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Biomedical subjects

R Dorent

Publications and source records attributed to R Dorent.

At least 19 recordsLinked to original sources
PubMed1999

Safety, tolerability and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil based formulation of cyclosporine--results at six months after transplantation.

BACKGROUND: The introduction of cyclosporine has resulted in significant improvement in the survival of cardiac allograft recipients due to decreased mortality from infection and rejection. The original oil-based cyclosporine formulation exhibits variable and unpredictable bioavailability that correlates with an increased incidence of acute and chronic rejection in those patients in whom this is most pronounced. The primary objectives of this prospective, multicenter, randomized, double-blind study in cardiac transplant patients were: to compare the efficacy of cyclosporine microemulsion (CsA-NL) with oil-based cyclosporine (CsA-SM) as measured by cardiac allograft and recipient survival and the incidence and severity of acute rejection episodes; and to assess the safety and tolerability of CsA-NL compared with CsA-SM in this population. This report represents the analysis of results 6 months after transplantation. METHODS: A total of 380 patients undergoing their first cardiac transplant at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial examining the safety and efficacy of CsA-NL versus CsA-SM. Rejection was diagnosed using endomyocardial biopsy and were graded according to standardized criteria of the International Society of Heart and Lung Transplantation (ISHLT). Clinical parameters were monitored during the study. Survival and freedom from were used for analysis as was Fisher's exact test for comparisons between groups. RESULTS: At 6 months after transplantation, allograft and patient survival were the same for both groups. The frequency of ISHLT grade 3A or greater episodes in the two groups was identical. Fewer CsA-NL patients (5.9%) required antilymphocyte antibody (ATG or OKT-3) therapy for rejection compared with the CsA-SM-treated patients (14.1%, P=0.01). Females with ISHLT rejection grade > or = 3A treated with CsA-NL had a 46% lower incidence of rejection compared with the CsA-SM-treated group (31.3% vs. 57.6%, P=0.032). Fewer infections were seen in the CsA-NL. With the exception of baseline and 1 week posttransplant creatinines which were higher in the CsA-NL group, the overall creatinine was not significantly different between the two groups. CONCLUSIONS: This multicenter, randomized study of cardiac transplant recipients documented less severe rejection (in particular those requiring antibody therapy) and a lower incidence of infection in CsA-NL-treated patients. Results from the female subgroup analysis suggest that the improved bioavailability of CsA-NL might reduce the frequency of rejection episodes in female patients. The use of CsA-NL was not associated with an increased risk of adverse events.

Adolescent↗
PubMed1999

Three cases of severe subfulminant hepatitis in heart-transplanted patients after nosocomial transmission of a mutant hepatitis B virus.

Fulminant and severe viral hepatitis are frequently associated with mutant hepatitis B virus (HBV) strains. In this study, the genetic background of a viral strain causing severe subfulminant outcome in heart-transplanted patients was studied and compared with viral hepatitis B strains that were not linked to severe liver disease in the same setting. A total of 46 patients infected nosocomially with HBV genotype A were studied. Five different viral strains were detected, infecting 3, 9, 5, 24, and 5 patients, respectively. Only one viral strain was found to be associated with the subfulminant outcome and 3 patient deaths as a consequence of severe liver disease. The remaining 43 patients with posttransplantation HBV infection did not show this fatal outcome. Instead, symptoms of hepatitis were generally mild or clinically undiagnosed. Comparison of this virus genome with the four other strains showed an accumulation of mutations in the basic core promoter, a region that influences viral replication, but also in hepatitis B X protein (HBX) (7 mutant motifs), core (10 mutant motifs), the preS1 region (5 mutant motifs), and the HBpolymerase open reading frame (17 motifs). Some of these variations, such as those in the core region, were located on the tip of the protruding spike of the viral capsid (codons 60 to 90), also known in part as an important HLA class II-restricted epitope region. These mutations might therefore influence the immune-mediated response. The viral strain causing subfulminant hepatitis was, in addition, the only strain with a preCore stop codon mutation and, thus, hepatitis B e antigen (HBeAg) expression was never observed. The combination of these specific viral factors is thought to be responsible for the fatal outcome in these immune-suppressed heart-transplant recipients.

