Differential effect of everolimus on progression of early and late cardiac allograft vasculopathy in current clinical practice.

Randomized trials showed that mTOR inhibitors prevent early development of cardiac allograft vasculopathy (CAV). However, the action of these drugs on CAV late after transplant is controversial, and their effectiveness for CAV prevention in clinical practice is poorly explored. In this observational study we included 143 consecutive heart transplant recipients who underwent serial intravascular ultrasound (IVUS), receiving either everolimus or mycophenolate as adjunctive therapy to cyclosporine. Ninety-one recipients comprised the early cohort, receiving IVUS at weeks 3-6 and year 1 after transplant, and 52 the late cohort, receiving IVUS at years 1 and 5 after transplant. Everolimus independently reduced the odds for early CAV (0.14 [0.01-0.77]; p = 0.02) but it did not appear to influence late CAV progression. High-dose statins were found to be associated with reduced CAV progression both early and late after transplant (p ≤ 0.05). Metabolic abnormalities, such as high triglycerides, were associated with late, but not with early CAV progression. By highlighting a differential effect of everolimus and metabolic abnormalities on early and late changes of graft coronary morphology, this observational study supports the hypothesis that everolimus may be effective for CAV prevention but not for CAV treatment, and that risk factors intervene in a time-dependent sequence during CAV development.

Changes in exercise capacity induced by heart transplantation: prognostic and therapeutic implications.

Survival and exercise performance are key targets of heart transplantation (HT). We designed this study to help in identifying (1) patients with chronic heart failure (CHF) at risk of poor exercise capacity after HT and (2) HT recipients presenting risk factors modifiable with exercise showing a potential impact on outcome. We enrolled 49 HT recipients (age 52 ± 12 years, 84% males) who underwent a cardiopulmonary exercise test before (9 ± 6 months) and after (20 ± 14 months) HT. In the CHF phase, lower peak oxygen consumption (VO(2) ) (odds ratio 0.69, P=0.017) independently predicted peak VO(2) improvement after HT. In the post-HT phase, body mass index (BMI) [adjusted hazard ratio (HR) 1.16, P=0.034] and VE (ventilation)/VCO(2) (carbon dioxide production) slope (adjusted HR 1.07, P=0.031) independently predicted mortality. In conclusion, CHF patients with only a moderate impairment of peak VO(2) are at a risk of failing to achieve a significant improvement of exercise performance after HT. In the post-HT phase, a BMI≥28 and/or a VE/VCO(2) slope ≥47 represent risk factors for death, which are potentially modifiable with exercise. Prospective randomized studies are needed to analyze the effects of training on functional capacity and outcome in the different subsets of HT recipients.

Cardiac transplantation from a carbon monoxide intoxicated donor.

Heart transplantation is a demonstrated successful and life-saving treatment for an increasing number of patients. The growth of heart transplantation surgery is limited by the relative lack of suitable donors, and the increasing demand has lead to the expansion of acceptance criteria. Patients succumbing to carbon monoxide (CO) poisoning are usually considered not suitable organ donors and they are routinely rejected in many centers. Although organs from CO poisoning donors have been occasionally used, cardiac transplantation in this scenario remains very uncommon. We report the successful heart transplantation from a CO intoxicated donor, who was previously refused by two other transplantation teams. Standard donor evaluation criteria, transplantation techniques and management were used. Limited cases are described in literature. The present case may increase awareness among emergency department physicians, as well as transplantations teams, that patients dying of CO exposure may be acceptable cardiac donors.

Prevalence of substance-related disorders in heart transplantation candidates.

Substance abuse cessation is one of the leading factors in determining the eligibility for the heart transplantation waiting list, as noncompliance with this issue may seriously endanger posttransplantation outcomes. Yet, the prevalence of substance-related disorders among candidates for heart transplantation has not been evaluated enough. Eighty three heart transplantation candidates were assessed for prior or current substance-related disorders through the Structured Clinical Interview for mental disorders according to DSM-IV. A prior history of at least one substance-related disorder was found in 64% of patients, with nicotine dependence as the most prevalent diagnosis (61.4% of the sample). Ten subjects were currently smokers, despite heart failure. A prior history of alcohol abuse and caffeine intoxication was found in 9.6% and 2.4% of patients, respectively. Substance abuse or dependence behaviors should be monitored during all the phases of heart transplantation program. Early identification of current substance-related disorders may allow better allocation of organ resources and proper lifestyle modification programs provision. A prior history of substance-related disorders should alert physicians to assess patients for possible relapse, especially after transplantation. The inclusion of a specialist in the assessment and treatment of substance-related disorders in the heart transplantation unit may reduce the risk of unsuccessful outcomes due to noncompliance with an adequate lifestyle.

