrombosis., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Chronically supported left ventricular assist device (LVAD) patients may be candidates for novel therapies aimed at promoting reverse remodeling and myocardial recovery. However, the effect of hemodynamic unloading with a LVAD on myocardial viability and LV function in chronically supported LVAD patients has not been fully characterized. We aimed to develop a non-invasive imaging protocol to serially quantify native cardiac structure, function, and myocardial viability while at reduced LVAD support., Methods: Clinically stable (n = 18) ambulatory patients (83% men, median age, 61 years) supported by a HeartMate II (Thoratec, Pleasanton, CA) LVAD (median durations of heart failure 4.6 years and LVAD support 7 months) were evaluated by echocardiography and technetium-99m ((99m)Tc)-sestamibi single photon emission computed tomography (SPECT) imaging at baseline and after an interval of 2 to 3 months. Echocardiographic measures of LV size and function, including speckle tracking-derived circumferential strain, were compared between ambulatory and reduced LVAD support at baseline and between baseline and follow-up at reduced LVAD support. The extent of myocardial viability by SPECT was compared between baseline and follow-up at reduced LVAD support., Results: With reduction in LVAD speeds (6,600 rpm; interquartile range: 6,200, 7,400 rpm), LV size increased, LV systolic function remained stable, and filling pressures nominally worsened. After a median 2.1 months, cardiac structure, function, and the extent of viable myocardium, globally and regionally, was unchanged on repeat imaging while at reduced LVAD speed., Conclusions: In clinically stable chronically supported LVAD patients, intrinsic cardiac structure, function, and myocardial viability did not significantly change over the pre-specified time frame. Echocardiographic circumferential strain and (99m)Tc-sestamibi SPECT myocardial viability imaging may provide useful non-invasive end points for the assessment of cardiac structure and function, particularly for phase II studies of novel therapies aimed at promoting reverse remodeling and myocardial recovery in LVAD patients., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: B-type natriuretic peptide (BNP) is chronically elevated in heart transplantation and reflects diastolic dysfunction, cardiac allograft vasculopathy, and poor late outcome. This investigation studied peripheral gene expression signatures of elevated BNP concentrations in clinically quiescent heart transplant recipients in an effort to elucidate molecular correlates beyond hemodynamic perturbations., Methods and Results: We performed gene microarray analysis in peripheral blood mononuclear cells of 28 heart transplant recipients with clinical quiescence (absence of dyspnea or fatigue; normal left ventricular ejection fraction [EF >55%]; ISHLT biopsy score 0 or 1A; and normal hemodynamics [RAP <7 mm Hg, PCWP < or = 15 mm Hg, and CI > or = 2.5 L/min per m2]). BNP levels were performed using the Triage B-type Natriuretic Peptide test (Biosite Diagnostics Inc, San Diego, Calif) and median BNP concentration was 165 pg/mL. Seventy-eight probes (of 7370) mapped to 54 unique genes were significantly correlated with BNP concentrations (P<0.001). Of these, the strongest correlated genes (P<0.0001) were in the domains of gelsolin (actin cytoskeleton), matrix metallopeptidases (collagen degradation), platelet function, and immune activity (human leukocyte antigen system, heat shock protein, mast cell, and B-cell lineage)., Conclusions: In the clinically quiescent heart transplant recipient, an elevated BNP concentration is associated with molecular patterns that point to ongoing active cardiac structural remodeling, vascular injury, inflammation, and alloimmune processes. Thus, these findings allude to the notion that BNP elevation is not merely a hemodynamic marker but should be considered reflective of integrated processes that determine the balance between active cardiac allograft injury and repair.

Background: Cardiac allograft vasculopathy continues to represent the major limitation to long-term cardiac allograft survival. Routine angiography and intravascular ultrasound fall short in their ability to detect microcirculatory aberrations. Thrombolysis in myocardial infarction (TIMI) myocardial perfusion grades (TMPG) have been used as a measure of microvascular circulation in patients treated for acute myocardial infarction. We studied the correlation of epicardial coronary anatomy with microvascular flow as determined by TMPG and correlated it with patient outcome., Methods: We enrolled 66 consecutive cardiac transplant recipients (49 men; mean age 52 +/- 13 years; range 15-70 years) undergoing surveillance coronary angiogram during a 9-month period. All angiograms were interpreted for epicardial coronary anatomy by an independent investigator. Another investigator, blinded for clinical data and angiogram interpretation, interpreted TMPGs. TMPG 0 was defined as no apparent tissue-level perfusion; TMPG 1 indicated presence of myocardial blush but no clearance from the microvasculature; TMPG 2 blush cleared slowly; and TMPG 3 indicated that blush began to clear during washout (blush is minimally persistent after 3 cardiac cycles of washout). Cardiac deaths served as the primary outcome variable., Results: Fifty-eight of 66 patients had an abnormal TMPG. Mean TMPG in all these patients was 4.2 +/- 3 (normal is 9). Forty-four patients (Group A) with no angiographic coronary narrowing had TMPG 4.81 +/- 3.1, and 22 patients (Group B) with epicardial coronary narrowing 40% of lumen diameter had TMPG 3.0 +/- 2.5 (p = 0.007). There was no difference in TMPG related to the coronary territory involved. At a mean follow-up of 30 +/- 2.5 months, 6 (13.6%) of 44 patients in Group A had died, and 7 (31.8%) of 22 in Group B had died (p < 0.03)., Conclusions: Microcirculatory aberrations as assessed by tissue TMPG is abnormal across all coronary territories in cardiac transplant recipients and associated with poor survival, suggesting a generalized microvascular involvement even in the presence of a normal angiogram. Patients with focal epicardial coronary narrowing have significantly greater decline in tissue perfusion, independent of the coronary territory involved, and exhibit poor survival compared with patients without epicardial coronary disease.

