Corrigendum for health-related quality of life and hospitalizations in chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension: And analysis from the Pulmonary Hypertension Association Registry.

[This corrects the article DOI: 10.1177/20458940211053196.].

Combined heart and kidney transplantation provides an excellent survival and decreases risk of cardiac cellular rejection and coronary allograft vasculopathy.

BACKGROUND: We analyzed the results of combined heart-kidney transplantation (CHKTx) over a 10-year period. METHODS: Between September 1996 and May 2007 at Mayo Clinic, 12 patients (age 52 ± 12.2 years) underwent CHKTx as a simultaneous procedure in 10 recipients and as a staged procedure in two recipients with unstable hemodynamics after heart transplantation. RESULTS: There was no operative mortality. Patient survival rates for the CHKTx recipients at 1 and 3 months and 6 years were 91%, 83%, and 83% and did not differ from isolated heart transplantation (IHTx) recipients (97%, 95%, and 79%, P = 0.61). The freedom from cardiac allograft rejection (≥ grade 2) at 3 months was 73% for CHKTx and had not changed during further follow-up; for IHTx, freedom from rejection at 3 months and 1 and 6 years was 61%, 56%, and 42% (P = .08). Heart and renal allograft survival was 100% with and left ventricular ejection fraction 66% ± 8.4% and glomerular filtration rate 61 ± 25 at last follow-up. There were no signs of cardiac allograft vasculopathy in the CHKTx recipients. CONCLUSION: CHKTx yields favorable long-term outcome, with a low incidence of cardiac rejection and vasculopathy. Simultaneous CHKTx appears feasible, if hemodynamics is satisfactory. This approach expands the selection criteria for transplantation in patients with coexisting end-stage cardiac and renal disease.

Cardiac allograft remodeling after heart transplantation is associated with increased graft vasculopathy and mortality.

The aim of this study was to assess the patterns, predictors and outcomes of left ventricular remodeling after heart transplantation (HTX). Routine echocardiographic studies were performed and analyzed at 1 week, 1 year and 3-5 years after HTX in 134 recipients. At each study point the total cohort was divided into three subgroups based on determination of left ventricle mass and relative wall thickness: (1) NG-normal geometry (2) CR-concentric remodeling and (3) CH-concentric hypertrophy. Abnormal left ventricular geometry was found as early as 1 week after HTX in 85% of patients. Explosive mode of donor brain death was the most significant determinant of CH (OR 2.9, p = 0.01) at 1 week. CH at 1 week (OR 2.72, p = 0.01), increased body mass index (OR 1.1, p = 0.01) and cytomegalovirus viremia (OR - 4.06, p = 0.02) were predictors of CH at 1 year. CH of the cardiac allograft at 1 year was associated with increased mortality as compared to NG (RR 1.87, p = 0.03). CR (RR 1.73, p = 0.027) and CH (RR 2.04, p = 0.008) of the cardiac allograft at 1 year is associated with increased subsequent graft arteriosclerosis as compared to NG.

Beta blockade in patients with congestive heart failure. Why, who, and how.

In patients with CHF, physicians should aim to treat the LV dysfunction, not just the CHF symptoms. LV dysfunction is a chronic disease that is usually progressive, even when it seem compensated. The risk of sudden death or progressive CHF is very real. Adding a beta blocker to the treatment regimen while the disease is still compensated or after resolution of an acute exacerbation can stabilize or reverse the LV dysfunction and improve survival. Beta blockade is now a vital part of the standard of care for most patients with LV dysfunction.

Accuracy of Doppler echocardiography in the assessment of pulmonary hypertension in liver transplant candidates.