Intraoperative rupture of the donor aorta during heart transplantation: surgical management with a Bentall-de Bono procedure.

Aortic complications are uncommon in cardiac allograft recipients. Primary acute aortic rupture is an extremely rare and dramatic event that can occur in the early phase after transplantation. In this article we describe a case of acute intraoperative rupture of the donor aorta just after aortic declamping during orthotopic cardiac transplantation procedure, successfully treated with a Bentall-De Bono operation.

Long-term safety and effectiveness of statins for heart transplant recipients in routine clinical practice.

BACKGROUND: Whereas the efficacy of statins after heart transplantation (HT) in controlled study settings has been clearly demonstrated, more extensive data are required on the safety and effectiveness of long-term treatment in routine clinical practice. METHODS: We analyzed the risks and benefits in clinical practice of treatment with statins in all patients who survived HT for at least a month from December 1985 through 2001. RESULTS: During a mean follow-up of 4.8+/-3.8 years, 186 patients were treated with statins (for a median duration [25th to 75th percentile] of 29 [12 to 54] months), while 48 received dietary therapy alone. Patients treated with statins (pravastatin, 48%; atorvastatin, 37%; simvastatin, 14%) presented linearized rates of rhabdomyolisis, myositis, and significant transaminase elevation of 0.37%, 0.74%, and 0.37% per year of treatment, respectively (no fatal event occurred). Low-density lipoprotein decreased after statins by 19% (P<.001). At multivariate analysis, treatment with statins was independently associated with reduced risk of cardiac allograft vasculopathy and overall mortality (P<.001). CONCLUSIONS: Our data provide necessary confirmation of the safety and effectiveness in routine clinical practice of appropriately monitored long-term administration of statins (particularly atorvastatin, pravastatin, and simvastatin) in the chronic post-HT phase. Strict follow-up is needed for HT recipients receiving high doses of statins with/without other medications potentially exacerbating the risk of adverse effects.

Unusual rapid evolution of type B aortic dissection in a marfan patient following heart transplantation: successful endovascular treatment.

A patient with Marfan syndrome with previous Bentall operation for mitral and tricuspid valve repair, required orthotopic cardiac transplantation for end stage cardiomyopathy. Postoperatively he suffered type-B aortic dissection, despite normal aortic diameters. Following sudden increase of aortic diameters, two years later, he underwent successful stent graft implantation. In patients with Marfan syndrome, post transplantation morbidity is high, with a 40% incidence of thoracic aortic dissection. This case highlights the potential of endovascular approach for treating post-transplantation aortic dissection.

IgE antibodies of fish allergic patients cross-react with frog parvalbumin.

BACKGROUND: The major allergens in fish are parvalbumins. Important immunoglobulin (Ig)E cross-recognition of parvalbumins from different fish species has been shown. Recently frog parvalbumin alpha has been found to be responsible for a case of IgE-mediated anaphylaxis triggered by the ingestion of frog meat. The aim of this study was to investigate whether IgE antibodies of fish allergic persons cross-react with frog parvalbumin and to appreciate its clinical relevance. METHODS: The sera of 15 fish allergic patients and one fish and frog allergic patient were tested by IgE-immunoblotting against frog muscle extract. Sera were tested against recombinant parvalbumin alpha and beta from Rana esculenta. Skin prick tests were performed in selected patients with recombinant frog parvalbumin. Ca(2+) depletion experiments and inhibition studies with purified cod and frog recombinant parvalbumin were done to characterize the cross-reactive pattern. RESULTS: Fourteen of the sera tested had IgE antibodies recognizing low molecular weight components in frog muscle extract. Calcium depletion experiments or inhibition of patient sera with purified cod parvalbumin led to a significant or complete decrease in IgE binding. When tested against recombinant parvalbumins, three of 13 sera reacted with alpha parvalbumin and 11 of 12 reacted with beta parvalbumin from R. esculenta. Skin prick tests performed with recombinant frog parvalbumin were positive in fish allergic patients. Inhibition studies showed that a fish and frog allergic patient was primarily sensitized to fish parvalbumin. CONCLUSION: Cod parvalbumin, a major cross-reactive allergen among different fish species, shares IgE binding epitopes with frog parvalbumin. This in vitro cross-reactivity seems to be also clinically relevant. Parvalbumins probably represent a new family of cross-reactive allergens.

