Changes in Outcomes of Cardiac Allograft Vasculopathy Over 30 Years Following Heart Transplantation.

OBJECTIVES: This study investigated temporal changes in the demographics and the prognosis of cardiac allograft vasculopathy (CAV) over 30 years following heart transplantation (HTx). BACKGROUND: Effects of the changing HTx demographics on CAV outcomes, based on International Society for Heart and Lung Transplantation (ISHLT) classification of CAV, have been incompletely investigated. METHODS: Patients who underwent HTx at the Montreal Heart Institute were classified according to the severity of CAV (CAV 0 is no presence of CAV; CAV 1 is mild, CAV 2 to 3 is moderate to severe) and era of HTx (early: 1983 to 1998; recent: 1999 to 2011). We compared the risk of progression, survival, and independent predictors of outcomes among the groups. RESULTS: A total of 298 patients were followed for 11.6 ± 6.6 years. Patients who received transplants in the early era exhibited a higher risk for progression from CAV 1 to a higher grade (adjusted odds ratio: 8.0; 95% confidence interval [CI]: 1.01 to 62.6). The presence of CAV was associated with a significantly increased risk for all-cause mortality in the early era (hazard ratio [HR]: 1.6; 95% CI: 1.1 to 2.5) but not in the recent era (HR: 1.1; 95% CI: 0.2 to 4.9). Regardless of the era, CAV classes 2 to 3 and CAV 1 were associated with a significantly increased risk for all-cause mortality compared to CAV 0 (HR: 6.5; 95% CI: 2.7 to 15.7; and HR: 1.750; 95% CI: 1.001 to 3.046, respectively). CONCLUSIONS: The progression and prognosis of CAV have improved over 30 years. The ISHLT CAV classification accurately and independently predicts long-term outcome following HTx.

Decreased circulating and neutrophil mediated VEGF-A165 release in stable long-term cardiac transplant recipients.

BACKGROUND: Vascular endothelial growth factor (VEGF) may play a role on the allograft remodelling following cardiac transplantation (CTx). We measured the circulating levels of VEGF-A165 concomitantly with the proinflammatory (Interleukin-8; IL-8), anti-inflammatory (IL-1 receptor antagonist; IL-1RA) and their release from neutrophils of CTx recipients. METHODS: Eighteen CTx recipients aged 49.6 ± 3.1 years, being transplanted for 145 ± 20 months were age-matched to 35 healthy control (HC) subjects. Concomitantly to plasma assessment, circulating neutrophils were isolated, purified and stimulated by vehicle (PBS), N-formyl-Met-Leu-Phe (fMLP, 10(-7) M), bacterial lipopolysaccharide (LPS, 1 µg/mL), or tumour necrosis factor alpha (TNF-α, 10 ng/mL). RESULTS: Compared with HC, CTx recipients exhibited a decrease (-80%) in plasmatic levels of VEGF-A165 (225 ± 42 (HC) vs 44 ± 10 pg/mL (CTx); (p < 0.001). There were no differences in the levels of IL-8 and IL-1RA. Under basal or stimulated conditions, neutrophils from CTx patients exhibited a marked decrease ranging from -30 to -88% on their capacity to release VEGF-A165, IL-8 and IL-1RA upon stimulation. CONCLUSIONS: Long-term CTx recipients exhibit a marked reduction in the circulating levels of VEGF-A165, as well as neutrophil-mediated release of VEGF-A165, IL-1RA and IL-8 compared to healthy volunteers. The mechanisms and physiological impacts of these findings deserve additional investigations.

Sirolimus Immunoprophylaxis and Renal Histological Changes in Long-Term Cardiac Transplant Recipients: A Pilot Study.