Pulmonary hypertension has been associated with poor outcome after liver transplantation. We assessed the diagnostic accuracy of Doppler echocardiography in detecting significant pulmonary hypertension. Seventy-four potential liver transplant candidates underwent Doppler echocardiography in which the systolic right ventricular pressure (RVsys) was used to estimate the systolic pulmonary artery pressure (PAsys). Group 1 included 39 consecutive patients with RVsys >/=50 mm Hg who underwent elective right heart catheterization. Group 2 consisted of 35 patients with RVsys <50 mm Hg in whom pulmonary artery pressures were measured at the beginning of the transplantation procedure. The accuracy of the estimates by Doppler echocardiography was assessed against measurements made by direct catheterization. Patients in groups 1 and 2 were comparable in their demographic and liver disease characteristics. There was a strong correlation between RVsys by Doppler echocardiography and PAsys by right heart catheterization (r =.78, P <.01). Of the 39 patients in group 1, 29 (72%) had at least moderate pulmonary hypertension (mean pulmonary artery pressure [MPAP] >/=35 mm Hg), including 12 (30%) with severe pulmonary hypertension (MPAP >/=50 mm Hg). Only 1 of the group 2 patients had MPAP >/=35 mm Hg. Thus, in the diagnosis of moderate to severe pulmonary hypertension, the sensitivity of echocardiography was 97% and specificity was 77%. Doppler echocardiography is an accurate screening test to detect moderate to severe pulmonary hypertension. We advise that liver transplant candidates with RVsys >/=50 mm Hg undergo right heart catheterization to fully characterize pulmonary hemodynamics.

Heart transplantation for radiation-associated end-stage heart failure.

Radiation-induced heart disease is an increasingly recognized late sequela of mediastinal radiation therapy for malignant neoplasms. We report four cases of heart transplantation for end-stage heart failure induced by mediastinal radiation therapy. Short-term and intermediate-term results are excellent with all four patients currently surviving a mean of 48 months after transplantation. Neither a second malignancy nor recurrence of the primary malignancy has been observed to date. The early results of heart transplantation for end-stage, radiation-induced heart disease are encouraging.

Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe portopulmonary hypertension.

Pulmonary hypertension associated with increased pulmonary vascular resistance (PVR) and occurring in the setting of portal hypertension is referred to as "portopulmonary hypertension." Intravenous epoprostenol (prostacyclin) is a potent pulmonary and systemic vasodilator with antithrombotic properties. It can decrease PVR and pulmonary artery pressure in patients with primary (idiopathic) pulmonary hypertension. Using right-heart catheterization, we evaluated the acute pulmonary hemodynamic effects of intravenous epoprostenol in patients with moderate to severe pulmonary hypertension (mean pulmonary artery pressure [MPAP] >/=35 mm Hg) associated with clinical manifestations of portal hypertension. Effects of long-term infusion of epoprostenol were also evaluated. We studied 15 consecutive patients with portopulmonary hypertension; 14 underwent acute administration of epoprostenol, and no significant side effects were noted. Ten patients received continuous epoprostenol (range, 8 days-30 months). Acute changes in PVR (-34% +/- 18%), MPAP (-16% +/- 10%), and cardiac output (CO) (+21 +/- 18%), were statistically significant (P <.01). Long-term use of epoprostenol further lowered PVR (-47% +/- 12% from baseline and -31% +/- 22% from the acute change; P <.05) in the 6 patients restudied by right-heart catheterization. Death occurred in 6 of 10 (60%) of those receiving long-term epoprostenol. In moderate to severe portopulmonary hypertension, intravenous epoprostenol resulted in a significant improvement (both acute and long-term) in PVR, MPAP, and CO. Potential adverse effects on portal hypertension and implications for orthotopic liver transplantation (OLT), however, require further study.

Recipient selection and management before cardiac transplantation.

Cardiac transplantation is a proven, effective therapy for selected patients with end-stage congestive heart failure. Recipient selection is performed by a multidisciplinary team consisting of transplant physicians and surgeons. Clinicians responsible for patient assessment must establish the severity of cardiac dysfunction, formulate a prognosis, and stratify patients according to risk for mortality. Patients whose survival and quality of life are most limited without cardiac transplantation are candidates for therapy. The scarcity of organ donors makes careful screening of potential recipients necessary to identify those individuals most likely to obtain a long-term benefit. Recipient selection criteria and management strategies are evolving because of extended waiting times and high mortality caused by the lack of sufficient numbers of donors. Alternative therapies should be applied wherever possible.

Effects of pentoxifylline on renal function and blood pressure in cardiac transplant recipients: a randomized trial.