Objectives: We evaluated the association of mode of brain death with cardiac allograft vasculopathy., Background: Explosive brain death (EBD) is accompanied by a sudden increase in intracranial pressure, with recruitment of pro-inflammatory cytokines, as well as adhesion cell and co-stimulatory molecules. Whether these early events influence the later development of cardiac allograft vasculopathy following heart transplantation remains unknown., Methods: An inception cohort of 61 consecutive heart transplant recipients between 1993 and 1995 who underwent intravascular ultrasound examination of the coronary arteries were evaluated. Based on the mode of donor brain death, this cohort was divided into either an EBD group (n = 27) or non-EBD (n = 34), and the development of intimal thickness and cardiac events (sudden cardiac death, myocardial infarction, and need for coronary revascularization via percutaneous techniques or surgical bypass) was assessed., Results: Despite similar posttransplant survival and distribution of nonimmunological and immunological variables, heart transplant recipients with EBD demonstrated greater intimal thickening (0.59 +/- 0.1 vs. 0.32 +/- 0.2 mm; p = 0.02) and higher cardiac events (37% vs. 12%; p = 0.01) when compared to those with non-EBD donors. Hearts from donors with EBD had lower survival (63 +/- 19 vs. 72 +/- 17 months) than with non-EBD donors (p = 0.04)., Conclusions: Explosive brain death is a significant determinant for the late development of cardiac allograft vasculopathy and influences long-term allograft survival. Thus, strategies focusing on limitation of vascular allograft injury in the pre-engraftment phase of cardiac transplantation are warranted.

Background: Pre-angiographic detection of intimal proliferation using intravascular ultrasound in heart transplant recipients has focused investigators' attention on the prognostic utility of such early information. Not all heart transplant recipients who exhibit a "prognostically relevant" threshold of severe (>0.5 mm) intimal thickening experience cardiac events. We sought to contrast clinical characteristics of heart transplant recipients who have prognostically relevant, severe intimal proliferation and who experience cardiac events with those who remain event free., Methods: We prospectively followed an inception cohort of 54 consecutive heart transplant recipients with severe intimal proliferation (intimal thickness >0.5mm) of the coronary arteries after index intravascular ultrasound examination to assess the development of cardiac events (sudden cardiac death, myocardial infarction) and/or the necessity for coronary revascularization with percutaneous techniques (angioplasty, atherectomy, stent implantation) or surgical bypass., Results: Based on the occurrence of adverse cardiac events during the subsequent 24 months, we divided the study cohort into 2 groups: Group 1 (no event, n = 33) and Group 2 (cardiac event, n = 21). Both groups demonstrated similar intimal thickness at the index ultrasound (Group 1, 0.89 +/- 0.27 mm, vs Group 2, 0.94 +/- 0.36 mm; p = not significant). Those with cardiac events were more likely than those without events to have hyperlipidemia, to have greater exposure to cumulative and average daily prednisone, and to exhibit greater average biopsy rejection scores at follow-up., Conclusions: These observations underscore the importance of the quality and not merely the quantity of intimal proliferation in determining occurrence of morbid cardiac events and further emphasize the interaction of immunologic and non-immunologic factors in determining event vulnerability in cardiac allograft vasculopathy.

We investigated the relationship of QT dispersion and cardiac allograft vasculopathy in heart transplant recipients. The findings suggest that the development of cardiac allograft vasculopathy is associated with an increase in QT dispersion, suggesting the presence of abnormal repolarization in these patients.

Transmyocardial laser revascularization (TLR) was initially touted as a promising therapeutic alternative for tackling the growing problem of cardiac allograft vasculopathy in late heart transplant survivors. We first described 4- and 8-week observations of application of this surgical technique, in which we professed enthusiasm for TLR in providing symptomatic relief and in reducing ischemic burden. In this report, we present the long-term (24-month) impact of TLR on clinical outcome, channel patency, and recrudescence of ischemic burden. In the long term, surgical TLR provides neither consistent symptomatic improvement nor an ameliorative effect on the natural history of cardiac allograft vasculopathy.