BACKGROUND: The effects of sirolimus (SIR), as a substitution for calcineurin inhibitor (CNI) immunoprophylaxis, on renal function in very-long-term cardiac transplant recipients have been a matter of controversy. OBJECTIVE: To assess the impacts of SIR as a substitution for CNI on renal function up to 24 months in long-term cardiac recipients as well as the renal histological changes in patients with suspected CNI-induced nephrotoxicity. METHODS: A total of 23 cardiac transplant recipients aged 57.7 ± 11.2 years, 91 months post-cardiac transplantation were recruited; 15 patients were randomized to CNI-free immune suppression with SIR, and 8 patients were allocated to continue their CNI regimens. Serum creatinine and calculated serum creatinine clearance were measured at prespecified time points up to 24 months. Renal structure and function were assessed by renal biopsies, renal ultrasound, and magnetic resonance imaging at baseline. RESULTS: There were no significant changes in creatinine clearance during the course of the study in patients treated with SIR. However, SIR-treated patients exhibited a significant decrease in 24-hours and nighttime systolic and diastolic blood pressures. Typical findings of significant hypertensive renal disease were detected in 9 of the 11 (82%) patients. Features of chronic CNI toxicity were detected in 6 (55%) patients. CONCLUSIONS: There is a very high rate of hypertensive renal disease concomitantly with some degree of CNI toxicity in long-term cardiac transplant recipients with renal dysfunction. This very high rate of hypertension-related disease may limit the impact of SIR on improving renal function long term following cardiac transplantation.

An unusual case of giant cell myocarditis missed in a Heartmate-2 left ventricle apical-wedge section: a case report and review of the literature.

Herein we present a case of fulminant myocarditis in a woman previously treated for B-cell lymphoma. While the clinical context was suggestive of adriamycin-induced cardiomyopathy, the initial pathology of the Heartmate-2 apical core showed lymphocytic myocarditis. After 8 months of stability, the patient presented with progressive heart failure and recurrent ventricular arrhythmias. An endomyocardial biopsy revealed findings typical of giant cell myocarditis (GCM); poor response to immunosuppressive therapy and marked hemodynamic instability led to urgent transplantation. To our knowledge, this is the first reported case of GCM following an acute lymphocytic myocarditis and the second GCM case associated with B-cell lymphoma.

Multiplanar transesophageal echocardiography for the evaluation and percutaneous management of ostium secundum atrial septal defects in the adult.

The purpose of this paper is to review the usefulness of multiplanar transesophageal echocardiography before, during and after percutaneous transcatheter closure of secundum atrial septal defects. Transesophageal echocardiography imaging techniques,including their role in patient selection, procedural guidance and immediate assessment of technical success and complications are described and discussed in this review. Percutaneous transcatheter closure is indicated for ostium secundum atrial septal defects of less than 40 mm in maximal diameter. The defect must have a favorable anatomy, with adequate rims of at least 5 mm to anchor the prosthesis. Transesophageal echocardiography plays a critical role before the procedure in identifying potential candidates for percutaneous closure and to exclude those with unfavorable anatomy or associated lesions, which could not be addressed percutaneously. Transesophageal echocardiography is also important during the procedure to guide the deployment of the device. After device deployment, the echocardiographer must assess the device (integrity, position and stability), residual shunt, atrio-ventricular valve regurgitation, obstruction to systemic or venous return and pericardial effusion, in order to determine procedural success and diagnose immediate complications.

Multiplanar transesophageal echocardiography for the evaluation and percutaneous management of ostium secundum atrial septal defects in the adult / Ecocardiografía transesofágica multiplanar para la evaluación y el tratamiento percutáneo de la comunicación interauricular tipo ostium secundum en el adulto

The purpose of this paper is to review the usefulness of multiplanar transesophageal echocardiography before, during and after percutaneous transcatheter closure of secundum atrial septal defects. Transesophageal echocardiography imaging techniques, including their role in patient selection, procedural guidance and immediate assessment of technical success and complications are described and discussed in this review. Percutaneous transcatheter closure is indicated for ostium secundum atrial septal defects of less than 40 mm in maximal diameter. The defect must have a favorable anatomy, with adequate rims of at least 5 mm to anchor the prosthesis. Transesophageal echocardiography plays a critical role before the procedure in identifying potential candidates for percutaneous closure and to exclude those with unfavorable anatomy or associated lesions, which could not be addressed percutaneously. Transesophageal echocardiography is also important during the procedure to guide the deployment of the device. After device deployment, the echocardiographer must assess the device (integrity, position and stability), residual shunt, atrio-ventricular valve regurgitation, obstruction to systemic or venous return and pericardial effusion, in order to determine procedural success and diagnose immediate complications.

