Hyperhomocysteinemia and transplant coronary artery disease

BACKGROUND: Transplant coronary artery disease (TCAD) is a major cause of morbidity and mortality among heart transplant recipients. A variety of immunologic and nonimmunologic mechanisms are involved in the pathogenesis of the disease. Hyperhomocysteinemia has been recognized as an important risk factor for atherosclerotic vascular disease. The purpose of this article is to evaluate the prevalence of hyperhomocysteinemia in heart transplant recipients but more specifically to assess the published literature regarding the association between hyperhomocysteinemia and TCAD. METHODS: A MEDLINE search using the key words hyperhomocysteinemia, transplant coronary artery disease, and heart transplant was performed. RESULTS: Hyperhomocysteinemia has been commonly found among heart transplant recipients (average prevalence 51% to 76%). Worsening renal function and impaired vitamin metabolism seem to be the major causes of hyperhomocysteinemia in this particular population. TCAD has been found to be more prevalent and severe among patients with higher serum homocysteine levels. Vitamin supplementation is safe and effective in reducing serum homocysteine among heart transplant recipients. CONCLUSION: A large, long-term, double-blind, placebo-controlled prospective trial aimed at assessing the clinical significance of homocysteine-lowering therapy on the natural history of TCAD seems warranted.     

Microvascular prothrombogenicity and transplant coronary artery disease

A major impediment for the long-term success of heart transplantation is the development of transplant coronary artery disease (CAD). Several risk factors for the development of transplant CAD are associated with the transformation of a normal thromboresistant microvasculature into a prothrombogenic microvasculature. Prothrombogenicity is characterized by loss of anticoagulation (i.e. loss of antithrombin), loss of fibrinolytic activity (i.e., loss of tissue plasminogen activator) and presence of endothelial activation (i.e. upregulation of endothelial intercellular adhesion molecule-1 and major histocompatibility class II antigen human leukocyte antigen-DR) in the arterial allograft microvasculature. Microvascular prothrombogenicity during the first trimester after transplantation is directly associated with subsequent development of transplant CAD. Although the mechanisms responsible for the loss of thromboresistant endothelium are unclear, the fact that changes in the anticoagulant, fibrinolytic, and activational status of endothelial cells may occur early after transplantation suggests a peritransplant phenomenon as an initiating event. Reducing prothrombogenicity of the cardiac microvasculature early after transplantation could slow the development of transplant CAD and significantly improve allograft survival.     

Hyperhomocysteinemia and transplant coronary artery disease in cardiac transplant recipients

BACKGROUND: In cardiac transplant recipients, long-term survival may be limited by transplant coronary artery disease (TxCAD). Hyperhomocysteinemia (Hhcy) has been associated with vascular disease and is common in transplant recipients. The objective of this study was to determine the relationship between fasting homocysteine (Hcy) concentrations and TxCAD in a cohort of cardiac transplant recipients. METHODS: Forty-eight patients more than 5 yr after transplant were recruited from a cohort of 72 consecutive patients with in-depth analysis of homocysteine levels from the Cardiac Transplant Clinic. Early morning fasting blood was obtained, and the plasma separated and frozen within 30 min. Hcy concentrations were determined by high-performance liquid chromatography (HPLC) with pulsed integrated amperometry. Coronary angiograms were reviewed in a blinded fashion. TxCAD was diagnosed, using the most recent angiogram, when a >25% lesion was present anywhere in the coronary tree. RESULTS: Forty-eight patients transplanted between 1985 and 1994 were studied. The mean Hcy concentration for the cohort was 23.5+/-5.0 micromol/L, all patients had homocysteine levels above the upper range of normal (5-15 micromol/L). Hcy concentrations were significantly higher in patients with angiographic evidence of TxCAD: 25.0+/-5.9 vs. 21.9+/-3.4 micromol/L, p=0.03. This effect persisted when covariates were taken into account using logistic regression analysis. CONCLUSIONS: Hhcy is associated with TxCAD. Prospective studies are required to confirm this association and to assess the efficacy of Hcy-lowering therapy in this patient population.     

Transplant coronary artery disease in pediatric heart transplant recipients.

BACKGROUND: Transplant coronary artery disease (TxCAD) contributes to a large percentage of late morbidity and mortality among adult heart transplant recipients. Intracoronary ultrasound (ICUS) is a sensitive tool in the diagnosis of TxCAD in adult patients and has allowed analysis of factors contributing to disease development. Experience with ICUS in pediatrics, however, has been limited. By using ICUS we sought to determine the overall prevalence of TxCAD in pediatrics and to characterize factors associated with its development in this population. METHODS: Eighty-six studies were performed in 51 pediatric patients a median of 3.4 years after heart transplantation. Evaluation included angiography and ICUS in 83 and angiography alone in 3 studies. Donor and recipient characteristics were obtained. The ICUS images were analyzed for intimal thickening and compared with coronary angiograms. The presence of any intimal thickening on ICUS was considered TxCAD. An intimal index and point of maximal intimal thickening (MIT) were measured. Vessel disease was graded 0 to 4 based on these results. Four patients had evidence of vasculopathy by angiography, whereas 32 patients (63%) had evidence of intimal proliferation by ICUS. Grade 2 or greater disease was present in 19 (37%) patients. A positive correlation was found when comparing time from transplant with intimal index and MIT (p < 0.001). No other factors were found to predict the development of disease. The overall prevalence of disease was 74% in patients studied at least 5 years after transplant.Intracoronary ultrasound can be performed safely in pediatric patients. Transplant coronary artery disease is common in infants and children after heart transplantation, although its prevalence appears to be less than in adult recipients at similar time intervals. We found no factor other than time from transplant was associated with development of disease.     