Combined heart and liver transplantation in four adults with familial amyloidosis: experience of a single center.

There are few reports of combined heart and liver transplantation (CHLT) for familial amyloidotic polyneuropathy (FAP). The technique for the operation remains to be defined. Four CHLTs were performed for amyloidogenic transthyretin-related (variant Glu89Gln-ATTR Glu89Gln) cardiomyopathy in our center. Patients 1 and 4 had no serious involvement of other organs, whereas patients 2 and 3 had evident peripheral neuropathy and gastrointestinal motility alterations. Patient 3 also had high-grade orthostatic hypotension. All four patients underwent cardiac and sequential hepatic transplantation with organs procured from the same donor. Venovenous bypass was used in patients 1 and 4 who experienced uncomplicated procedures. The amyloidotic liver of patient 4 was successfully utilized for a domino procedure to treat a patient with hepatocellular carcinoma on cirrhosis. The cardiac performance of patients 1 and 4 remains normal; there has been no progression of amyloidosis at 42 and 1 months after transplantation. Patient 2 had no intraoperative complications but experienced postoperative bleeding, renal failure, sepsis, and heart failure, and finally died of multiorgan failure 2 months after transplant. In patient 3, right hemicolectomy was required intraoperatively due to intestinal ischemia, without significant hemodynamic instability, while extracardiac symptoms of amyloidosis gradually worsened postoperatively. In conclusion, CHLT for ATTR Glu89Gln may be performed even in patients with advanced disease. However, the most compromised patients are more likely to display intraoperative risks, postoperative complications, and worsening of extracardiac, extrahepatic symptoms.

[Determinants and prognosis of ischemic mitral regurgitation]. / Insuffisances mitrales ischémiques: mécanisme et pronostic.

Ischemic mitral regurgitation (IMR) is mitral regurgitation (MR) due to complications of coronary artery disease. Two mechanisms can be individualized. Acute MR secondary to ruptured papillary muscle is a rare but often fatal complication of myocardial infarction. We focus on functional MR, much more common, which occurs without any intrinsic valve disease. It was often underrated because of low murmur intensity but is observed between 15 and 20% after a myocardial infarction. The presence and degree of the regurgitation are related to local left ventricular remodeling. The apical and posterior displacement of papillary muscles leads to excess valvular tenting which in turn, in association with loss of systolic annular contraction, determines the severity of the regurgitation. IMR presence is associated with an excess mortality. The mortality risk is directly related to the degree of the regurgitation and a regurgitant volume > or = 30 ml or an effective regurgitant orifice > or = 20 mm2 define a high-risk group. In current clinical practice, IMR is mainly corrected with ring annuloplasty. However, this technique does not correct local alterations of left ventricular remodeling and its benefits on long-term outcome remains to be demonstrated.

Severe IgE-mediated anaphylaxis following consumption of fried frog legs: definition of alpha-parvalbumin as the allergen in cause.