El propósito de esta revisión es analizar la utilidad de la ecocardiografía transesofágica multiplanar antes, durante y después del cierre percutáneo de la comunicación interauricular tipo ostium secundum. Las consideraciones técnicas de imagen durante la ecocardiografía transesofágica multiplanar, su utilidad en la evaluación de los pacientes, la guía peri-procedimiento, la evaluación del éxito técnico y las complicaciones son descritas y discutidas en esta revisión. El cierre percutáneo está indicado en la comunicación interauricular tipo ostium secundum con diámetro máximo de 40 mm. El defecto debe tener una anatomía favorable con bordes de al menos 5 mm. La ecocardiografía transesofágica multiplanar tiene un papel determinante antes del procedimiento para identificar a candidatos potenciales para el cierre percutáneo y para excluir aquéllos con anatomía no favorable o lesiones asociadas que no pueden ser manejados vía percutánea. La ecocardiografía transesofágica multiplanar es importante durante el procedimiento para guiar la liberación del dispositivo. Después de la liberación del dispositivo el ecocardiografista debe evaluar la posición y estabilidad del dispositivo, la presencia de corto-circuito residual, la regurgitación de las válvulas A-V, el retorno venoso sistémico y pulmonar, y el pericardio, a fin de determinar el éxito del procedimiento y descartar complicaciones asociadas.

Hemodynamic and clinical benefits associated with chronic sildenafil therapy in advanced heart failure: experience of the Montréal Heart Institute.

BACKGROUND: Pulmonary hypertension is highly prevalent in advanced heart failure (HF) despite optimal medical and device therapies. The objective of this investigation was to report on a single centre's experience of open-label chronic sildenafil therapy in patients with advanced HF. METHODS: We conducted a retrospective systematic medical record review of all patients evaluated at our institution for heart transplantation who had also been treated with chronic sildenafil therapy. Baseline demographics, comorbidities, and concomitant medications, as well as the results of laboratory investigations and physiological testing, were abstracted from patient medical records. Change in systolic and mean pulmonary artery pressure (PAP), transpulmonary gradient, cardiac output and cardiac index, and selected laboratory parameters was analyzed by means of the Wilcoxon rank sum test. Outcomes of interest included New York Heart Association (NYHA) functional class after 6 months of therapy and adverse effects attributable to sildenafil. RESULTS: The 16 patients undergoing evaluation for cardiac transplantation combined for 4166 patient-days on sildenafil, with a mean dose of 102.5 ± 54.0 mg/d. None discontinued because of side effects. At 6 months, there was an improvement in the cardiac index (P = 0.014) and systolic PAP (P = 0.049) without any significant change in other hemodynamic parameters. Ten patients (62.5%) experienced an improvement in their NYHA functional class, 8 (50%) received a heart transplantation, and 2 (12.5%) improved sufficiently to be removed from the transplant list. CONCLUSION: Chronic sildenafil therapy was well tolerated and associated with improved functional capacity and decreased systolic PAP. Properly controlled randomized studies of the long-term usefulness of sildenafil therapy in advanced HF populations are warranted.

Effects of angiotensin-converting enzyme inhibitor versus valsartan on cellular signaling events in heart transplant.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) provide similar biologic effects in model systems and similar clinical impacts in humans. The changes in the cardiac angiotensin system signaling pathways in the human heart in response to ACE inhibitors versus ARBs have been incompletely studied. OBJECTIVE: To investigate the effects of ACE inhibitors versus valsartan on the angiotensin II signal transduction pathways in the transplanted human heart. METHODS: Twenty-seven stable cardiac transplant recipients were randomized to remain on ACE inhibitor therapy (n = 8) or to receive valsartan (n = 19). Two additional endomyocardial biopsy samples were obtained at baseline and after 9 months of therapy. The expression of cardiac angiotensin type I and II receptors and atrial natriuretic factor (ANF) was measured by quantitative polymerase chain reaction. The expression and phosphorylation levels of selected signal transduction pathways were analyzed by immunoblotting. RESULTS: The mean dose of valsartan was 114 +/- 41 mg/day. The use of valsartan resulted in a similar impact on blood pressure and biochemistry profile. There were no significant changes in the expression of angiotensin type I and II receptors and ANF with valsartan. Similarly, no significant changes in the expression and phosphorylation of Jun N-terminal kinase, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinases or AKT, and mammalian target of rapamycin was observed in the valsartan-treated group. CONCLUSIONS: Valsartan use is associated with similar clinical and molecular cardiac effects as ACE inhibitor therapy in stable long-term cardiac transplant recipients.