Base Sequence↗
PubMed1999

Characterization of a unique genetic variant in the beta1-adrenoceptor gene and evaluation of its role in idiopathic dilated cardiomyopathy. CARDIGENE Group.

The genetic factors that underlie idiopathic dilated cardiomyopathy (IDCM) have not yet been elucidated. Since beta1-adrenoceptors are downregulated in patients with IDCM, and since beta-blocker therapy is consistently beneficial in this setting, we hypothesized that genetic variation in the beta1-adrenoceptor might affect susceptibility to and/or severity of IDCM. As no intragenic polymorphism was available, a systematic screening of the gene was first performed. The organization and sequence of the human beta1-adrenoceptor gene were established using polymerase chain reaction, single-strand conformation polymorphism analysis and sequencing. The gene comprises 1434 bp and no intron was observed. We found a unique and frequent polymorphism (C1165G) which predicts an Arg389Gly substitution. The association of this polymorphism with IDCM was then analysed using the PCR-restriction fragment length polymorphism method in the CARDIGENE population, a clinically well-characterized population of IDCM. Genotypic distribution was in agreement with Hardy-Weinberg equilibrium. There were no differences in the beta1-adrenoceptor allele frequencies between IDCM (n=426; C/G=0.76/0.24) and age- and sex-matched control subjects (n=395; C/G=0.78/0.22). Within the patient group, no association was observed with the severity of the disease. In conclusion, the genomic organization of beta1-adrenoceptor is described here for the first time. We found a unique and frequent polymorphism in the coding sequence of the gene. No association was observed between IDCM and the genetic variant. Its possible involvement in other cardiac diseases related to the beta1-adrenoceptor remains to be analysed.

Adult↗
PubMed1999

Posttransplantation cytotoxic immunoglobulin G is associated with a high rate of acute allograft dysfunctions in heart transplant recipients.

BACKGROUND: The significance of anti-human leukocyte antigen immunoglobin G (IgG) detected in the posttransplantation course of heart graft recipients remains unclear. METHOD: Sera from 121 cardiac allograft recipients transplanted between January 1992 and December 1994 were screened for the presence of lymphocytotoxic antibodies in the first year after transplantation. Dithiothreitol was used to differentiate IgG from immunoglobulin M. RESULTS: Nineteen patients (15%) had cytotoxic IgG develop, mainly during the first month after transplantation. The percentage of women was higher in this group (42% vs 15.7%; P <.05). Donor to recipient mismatches for sex, blood typing, cytomegalovirus serology, and human leukocyte antigen typing were comparable between IgG producers and nonproducers. The frequency of acute allograft dysfunction during the first year after transplantation was significantly higher among patients producing IgG (42% vs 5.9; P <.001). Most of these acute allograft dysfunctions were independent of cellular rejection lesions but were associated with a thickening of the posterior wall and the interventricular septum during the acute episode. Finally, all the patients but one recovered. Recurrences were not uncommon and, at 1 year after transplantation, the dose of cyclosporine used in patients producing IgG was significantly greater, as was the left ventricular thickness. CONCLUSION: Posttransplantation cytotoxic IgG is not uncommon and appears to be associated with a high rate of acute allograft dysfunction. Development of these antibodies can be caused by a previous undetected immunization, as suggested by the higher percentage of women in the producer group. Correlation with histologic lesions of humoral rejection are discussed.

Adolescent↗
PubMed1998

Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group.