BACKGROUND: IgE-mediated allergic reactions to bullfrog and edible frog have been reported. The implicated allergens have not been defined so far. The frog material and the patient's serum from a case of severe food-induced anaphylaxis were used to define the implicated allergen at the protein and DNA level. METHODS: Immunoblotting techniques and N-terminal protein microsequencing were used to define the allergen recognized by the patient's serum. Back translation from the identified protein sequence was used to design degenerated primers to amplify the allergen's cDNA by polymerase chain reaction (PCR). We defined the nucleotide sequence of the allergen from the frog of Indonesian origin that was consumed by the patient, and the homologous cDNA from Rana esculenta. RESULTS: Protein microsequencing revealed that the implicated frog allergen belonged to the parvalbumin family. cDNAs coding for alpha- and beta-parvalbumin of R. esculenta and Rana species were cloned. Recombinant proteins were expressed in Escherichia coli. The patient's serum IgE antibodies recognized parvalbumin prepared from frog muscle and recombinant alpha-parvalbumin from R. species but not from R. esculenta. Recombinant beta-parvalbumin was not recognized by the IgE antibodies. CONCLUSION: This work defines at the protein and DNA levels alpha-parvalbumin as the allergen implicated in a case of IgE-mediated anaphylaxis to frog muscle. It also shows that a protein belonging to the parvalbumin family is implicated in type I allergies outside the fish species.

Folate supplementation after heart transplantation: effects on homocysteine plasma levels and allograft vascular disease.

BACKGROUND AND AIMS: After heart transplantation, the effects of folate supplementation on total homocysteine plasma levels (THcy) and heart allograft vascular disease (AVD) remain unclear. METHODS: Accordingly, we prospectively analyzed 48 heart transplant receipients referred for routine follow-up from July to September 1998 (age 54+/-11 years, 75% male, 35+/-27 months from transplant). Among these patients, 17 were treated with folate supplementation for 12 months (Group F), while 31 cross-matched for age, gender, serum creatinine and time from transplant (P>0.3 vs Group F for all) did not assume folate supplementation (Group NF). Routine coronary angiography for AVD detection was routinely obtained in every patient. RESULTS: THcy overall increased during the study period (from 16.6+/-6.5 to 19.4+/-7.6 micromol/l, P<0.001), and a strong trend toward higher THcy was observed in patients presenting AVD (22.4+/-8.7 vs 17.6+/-6.8 micromol/l, P=0.051). After 12 months THcy was lower in Group F as compared to Group NF (16.2+/-5.6 vs 21.1+/-8.1 micromol/l, respectively, P=0.033). CONCLUSIONS: Our results demonstrate that THcy increases over time in heart transplant recipients, and a strong trend toward higher THcy is observed in the presence of AVD. Since folate supplementation appears to positively influence THcy, a favorable effect of folate on AVD can be hypothesized.

Interplay between methylenetetrahydrofolate reductase gene polymorphism 677C-->T and serum folate levels in determining hyperhomocysteinemia in heart transplant recipients.

BACKGROUND: Homocysteine metabolism is often impaired in heart transplant recipients, and increased total homocysteine plasma levels may constitute a risk factor for the development of heart allograft vascular disease. Although 677C-->T transition in methylenetetrahydrofolate reductase (MTHFR) is associated with increased homocysteine levels in the general population, it is unclear whether MTHFR polymorphism influences homocysteine metabolism after heart transplant. METHODS: Homocysteine, serum folate, renal function, concentrations of cyclosporine and its metabolites, and MTHFR genotype were determined in 57 heart transplant recipients (age, 55 +/- 11 yr; 21% women; time from transplant, 48 +/- 42 months). RESULTS: Forty nine percent of the study population presented with hyperhomocysteinemia. Homocysteine was 17.1 +/- 5.9 micromol/liter, 19.4 +/- 4.9 micromol/liter, and 26.3 +/- 14.2 micromol/liter for genotypes CC, CT, and TT, respectively (p = 0.028, Kruskal-Wallis test). At multivariate analysis, MTHFR genotype was independently associated with homocysteine (p = 0.005). When the study population was divided into 2 groups accordingly to serum folate levels (above/below the median value of 6.1 ng/ml), MTHFR genotype remained a significant predictor of homocysteine only in patients with low serum folate (p = 0.048). CONCLUSIONS: This study demonstrates that hyperhomocysteinemia is frequent in heart transplant recipients and that the 677C-->T transition in the MTHFR gene independently and unfavorably influences homocysteine metabolism in this group of patients. Adequate folate intake may overcome genetic predisposition to hyperhomocysteinemia.