Genetic variants of the hemostatic system and development of transplant coronary artery disease.

BACKGROUND: The occurrence of coronary artery disease (CAD) after heart transplantation may represent an accelerated inflammatory and thrombotic response to coronary vascular endothelial cell injury. Several common mutations involving hemostasis and cellular adhesion proteins have been associated with genetic susceptibility to native coronary heart disease. The clinical setting of heart transplantation provides a unique opportunity to examine the relative contribution of circulating (i.e., recipient) vs local vascular (i.e., donor) hemostatic components to the occurrence of CAD. METHODS: We performed genotyping for several common hemostatic polymorphisms among 53 cardiac transplant patients and their heart donors. Patients were observed for an average of 43 months, and the presence of transplant CAD was determined by coronary angiography. RESULTS: The development of transplant CAD did not relate to recipient hemostatic genotype, but 2 donor polymorphisms (PAI-1 4G/5G and alpha(2) integrin C807T) were important predictors of transplant CAD. The risk ratio (RR) of transplant CAD associated with donor PAI-1 4G/4G genotype was 2.6 (95% confidence interval [CI] 1.1-6.2) and was modified by recipient cytomegalovirus status, hyperlipidemia, diabetes, and recipient factor XIII Val34Leu genotype. The RR of transplant CAD associated with donor alpha(2) integrin 807 T/T genotype was 7.4 (95% CI, 2.5-22.0). CONCLUSIONS: Genetic and metabolic factors contributed by both donor and recipient may interact at the level of the coronary vessel wall in the development of transplant-associated CAD, and this finding may provide additional support for the importance of local thrombotic response to endothelial injury in the pathogenesis of this disorder.     

代谢综合征患者餐后三酰甘油与冠状动脉病变程度关系

目的探讨代谢综合征（MS）患者餐后三酰甘油（TG）与冠状动脉病变程度的关系。方法选择住院MS患者91例,分为空腹及餐后4hTG正常（MS1）组31例;空腹TG正常而餐后4hTG增高（NS2）组29例;空腹TG增高（MS3）组31例。检测餐后4hTG及行冠状动脉造影明确冠状动脉病变支数,并分析两者关系。结果冠状动脉病变支数与餐后4hTG呈显著正相关,相关系数为0．42（P〈0．01）。结论在临床工作中应增加对MS患者餐后4hTG的检测以便及时发现血脂代谢紊乱并采取相应干预措施,降低MS患者心血管疾病的发生率和病死率。     

Heart transplant coronary artery disease in Chinese recipients

BACKGROUND: Transplant coronary artery disease is the principle limiting factor for long-term survival of heart transplantation (HTx) recipients. We reviewed our data to assess the incidence of this disorder among Chinese HTx recipients and to compare it with the results of Western studies. MATERIAL AND METHODS: From July 1988 to May 2002, 182 patients received 184 orthotopic HTx. One hundred sixty-three recipients survived for at least 1 year with available SPECT scans or coronary angiogram studies. The data set included donor characteristics, recipient characteristics, active cytomegalovirus (CMV) infection rate, rejection episodes, immunosuppressants, and human leukocyte antigen (HLA) mismatches. RESULTS: Surgical mortality in our program was 4.3% and the actuarial freedom from coronary artery disease at 1, 3, and 5 years was 99%, 95%, and 92%, respectively. Angiogram results were stratified into coronary artery disease (n = 15) or absence of the disorder (n = 148) groups. Only older donor age showed statistical significance between the groups. Compared with the Western series, the present data show higher actuarial survival rates and freedom from coronary artery disease. There were statistically significant differences in regard to graft ischemia time, proportion of male recipients, ischemic heart disease, rejection episodes during the first year, and incidence of CMV infection. CONCLUSIONS: SPECT scan can detect coronary artery disease before there is significant stenosis of the coronary artery with acceptable survival rates. Chinese HTx recipients show a lower incidence of the disorder, lower rates of ischemia heart disease, lower proportion of male gender, lower incidence of CMV infection, fewer rejection episodes during the first year, and less ischemic time than Western recipients, which maybe the contributing factors to their better survival.     

Reversal of diabetes-induced rat graft transplant coronary artery disease by metformin.