BACKGROUND: Photopheresis is an immunoregulatory technique in which lymphocytes are reinfused after exposure to a photoactive compound (methoxsalen) and ultraviolet A light. We performed a preliminary study to assess the safety and efficacy of photopheresis in the prevention of acute rejection of cardiac allografts. METHODS: A total of 60 consecutive eligible recipients of primary cardiac transplants were randomly assigned to standard triple-drug immunosuppressive therapy (cyclosporine, azathioprine, and prednisone) alone or in conjunction with photopheresis. The photopheresis group received a total of 24 photopheresis treatments, each pair of treatments given on two consecutive days, during the first six months after transplantation. The regimen for maintenance immunosuppression, the definition and treatment of rejection episodes, the use of prophylactic antibiotics, and the schedule for cardiac biopsies were standardized among all 12 study centers. All the cardiac-biopsy samples were graded in a blinded manner at a central pathology laboratory. Plasma from the subgroup of 34 patients (57 percent) who were enrolled at the nine U.S. centers was analyzed by polymerase-chain-reaction amplification for cytomegalovirus DNA. RESULTS: After six months of follow-up, the mean (+/-SD) number of episodes of acute rejection per patient was 1.44+/-1.0 in the standard-therapy group, as compared with 0.91+/-1.0 in the photopheresis group (P=0.04). Significantly more patients in the photopheresis group had one rejection episode or none (27 of 33) than in the standard-therapy group (14 of 27), and significantly fewer patients in the photopheresis group had two or more rejection episodes (6 of 33) than in the standard-therapy group (13 of 27, P=0.02). There was no significant difference in the time to a first episode of rejection, the incidence of rejection associated with hemodynamic compromise, or survival at 6 and 12 months. Although there were no significant differences in the rates or types of infection, cytomegalovirus DNA was detected significantly less frequently in the photopheresis group than in the standard-therapy group (P=0.04). CONCLUSIONS: In this pilot study, the addition of photopheresis to triple-drug immunosuppressive therapy significantly decreased the risk of cardiac rejection without increasing the incidence of infection.

Combined Modality Therapy↗
PubMed1998

Pacemaker infective endocarditis.

We identified 33 patients with definite pacemaker endocarditis--that is, with direct evidence of infective endocarditis, based on surgery or autopsy histologic findings of or bacteriologic findings (Gram stain or culture) of valvular vegetation or electrode-tip wire vegetation. Most of the patients (75%) were > or = 60 years of age (mean 66 +/- 3; range 21 to 86). Pouch hematoma or inflammation was common (58%), but other predisposing factors for endocarditis were rare. At the time that pacemaker endocarditis was found, the mean number of leads was 2.4 +/- 1.1 (range 1 to 7). The interval from the last procedure to diagnosis of endocarditis was 20 +/- 4 months (range 1 to 72). Endocarditis appeared after pacemaker implantation, early (< 3 months) in 10 patients and late (> or = 3 months) in 23 patients. Fever was the most common symptom, being isolated in 36%, associated with a poor general condition in 24%, and associated with septic shock in 9%. Transthoracic echocardiography showed vegetations in only 2 of 9 patients. Transesophageal echocardiography demonstrated the presence of lead vegetations (n = 20) or tricuspid vegetations (n = 3) in 23 of 24 patients (96%; p <0.0001 compared with transthoracic echocardiography). Pulmonary scintigraphy showed a typical pulmonary embolization in 7 of 17 patients (41%). Pathogens were mainly isolated from blood (82%) and lead (91%) cultures. The major pathogens causing pacemaker endocarditis were Staphylococcus epidermidis (n = 17) and S. aureus (n = 7). S. epidermidis was found more often in early than in late endocarditis (90% vs 50%; p = 0.05). All patients were treated with prolonged antibiotic regimens before and after electrode removal. Electrode removal was achieved by surgery (n = 29) or traction (n = 4). Associated procedures were performed in 9 patients. After the intensive care period, only 17 patients needed a new permanent pacemaker. Overall mortality was 24% after a mean follow-up period of 22 +/- 4 months (range 1 to 88). Eight patients who were significantly older (74 +/- 3 vs 63 +/- 3 years; p = 0.05) died < or = 2 months after electrode removal, whereas 25 were alive and asymptomatic.

Adult↗
PubMed1998

Biliary surgery after heart transplantation.

BACKGROUND: Biliary tract diseases are frequent in heart transplant recipients, with significant morbidity and mortality. Since the first presentation of gallstones in this population is often acute cholecystitis, asymptomatic cholelithiasis should not be considered benign. PATIENTS AND METHODS: We retrospectively reviewed 18 heart transplant recipients who underwent cholecystectomy from January 1991 to June 1997. We intentionally chose to perform a straightforward open procedure when acute cholecystitis was suspected (3 patients). A laparoscopic cholecystectomy was performed in all the other cases (15 patients) without conversion to open procedure. CONCLUSION: Since no significant complications were observed in our patients, we believe that transplant recipients with cholelithiasis should undergo laparoscopic cholecystectomy in their posttransplantation course regardless of the symptomatic status of their biliary tract.