[Familial predisposition to ischemic cardiopathy: role of homocysteine and genetic polymorphism of methylenetetrahydrofolate reductase]. / La predisposizione familiare alla cardiopatia ischemica: ruolo dell'omocisteina e del polimorfismo genetico della metilenetetraidrofolato reduttasi.

Homocysteine represents a risk factor for coronary artery disease determined not only by nutritional habits, but also by the genetic polymorphism of the enzymes involved in its metabolism (i.e. methylenetetrahydrofolate reductase - MTHFR). However, recent prospective studies questioned the initial evidence of a clear epidemiological and pathogenetic link between homocysteine levels and coronary artery disease. Moreover, the relationships between MTHFR polymorphism and coronary artery disease remain unclear. In this paper, the recent literature analyzing the role of homocysteine and MTHFR polymorphism as a risk factor for coronary artery disease has been reviewed.

Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment.

BACKGROUND: Myocardial infarction (MI) can directly cause ischemic mitral regurgitation (IMR), which has been touted as an indicator of poor prognosis in acute and early phases after MI. However, in the chronic post-MI phase, prognostic implications of IMR presence and degree are poorly defined. METHODS AND RESULTS: We analyzed 303 patients with previous (>16 days) Q-wave MI by ECG who underwent transthoracic echocardiography: 194 with IMR quantitatively assessed in routine practice and 109 without IMR matched for baseline age (71+/-11 versus 70+/-9 years, P=0.20), sex, and ejection fraction (EF, 33+/-14% versus 34+/-11%, P=0.14). In IMR patients, regurgitant volume (RVol) and effective regurgitant orifice (ERO) area were 36+/-24 mL/beat and 21+/-12 mm(2), respectively. After 5 years, total mortality and cardiac mortality for patients with IMR (62+/-5% and 50+/-6%, respectively) were higher than for those without IMR (39+/-6% and 30+/-5%, respectively) (both P<0.001). In multivariate analysis, independently of all baseline characteristics, particularly age and EF, the adjusted relative risks of total and cardiac mortality associated with the presence of IMR (1.88, P=0.003 and 1.83, P=0.014, respectively) and quantified degree of IMR defined by RVol >/=30 mL (2.05, P=0.002 and 2.01, P=0.009) and by ERO >/=20 mm(2) (2.23, P=0.003 and 2.38, P=0.004) were high. CONCLUSIONS: In the chronic phase after MI, IMR presence is associated with excess mortality independently of baseline characteristics and degree of ventricular dysfunction. The mortality risk is related directly to the degree of IMR as defined by ERO and RVol. Therefore, IMR detection and quantification provide major information for risk stratification and clinical decision making in the chronic post-MI phase.

Differential binding of IgG and IgA antibodies to antigenic determinants of bovine serum albumin.

The aim of this study was to investigate the recognition pattern of bovine serum albumin (BSA), a major dietary protein by serum IgG and IgA antibodies. Anti-BSA IgG and IgA antibodies were measured by ELISA technique in 3 different cohorts: 578 unselected persons, 84 new-onset insulin-dependent diabetes mellitus (IDDM) patients and 103 atopic persons. In order to characterize the recognition pattern of the different BSA domains, recombinant BSA and recombinant fragments covering the 3 BSA domains were produced. BSA digestion was monitored in simulated gastric fluid experiments by means of domain specific monoclonal antibodies. IgG and IgA antibody titres to native BSA were highest in IDDM patients. The three major BSA domains were equally well recognized by IgG antibodies of the three cohorts. Interestingly all three study groups showed a dissociation of their IgG and IgA antibody response to the first BSA domain. The ratio of IgG to IgA antibodies recognizing this domain was 93%/42% in controls, 92%/37% in IDDM patients and 80%/47% in atopic persons. In simulated gastric fluid experiments, the first BSA domain was the first to become undetectable to specific monoclonal antibodies during digestion. In conclusion humoral IgG and IgA antibodies recognize the major BSA domains with different frequencies. The N-terminal domain of BSA, the first to be degraded during simulated gastric digestion is less well recognized by IgA antibodies. This suggests that early digestion is negatively correlated to the IgA antibody response and that the IgA response associated to the gut associated lymphoid tissue (GALT) and the systemic IgG antibody responses are independent.