Impact of ezetimibe on cholesterol subfractions in dyslipidemic cardiac transplant recipients receiving statin therapy.

BACKGROUND: Ezetimibe decreases cholesterol in cardiac transplant recipients intolerant to statins therapy. The effects of ezetimibe in addition to statins therapy and its relationship with the magnitude of dyslipidemia and statins utilization have not been studied in cardiac transplant recipients. METHODS: The design of this investigation was a retrospective case control study. Twenty-two patients receiving the combination of therapy of statins plus ezetimibe were compared with 43 patients treated with statins only. The endpoints were assessed after three months of follow-up. RESULTS: The addition of ezetimibe decreased low density lipoprotein-cholesterol by 25% compared with a 4% increase in patients receiving statins only. The impact of ezetimibe was similar regardless of the magnitude of dyslipidemia or statins dosage. Ezetimibe increase high density lipoprotein (HDL)-cholesterol only in patients with baseline HDL-cholesterol above 1.3 mM/L (p < 0.05). There was an asymptomatic, but significant increase in creatinine kinase level [+31.4 +/- 8.1 (ezetimibe) vs. + 1.5 +/- 5.0 mM/L (placebo); p = 0.005]. CONCLUSION: Ezetimibe therapy provides a significant reduction in most cholesterol subfractions regardless of the magnitude of dyslipidemia and statins dosage.

Results following implantation of mechanical circulatory support systems: the Montreal Heart Institute experience.

BACKGROUND: Mechanical circulatory support systems (MCSS) have been available in Canada since 1986. Accepted indications include bridging to transplantation or recovery. The present study reviewed the results following MCSS implantation at the Montreal Heart Institute (Montreal, Quebec). METHODS: From September 1987 to September 2006, 43 MCSS were implanted (32 Thoratec [Thoratec Corporation, USA], nine CardioWest TAH [SynCardia Systems Inc, USA], two Novacor [WorldHeart Corporation, Canada]) in 43 patients (mean [+/- SD] age 44+/-13 years; range 19 to 64 years). Indications for implantation included cardiogenic shock due to ischemic (n=19), viral (n=10) or other types of cardiomyopathies (n=14). RESULTS: The mean ejection fraction before implantation was 17.6+/-6.5% (range 10% to 45%). Before MCSS implantation, most patients showed signs of end-organ failure, including mechanical ventilation (77%), central venous pressure higher than 16 mmHg (44%), oliguria (35%) and hepatic dysfunction (19%). The mean duration of MCSS support was 22.8+/-32.8 days (range one to 158 days). Survival to transplantation or recovery was 74%. Only one patient was successfully bridged to recovery. Complications were common during MCSS support. They included reexploration for bleeding (47%), respiratory failure (44%), renal failure requiring temporary dialysis (40%), infection (33%) and neurological events (16%). Only one patient had device failure. In patients successfully bridged to transplantation, early actuarial survival (one month) following transplantation averaged 71+/-8% and was 57+/-9% at one year. CONCLUSION: MCSS support with a left ventricular assist device or a total artificial heart provides an effective means of bridging terminally ill patients to transplantation or recovery. Early survival after transplantation shows satisfactory results. However, these results come at the expense of frequent device-related complications, and device failure remains a constant threat.

Two decades of cardiac transplantation at the Montreal Heart Institute.