Adult↗
PubMed1998

Heart retransplantation: a 23-year single-center clinical experience.

BACKGROUND: The main causes of allograft failure after cardiac transplantation are primary graft dysfunction, intractable acute rejection, and coronary graft disease. Despite the important progress in the last several years in graft preservation, surgical techniques, immunosuppression, and treatment of coronary graft disease, retransplantation in selected cases is the only way to achieve long-term recipient survival. METHODS: We compare here in a case-control study 24 retransplantations with 47 first transplants in patients matched for date of transplantation. RESULTS: Between 1973 and 1996, 1,063 patients underwent cardiac transplantation in our institution. In this cohort, 22 patients had a total of 24 retransplantations (2 second-time retransplantations). The causes of retransplantations were primary graft failure (n=4), acute rejection (n=7), coronary graft disease (n=11), and miscellaneous (n=2). Survival at 1 and 5 years of patients with retransplantations is 45.5% and 31.2%, and survival of control patients is 59.4% and 38.8% (p=0.07). An interval between first transplantation and retransplantation shorter (n=11) or longer (n=13) than 1 year is associated with a 1-year survival of 27.3% and 61.5% and a 4-year survival of 27.3% and 46%, respectively (not significant). Intervals shorter than 1 year between first transplantation and retransplantation were exclusively secondary to primary graft failure or intractable acute rejection. CONCLUSIONS: In the face of lack of donor grafts, these and other data indicate that retransplantation should be considered cautiously, especially when the interval between the first transplantation and retransplantation is short.

Acute Disease↗
PubMed1998

Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity?

PURPOSE: Organ recipients are at a high risk of posttransplant lymphoproliferative disorders (PTLD) as a result of immunosuppressive therapy. Most B-cell lymphomas are associated with Epstein-Barr virus (EBV) infection. We describe a morphologically and clinically distinct group of PTLD in 11 patients that occurred late after organ transplantation and were not associated with EBV. PATIENTS AND METHODS: There were seven kidney, three heart, and one liver transplant recipients (group I). The clinical manifestations, pathologic findings, treatment, and outcome were compared with those in 21 patients with EBV-associated PTLD treated in our institution (group II). EBV was detected with at least two techniques: Epstein-Barr-encoded RNA (EBER) in situ hybridization with EBER 1 + 2 probes, Southern blotting, and detection of latent membrane protein 1 (LMP1) expression by immunohistochemistry. RESULTS: The time between transplantation and the diagnosis of lymphoma ranged from 180 to 10,220 days in group I (mean, 2,234; median, 1,800) and from 60 to 2,100 days in group II (mean, 546; median, 180), and was significantly shorter in group II (P = .02). Among 19 tumors diagnosed within 2 years after the graft, 16 were associated with EBV; among 13 tumors diagnosed after more than 2 years, only five were associated with EBV. All of the B-cell PTLDs in group I were classified as monomorphic, meeting the criteria of B diffuse large-cell lymphoma (B-DLCL) with a component of immunoblasts, and genotyping confirmed their monoclonality. Three tumors were T-cell pleomorphic lymphomas. Tumor sites were mainly bone marrow and lymph nodes. Overall median survival was 1 month in group I and 37 months in group II, with two patients still alive in group I and nine in group II. The survival time was significantly longer in group II (P < .01). CONCLUSION: EBV-negative PTLD may be a late serious complication of organ transplantation. Half the tumors observed after kidney transplantation in our center were not associated with EBV and emerged after more than 5 years, which suggests the number of EBV-negative PTLDs in organ recipients might increase with time.

Adolescent↗
PubMed1998

La Pitié heart transplantation: 30-year single center clinical experience.