BACKGROUND: The current success of cardiac transplantation is in part attributable to the development of effective immunosuppressive agents such as cyclosporine. However, concern remains regarding the potential for cyclosporine-induced nephrotoxicity. Animal studies and early reports of renal protective effects of pentoxifylline in bone marrow transplant recipients prompted a randomized trial in cardiac transplant recipients. METHODS: Twenty-nine patients were randomized to receive pentoxifylline 400 mg p.o. t.i.d. or matching placebo for 1 year after cardiac transplantation. Renal function was assessed preoperatively and at 1, 6, and 12 months postoperatively. Glomerular filtration rate and renal plasma flow were measured with iothalamate and para-aminohippurate, respectively. Serum creatinine was also measured. Ambulatory blood pressure monitoring after withdrawal of antihypertensives for 3 days was performed 12 months postoperatively. RESULTS: Twenty-seven patients completed the study. Glomerular filtration rate rose between 1 and 6 months after transplantation, presumably due to the reduction in goal cyclosporine level in that period, and then fell modestly between 6 and 12 months, presumably due to ongoing nephrotoxic effects of cyclosporine. No difference in glomerular filtration rate or creatinine was seen between pentoxifylline and placebo groups at any interval. Renal plasma flow increased modestly between baseline and 6 months in the pentoxifylline group, but not in the placebo group, and then fell between 6 and 12 months. Serum creatinine increased between baseline and 6 months in both groups, apparently due to increased body weight. Results of 18-hr ambulatory blood pressure monitoring obtained 1 year after transplantation was not different between groups. CONCLUSIONS: Renal function declines only modestly in the first year after cardiac transplantation. Pentoxifylline did not attenuate this process and had no effect on blood pressure. The modest decline in renal function may be related to current immunosuppressive strategies.

Predictors of reversibility of pulmonary hypertension in cardiac transplant recipients in the first postoperative year.

BACKGROUND: Pulmonary hypertension remains a risk factor for early postoperative mortality in heart transplantation and may reduce the long-term benefits of the procedure. This study was undertaken to assess the value of baseline hemodynamic studies with nitroprusside used to predict the degree of postoperative reversibility of pulmonary hypertension in cardiac transplant recipients and to identify clinical risk factors for fixed pulmonary hypertension. METHODS AND RESULTS: Hemodynamic data from 55 consecutive patients who underwent orthotopic cardiac transplantation from June 1988 through September 1993 were analyzed. The effects of nitroprusside and transplantation on pulmonary artery pressure, cardiac output, and pulmonary vascular resistance were compared. Multiple regression analysis was used to identify the predictors of reversibility of pulmonary hypertension. Nitroprusside reduced pulmonary vascular resistance by increasing cardiac output and, to a lesser extent, by reducing the transpulmonary gradient. Pulmonary hypertension was less reversible in patients with ischemic heart disease (versus dilated cardiomyopathy) and in former smokers (versus nonsmokers). Patients with nonischemic heart failure and no smoking history had significantly lower posttransplant pulmonary vascular resistance (1.24 +/- 0.45 Wood units) than ischemic patients (who were all former smokers; 2.20 +/- 1.01 wood units) or nonischemic former smokers (1.72 +/- 0.70 Wood units). The correlation of pulmonary vascular resistance during nitroprusside challenge with posttransplant pulmonary vascular resistance was better than that of baseline pulmonary vascular resistance with posttransplant pulmonary vascular resistance. CONCLUSIONS: Nitroprusside testing improves the prediction of late posttransplant pulmonary vascular resistance; hence, it provides data that may be relevant to both early operative risk and later long-term effectiveness of cardiac transplantation. The finding of increased risk of fixed pulmonary hypertension associated with ischemic heart disease and smoking suggests that underlying atherosclerotic vascular disease may contribute to the irreversibility of pulmonary vascular resistance.

Increased incidence of chronotropic incompetence in older donor hearts.