Cyclosporine-induced hypertension occurs in more than 90% of patients following cardiac transplantation. This article underlines the clinical characteristics as well as the mechanisms that can be associated with the development of cyclosporine-induced hypertension. In addition, the clinical trials up to date for the treatment of hypertension following cardiac transplantation are discussed. However, in view of the possible long-term sequelae associated with cyclosporine-induced hypertension, further studies to evaluate the long-term efficacy and safety of antihypertensive agents and finally the long-term effects of hypertension on the cardiac allograft are needed.

Background: The clinical use of cyclosporine as an immunosuppressive agent enhanced long-term survival in transplant recipients at the expense of a high incidence of induced hypertension. Altered neurovegetative (autonomic) cardiovascular control is suspected as a mechanism of this form of hypertension., Methods: Spectral analysis of systolic arterial pressure and R-R interval variability (electrocardiographic recordings) were performed, and the index alpha of baroreflex gain was computed in four groups of subjects matched for age: 13 orthotopic heart transplant recipients; 13 solid organ transplant recipients; 13 patients with essential hypertension; and 18 control subjects with normal blood pressure. All but the control subjects were treated with similar dihydropyridine calcium entry blockers. Heart and solid organ transplant recipients also received cyclosporine., Results: R-R variance was lowest in the heart transplant recipients. The spectral profile of R-R interval was suggestive of sympathetic predominance in the patients with hypertension, but not in the solid organ transplant recipients or the control subjects. Systolic blood pressure variability and low frequency component (a marker of sympathetic vasomotor modulation) were similar in the four groups. The index alpha was 1.8 +/- 2.2 in heart transplant recipients, 11.7 +/- 6.6 in solid organ transplant recipients, 7.3 +/- 3.6 in patients with hypertension, and 13.5 +/- 6.4 msec/mm Hg in control subjects (p = 0.0001)., Conclusions: These data indicate that (1) cyclosporine-induced hypertension in heart transplant recipients is associated with a loss of baroreflex function as a result of cardiac denervation-related uncoupling; (2) compared with patients with hypertension, organ transplant recipients with hypertension demonstrated a maintained baroreflex function as indicated by a lack of reduction of the index alpha; (3) baroreflex heart rate control in dihydropyridine-treated cyclosporine-induced hypertension is well maintained.

Background: The clinical utility of intimal hyperplasia detected by intravascular ultrasonography in predicting cardiac events in heart transplant recipients with cardiac allograft vasculopathy has not been previously investigated., Methods: Intravascular ultrasonographic examination of 74 consecutive heart transplant recipients, including 62 men and 12 women with a mean age of 51 +/- 10 years (range 22 to 68 years), was performed at the time of annual angiography. Two groups of study patients were identified: group I consisted of patients with minimal, mild, or moderate intimal thickness by intravascular ultrasonography, whereas group II patients had severe intimal thickness., Results: Patient characteristics were similar in both groups except for higher serum triglycerides (220 +/- 95 versus 165 +/- 79 mg/dl), more advanced donor age (28 +/- 11 versus 23 +/- 6 years) and greater duration of follow-up after transplantation (3.3 +/- 1.4 versus 1.8 +/- 1.2 years) in group II patients with severe intimal thickening (p < 0.01). Cardiac events were defined as the occurrence of sudden death, myocardial infarction, or the need for coronary revascularization via percutaneous or surgical intervention. One cardiac event occurred in group I patients (sudden death), whereas seven events were noted in the group II patients (p = 0.006). Cardiac events in the group of patients with severe intimal thickening included four patients with sudden cardiac death and three patients who underwent percutaneous revascularization procedures involving directional coronary atherectomy. Angiograms were normal in 62% of patients who had cardiac events., Conclusions: This study represents one of the first reports that provides evidence that severe intimal hyperplasia predicts the development of cardiac events even in the presence of a normal coronary angiogram.

The major cause of late death in cardiac transplant recipients is cardiac allograft vasculopathy, also referred to as cardiac transplant atherosclerosis, which occurs in as many as 45% of transplant recipients who survive longer than 1 year. It differs from typical atherosclerosis in that intimal hyperplasia is concentric and diffuse, the internal elastic lamina remains intact, calcification is rare, and the disease tends to develop rapidly. Intravascular ultrasound and coronary angioscopy are more sensitive diagnostic measures of cardiac allograft vasculopathy than is coronary angiography. Although retransplantation at present seems to be the only definitive therapy for cardiac allograft vasculopathy, it has shown only fair results. Recent studies have suggested that calcium entry blockers and angiotensin-converting enzyme inhibitors may play a beneficial role in delaying the progression of cardiac allograft vasculopathy.