At La Pitié Hospital, 1,184 patients underwent cardiac transplantation for end-stage cardiac disease (1,122 orthotopic and 62 heterotopic) between April 1968-November 1998. Since April 1986, 140 patients have been supported using several different mechanical assist devices as a bridge to transplantation. Twenty-four retransplantations (2.2%) were performed for primary graft failure in 4 (17%), refractory acute rejection in 7(29%), coronary graft disease in 11 (46%) and others in 2 (8%) patients. In a case-control study, retransplanted patients were matched with first transplant patients and survival rates at one and 5 years were 59.4% and 38.8% compared with survival rates for retransplanted patients of 45.4% and 31.2%, respectively. Seventy-four patients survived more than 10 years (61 males, 13 females). Mortality did not increase after 10 years. Unfortunately many suffered complications: 77% had hypertension, hypercholesterolemia (22%), hyperuricemia (41%), osteoporosis (11%), osteonecrosis (5%) and diabetes (7%). Renal function remains one of the main problems; 16% had a creatinine > 180 mumol/L and patients are on chronic dialysis.

Actuarial Analysis↗
PubMed1998

European Multicenter Tacrolimus (FK506) Heart Pilot Study: one-year results--European Tacrolimus Multicenter Heart Study Group.

BACKGROUND: Tacrolimus (FK506) may represent a major advance in the management of allograft rejection after solid organ transplantation. In August 1994 a European heart transplantation pilot study was initiated to assess the efficacy and safety of tacrolimus when administered exclusively through an oral route. METHODS: Eighty-two heart transplant recipients were randomized to treatment (2:1 ratio) with either tacrolimus- (n=54) or cyclosporine-based therapy (n=28). RESULTS: No significant differences were evident between the two treatment groups in either rejection or survival rates at 1 year. Kaplan-Meier estimates of the freedom from rejection were 26.3% and 18.5%, respectively, for the tacrolimus and cyclosporine treatment groups (p=.444). Survival rates were 79.6% and 92.9% (p=.125). At 3 of the 5 centers, patients received antithymocyte globulin during the immediate postoperative period and fared better than those who did not (with acute rejection-free rates of 49.2% and 26.7% for tacrolimus and cyclosporine, respectively [p=.080], as opposed to 7.1% and 8.3% [p=.965]; patient survival rates of 84.6% and 93.3% [p=.382] vs 75.0% and 92.3% [p=.243]). The overall rates of infection, impaired renal function (31.5% vs 21.4%), and glucose intolerance (7.0% vs 4.3%) did not differ significantly between the tacrolimus and cyclosporine treatment groups. Tacrolimus seemed to possess an advantage with regard to a reduced requirement for antihypertensive therapy (59.5% vs 87.5%, p=.025). CONCLUSIONS: Immunosuppression with oral tacrolimus provides a viable alternative to treatment with cyclosporine, particularly when administered in conjunction with antibody therapy. Further studies are warranted to optimize the administration of tacrolimus in this indication.

Administration, Oral↗
PubMed1998

[Alcoholic cardiomyopathy and heart transplantation].

The recognition of alcoholic cardiomyopathy in patients with dilated cardiomyopathy is essential as they may regress, at least partially in a relatively short period, with abstention. The clinical history is the key to diagnosis because no other specific feature can identify the cause. Between January 1984 and July 1995, 26 candidates for cardiac transplantation with dilated cardiomyopathy and chronic alcoholism improved after withdrawal of alcohol. None of these patients was placed on the surgical waiting list. Patients with ischaemic cardiomyopathy, valvular disease or previous surgery for valvular hypertensive or congenital heart disease, documented viral myocarditis or connective tissue diseases, were excluded. The diagnostic criterion of chronic alcoholism was a total alcohol consumption of 292 kg and a duration of alcohol abuse of over 10 years. In addition to the clinical features, biological, electrocardiographic, echocardiographic and haemodynamic parameters were analysed. The mean age of the patients was 48 +/- 8 years. There were 25 men and 1 woman. The total mean alcohol consumption was 1,492 kg. The average follow-up period was 63 +/- 41 months. The interval between the onset of symptoms and abstention was 25 months. Haemodynamic improvement was observed in 25 cases. The average interval between alcoholic abstention and recovery was 11.7 months. One patient died suddenly. Improvement of symptoms, decrease of the cardiothoracic ratio and improvement of echocardiographic parameters were statistically significant. The increase in angiographic or isotopic ejection fraction and cardiac index and the decrease in mean pulmonary artery pressures were also statistically significant. These results confirmed the diagnosis of alcoholic cardiomyopathy. Therefore, patients with chronic alcohol abuse and dilated cardiomyopathy must be identified and treated for this problem and not placed on the waiting list for cardiac transplantation unless no improvement is observed after about 3 months of abstention.