BACKGROUND: Previous Registry studies have reported that heart transplantation with older donor hearts is associated with a more than twofold increase in early mortality. METHODS: An analysis of 77 consecutive patients undergoing heart transplantations at our institution between June 1988 and July 1994 was performed to assess the effect of donor age on mortality and morbidity. Recipients were grouped into those receiving hearts from younger donors (aged < 40 years, n = 60) and those receiving hearts from older donors (aged > 40 years, n = 17). RESULTS: There were two deaths within the first 30 days in the younger donor group and no deaths in the other group. One-year survival rate was 95% and 100% for the "younger" and "older" groups, respectively. The mean recipient age of the younger donor group was lower (46 +/- 14 years) compared with the older donor group (57 +/- 7 years). Morbidity was compared between the two groups; the length of hospital stay (22.6 +/- 15.8 days versus 21.3 +/- 9.4 days), the graft ejection fraction at 1 week (64% +/- 5% versus 62% +/- 7%), and the mean number of rejection episodes within the first 3 months (0.79 versus 0.65) were not statistically different between the two groups. However, the incidence of chronotropic incompetence requiring permanent pacemaker implantation was significantly greater in the group who received older donor hearts (41.2% versus 10.3%, p < 0.05), independent of the ischemic time. CONCLUSIONS: This study shows that older donor hearts may be used safely in selected patients with excellent outcome, although there is an increased incidence of chronotropic incompetence requiring implantation of permanent pacemakers.

Increase in total plasma homocysteine concentration after cardiac transplantation.

OBJECTIVE: To determine whether plasma homocysteine concentrations are increased in patients after cardiac transplantation. DESIGN: Total plasma homocysteine concentration was measured in 44 consecutive patients before and at 3, 6, and 12 months after orthotopic heart transplantation between June 1, 1988, and Oct. 15, 1992, and the data were analyzed statistically. RESULTS: Mean homocysteine concentrations (normal range, 4 to 17 mumol/L) increased 70% from 12.5 mumol/L before cardiac transplantation to 21.2 mumol/L (P < 0.002) 3 months after transplantation, at which time the concentrations were above normal in 14 of 26 patients (54%). Homocysteine concentrations remained elevated 6 and 12 months after transplantation (20.4 and 22.6 mumol/L, respectively) but did not increase further. Mean concentrations of plasma folic acid and vitamin B12, cofactors in homocysteine metabolism, decreased 20% and 49%, respectively, within 3 months after transplantation (11.6 to 9.3 micrograms/L [P = 0.04] and 584 to 295 ng/L [P = 0.01]). The mean glomerular filtration rate decreased 25% during this same interval (81 to 61 mL/min; P = 0.0001). Linear regression analysis revealed an association between the increase in homocysteine concentration and the folic acid concentration that approached statistical significance (P = 0.07); we found no statistically significant correlates of the increase in homocysteine concentration. CONCLUSION: The homocysteine concentration increases in most patients within 3 months after cardiac transplantation to levels previously associated with premature atherosclerotic coronary artery disease, and it remains increased for at least 1 year. Further investigation into the mechanism for the increase in homocysteine concentration and the relationship between homocysteine and coronary artery disease after transplantation is warranted.

Methylergonovine-induced diffuse coronary spasm in a patient with exercise-induced coronary spasm after heart transplantation.

Coronary artery spasm is a rarely reported condition after heart transplantation. We report a case of exercise-induced coronary artery spasm in a patient 1-year after orthotopic heart transplantation. Serial quantitative coronary angiography showed significant diffuse loss of luminal diameter. Provocative testing with intracoronary acetylcholine and intravenous methylergonovine maleate was performed in an effort to document efficacy of the antispasm regimen. Infusion of acetylcholine into the left anterior descending coronary artery resulted in transient closure of the vessel. Diffuse spasm resulting in hypotension and ventricular fibrillation occurred with intravenous methylergonovine maleate administration. Because of the risk of provoking diffuse spasm, intravenous administration of methylergonovine maleate should be avoided in the posttransplantation setting. Review of the literature suggests that coronary artery spasm after transplantation is often associated with severe transplant coronary artery disease and may be associated with a poor prognosis. Coronary artery spasm may be a more common cause of syncope and death after transplantation than it is currently thought to be.

Reductions of myocardial Na-K-ATPase activity and ouabain binding sites in heart failure: prevention by nadolol.