BACKGROUND: The first heart transplantation in Canada was performed in 1968 at the Montreal Heart Institute (Montreal, Quebec). After nine patients transplanted in the precyclosporine era, the program was stopped. With the advent of cyclosporine, the program was reactivated in 1983. OBJECTIVE: To review the experience of the Montreal Heart Institute with heart transplantation between 1983 and 2005. METHODS: Three hundred patients underwent heart transplantation and were followed at the transplant clinic. Patients were divided into two groups: group 1--first decade (1983 to 1993, n=145) and group 2--second decade (1994 to 2005, n=155). RESULTS: There were 125 men (86%) and 20 women (14%) with a mean age of 45+/-10 years in group 1 compared with 118 men (76%) and 37 women (24%) with a mean age of 48+/-12 years in group 2 (P=0.03 and P=0.02, respectively). Indications for transplantation included congestive heart failure and/or ischemic heart disease in the majority of patients of both groups, with 83% in group 1 and 73% in group 2, respectively. In group 1, 30 patients (21%) required preoperative pharmacological support and 13 patients (9%) were on mechanical support compared with 16 (10%) and 34 (22%) patients in group 2 (P<0.01). The mean age of donors was 27+/-10 years and 34+/-13 years in groups 1 and 2, respectively (P<0.01). Major causes of mortality for donors included a motor vehicle accident in 65 cases (45%) and brain hemorrhage in 43 cases (30%) in group 1 compared with 34 cases (22%) and 68 cases (44%) in group 2 donors (P<0.01). The one-, five- and 10-year actuarial survival rates were 86%, 77% and 71%, respectively, in group 1 compared with 84%, 80% and 68%, respectively, in group 2 (P=0.95). The one-, five- and 10-year freedom from rejection rates were 35%, 28% and 25%, respectively, in group 1 compared with 41%, 36% and 33%, respectively, in group 2 (P=0.13). The one-, five- and 10-year freedom from infection rates were 38%, 24% and 17%, respectively, in group 1 compared with 37%, 23% and 19%, respectively, in group 2 (P=0.72). The one- and five-year freedom from graft coronary artery disease rates were 93% and 67%, respectively, in group 1 compared with 88% and 81%, respectively, in group 2 (P<0.01). The one-, five- and 10-year cancer-free survival rates were 98%, 91% and 73%, respectively, in group 1 compared with 98%, 90% and 77%, respectively, in group 2 (P=0.76). CONCLUSIONS: Patients who underwent heart transplantation in the second decade of the investigators' experience were older and in worse preoperative clinical condition; the donors were also older. However, survival and event-free survival rates remained similar throughout both periods.

Cardiac transplantation for hypertrophic cardiomyopathy: a valid therapeutic option.

BACKGROUND: Hypertrophic cardiomyopathy is a rare indication for cardiac transplantation, with only anecdotal reports in the literature. Transplantation has been proposed to patients with hypertrophic cardiomyopathy who remained symptomatic despite optimal medical treatment or who progressed to congestive heart failure, and when conventional surgical correction was not or was no longer possible. In this report, we analyze the clinical results of cardiac transplantation in these patients. METHODS: We retrospectively reviewed complete clinical data and prospectively gathered complete follow-up data for 14 patients who underwent orthotopic cardiac transplantation for hypertrophic cardiomyopathy at the Montreal Heart Institute and Ste-Justine Hospital between 1984 and 2001. RESULTS: Ten male (71.4%, 5 adults and 5 children) and 4 female (28.6%, 2 adults and 2 children) patients underwent heart transplantation for hypertrophic cardiomyopathy. The median age of the recipients in the pediatric group was 13 years (range, 6-16) and was 40 years (range, 22-46) in the adult group. Median duration of follow-up was 9.5 years (mean, 8.8 +/- 4.8 years; range, 1-18) and was 100% complete. We found no operative mortality and found 2 late deaths related to coronary graft atherosclerosis. Long-term survival at 5, 10, and 15 years was 100%, 85%, and 64%, respectively. Freedom from acute rejection at 1, 5, and 10 years was 73%, 32%, and 9%, respectively. The remaining 11 survivors exhibit few symptoms and are currently in New York Heart Association Class I or II. CONCLUSIONS: Cardiac transplantation is a valid therapeutic option for patients with symptomatic hypertrophic cardiomyopathy who do not respond to optimal medical management and who are not candidates for conventional surgical treatment. The long-term outcome is excellent in these patients.