Adult↗
PubMed1997

Endothelin-1 in the lungs of patients with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is characterized by an increase in vascular tone and an abnormal proliferation of muscle cells in the walls of pulmonary arteries. Recent studies have found high plasma endothelin-1 (ET-1) concentrations in patients with PH. This study was conducted to assess whether elevated circulating ET-1 levels in PH really reflect excessive local pulmonary production. METHODS: We prospectively studied ET-1 concentration in lung specimens from 6 control subjects and 13 patients with severe PH referred for lung or heart-lung transplantation (6 patients had primary PH and 7 PH secondary to congenital heart defect). Endothelin-like immunoreactivity (ET-LI) was measured in plasma and lung tissue, using a radioimmunoassay, after ET-1 extraction. Reverse-phase high-performance liquid chromatography was also performed. RESULTS: Peripheral venous plasma ET-LI concentrations in patients with PH, whatever the cause, were greater than those in controls (10.7 +/- 0.8 vs 5.3 +/- 0.7 pg/ml; P < 0.0005). Pulmonary ET-LI was significantly higher in patients with PH, irrespective of its cause, than in controls (25.2 +/- 5.1 vs 8.1 +/- 1.1 pg/mg, P < 0.03). ET-LI pulmonary concentrations were slightly higher in Eisenmenger than in primary PH, but this was not significant (27.1 +/- 8.6 vs 22.8 +/- 5.4 pg/mg). Linear regression analysis indicated a small but significant correlation between ET-LI pulmonary concentrations and pulmonary vascular resistance in the patients with PH (r = 0.38; P = 0.047). In each case, HPLC separation of ET indicated that most of the immuno-reactivity was detected in the same fraction as ET-1. CONCLUSIONS: The striking increase in ET-1 pulmonary concentration provides new evidence that excessive local pulmonary ET-1 production may contribute to the vascular abnormalities of pulmonary hypertension.

Adult↗
PubMed1997

Position-related factors in mitral and tricuspid bioprostheses degenerative changes.

We report clinicopathological findings in 15 patients in whom the same bioprosthesis (BP) had been implanted simultaneously in both mitral and tricuspid positions. The aim of the study was to investigate whether position-related factors played an important role in BP degeneration. There were 14 women and 1 man with a mean age of 34 +/- 11 years. The indications for the initial operation were rheumatic in 14 cases and endocarditis in one patient. The mean interval before reoperation was 7.5 +/- 3.3 years. Predominant cause of reoperation was: structural deterioration of both mitral and tricuspid BPs (6), mitral regurgitation (5), tricuspid BP dysfunction (1), para-aortic leak (1), mitro-aortic thrombi (1). Calcific deposits were the principal cause of early deterioration of mitral BPs and the major cause of late tricuspid BPs dysfunction. This lesion was predominantly related to local factors. Cuspal tears were the principal cause of late (> 9 yrs) mitral BP failure and most probably related to mechanical stress. Extensive fibrosis affected only tricuspid bioprostheses. In 7 patients more extensive degenerative changes occurred in bioprostheses in the mitral rather than the tricuspid position (Group I). However, in the remaining eight the magnitude of the changes was very similar in the two positions (Group II). The interval before reoperation was significantly longer in patients of Group II (9.8 yrs, range 5-13) than patients in Group I (4.9 yrs, range 3-6), (p < 0.01). We concluded that position-related factors exert a major role in bioprosthetic failure. These factors are more deleterious in the mitral position than in the tricuspid position.

Adolescent↗
PubMed1996

Heart transplant for the failing ischaemic ventricle.

Clinical application of heart transplantation goes beyond 28 years experience. Ischaemic heart diseases remain, with idiopathic cardiomyopathies, the main indications for cardiac transplant. A combination of haemodynamic, contractile and viability measurements may be useful to choose between transplant and coronary revascularization for the failing ischaemic ventricle. Advances in the detection of early rejection, improved organ preservation procedures, and the introduction of new immunosuppressive therapy protocols have produced dramatic results in heart transplantation. Late graft atherosclerosis remains a serious threat despite retransplantation and, in some cases, mechanical circulatory support.

Contraindications↗