To study the changes in myocardial digitalis binding sites in heart failure, we measured myocardial ouabain binding sites, Na-K-adenosinetriphosphatase (ATPase) activity, and ventricular muscle mechanical responses to acetylstrophanthidin in dogs with right-heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. Sham-operated dogs were studied as the control. RHF produced a significant decrease in ouabain binding sites in the right and left ventricular myocardium, which was accompanied by a proportional decrease in Na-K-ATPase activity. However, RHF and sham-operated dogs did not differ in systemic hemodynamic or right ventricular trabeculate muscle isometric contractile responses to acetylstrophanthidin. To determine whether chronic beta-adrenergic stimulation contributed to the development of Na-K-ATPase downregulation, we administered nadolol (40 mg/day) to a separate group of dogs during an early stage of RHF development. Nadolol effectively prevented the reduction of myocardial ouabain binding sites that occurred in RHF. Thus we conclude that myocardial ouabain binding sites and Na-K-ATPase activity are reduced in dogs with experimental heart failure and that these changes probably occur as a result of the attendant heightened sympathetic activity.

Techniques of immunosuppression after cardiac transplantation.

Modulation of the normal immune response is the major challenge for successful organ transplantation. Cardiac allograft rejection is primarily the result of activation of T cells. Most currently used immunosuppressive agents mainly affect the T-cell-mediated limb of the immune system. Immunosuppressive strategies can be considered to have three goals: (1) prophylaxis against rejection early after cardiac transplantation, (2) long-term maintenance prophylaxis, and (3) treatment of acute rejection. The extent of immunosuppression needed varies with the time after transplantation and the rejection profile of the individual patient. The goal is to provide sufficient immunosuppression to retard rejection without causing undesirable side effects, including infection and neoplasms.

Chronic beta-adrenoceptor blockade prevents the development of beta-adrenergic subsensitivity in experimental right-sided congestive heart failure in dogs.

BACKGROUND: The reductions of myocardial beta-adrenergic receptor density and responsiveness to catecholamines in congestive heart failure are associated with excessive sympathetic stimulation. The purpose of this study was to determine whether the myocardial changes could be prevented by beta-receptor blockade. METHODS AND RESULTS: We administered the oral beta-receptor blocking agent nadolol (40 mg/day) to dogs during an early stage of experimental right heart failure and to sham-operated dogs for 5 weeks. Animals receiving no nadolol were studied concurrently. Nadolol treatment did not prevent right ventricular hypertrophy or elevated concentrations of plasma norepinephrine that occurred in right heart failure, nor did it affect the decrease in myocardial norepinephrine content and norepinephrine uptake activity, suggesting that the hemodynamic stress imposed on the right ventricle of dogs with right heart failure was similar regardless of the presence or absence of beta-receptor blockade. Resting heart rate, right atrial pressure, aortic pressure, cardiac output, right ventricular dP/dt, and left ventricular dP/dt and dP/dt/P measured 5 days after discontinuation of nadolol did not differ significantly from those without nadolol treatment in either right heart failure or sham-operated animals. Sham-operated dogs also showed no changes in myocardial beta-receptor or adenylate cyclase activity after nadolol treatment. However, nadolol treatment prevented the reduction of myocardial beta-receptor density and attenuated the decrease in the cardiac beta-adrenergic sensitivity that occurred in right heart failure. CONCLUSIONS: Excessive sympathetic stimulation may play an important role in the development of beta-receptor downregulation and beta-adrenergic subsensitivity in right heart failure.

The pharmacokinetics of racemic verapamil in patients with impaired renal function.

The pharmacokinetics of verapamil were studied in patients with renal failure who were undergoing maintenance hemodialysis and in normal subjects after an IV infusion of 10 mg and a single oral dose of 120 mg. Plasma levels of verapamil and its active metabolite, norverapamil, were analyzed by a sensitive and specific HPLC procedure. Severe renal failure requiring hemodialysis did not change the time course of verapamil and norverapamil plasma concentrations after either the IV or oral dose. The terminal elimination rate constant, clearance, volume of distribution, and bioavailability of verapamil were not significantly different between the two groups of subjects. In addition, the apparent maximal plasma concentration, terminal elimination rate constant, and area under the curve for norverapamil were similar in patients with renal failure and normal subjects. The study showed that the plasma disposition of verapamil and norverapamil was not affected in patients with impaired renal function. Furthermore, this study does not indicate that any change in dosage is necessary when single doses of verapamil are administered to patients with renal failure.