BACKGROUND: Induction of diabetes in rat heterotopic heart transplantation models leads to an accelerated form of severe transplant coronary artery disease (TxCAD). We undertook this study to determine whether treatment of diabetes with metformin would favorably affect TxCAD. METHODS: Heterotopic abdominal heart transplantation was performed in rat isograft and allograft models. After transplantation, diabetes was induced with streptozotocin. Fifty percent of the animals received metformin at 500 mg/kg twice daily. We quantitatively assessed TxCAD using histologic sections of harvested hearts at 30 and 60 days with computer-assisted morphometry. We compared vessels in the first tertile of the area distribution with vessels in the last tertile. RESULTS: Fasting glucose levels in metformin-treated animals were 161 +/- 45 mg/dl compared with 400 +/- 120 mg/dl (p < 0.05) in untreated rats. Treatment with metformin led to decreased diabetes-induced TxCAD in the larger vessels. This effect was sustained during the study course in the isografts but not in the allografts. Treatment with metformin did not prevent progression of TxCAD in the smaller vessels at 60 days. CONCLUSIONS: Metformin reduced luminal occlusion and severe TxCAD in the larger vessels but did not alter the course of TxCAD in the smaller vessels. These results may have therapeutic implications for patients.     

Inflammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links

OBJECTIVE: Erectile dysfunction (ED) may be the early clinical manifestation of a generalized vascular disease and carries an independent risk for cardiovascular events. Low-grade subclinical inflammation affects endothelial function and is involved in all stages of the atherosclerotic process. This review identifies potential pathophysiologic links among low-grade inflammation, ED, metabolic syndrome, and coronary artery disease (CAD) and presents the clinical implications in terms of ED diagnosis, assessment of patient risk, and therapy. METHODS: A comprehensive evaluation was performed for available published data in full-length papers that were identified in MedLine up to July 2007. RESULTS: Studies support an association between metabolic syndrome, ED, and increased inflammatory state. Increased circulating levels of inflammatory and endothelial-prothrombotic compounds are related to the presence and severity of ED. Specific inflammatory biomarkers and their combination appear to have the potential to aid ED diagnosis or exclusion. ED and CAD may confer a similar unfavorable impact on the inflammatory and prothrombotic state, whereas ED adds an incremental activation on top of CAD; these findings have important implications for cardiovascular risk. Lifestyle and risk factor modification, as well as pharmacologic therapy, are associated with anti-inflammatory effects. CONCLUSIONS: Low-grade systemic inflammation could be an important element of the association between metabolic syndrome, ED, and CAD. Its individualized assessment may be a valuable tool for ED diagnosis, risk assessment, and rationalized therapeutic approach especially in patients with ED who have metabolic syndrome and carry an intermediate risk for future cardiovascular events.     

Decreased endomyocardial RANKL expression in transplant coronary artery disease

Transplant-associated coronary artery disease (TxCAD) appears to be initiated by endothelial cell activation and inflammation involving inflammatory cytokines and chemokines. Osteoprotegerin (OPG) and receptor activator of nuclear Factor-kappaB ligand (RANKL) have been implicated in cardiovascular disease progression and we measured the expression of these mediators in serum and myocardial biopsies taken serially during the first year after heart transplantation (HTx), relating them to the development of TxCAD. Serum OPG as well as myocardial gene expression of RANK and OPG, but not RANKL, were highest early after HTx and declined progressively. Importantly, patients who develop TxCAD or experience episodes of acute rejection showed a lower myocardial RANKL expression throughout the first year after transplantation than patients without these complications. Our findings may suggest an unrecognized role RANKL in maintaining myocardial and/or endothelial integrity and suggest that RANKL should be further investigated as a parameter that may predict development of TxCAD.     

代谢综合征对不停跳冠状动脉旁路移植围术期的影响

目的 探讨代谢综合征(metabolic syndrome,MS)对不停跳冠状动脉旁路移植(OPCABG)围术期的影响.方法 2009年8月至2010年3月,连续1060例OPCABG病人分为MS组与非MS组,比较两组的病死率、房颤发生率、多器官衰竭评分(MODS)、心脏外科术后评分(PSCS)、PaO2/FiO2以及心率×中心静脉压/平均动脉压(pressure-adjusted heart rate,PAHR).结果 MS对OPCABG的病死率、房颤发生率、脑卒中、IABP和ECMO、透析的使用率无影响.但手术当天,MS组的MODS评分为2.57±1.62,PSCS评分为4.27±2.15,显著高于非MS组的2.15±1.65,3.92±2.29,P＜0.05;PaO2/FiO2在MS组为249.23±110.99,显著低于非MS组的283.33±114.35,P＜0.01;MS组的PAHR为9.98±3.54,显著高于非MS组的9.23±3.88,P＜0.05.手术后第1天,MS组的MODS评分为3.05±1.64.显著高于非Ms组的2.82±1.72,P＜0.05;PaO2/FiO2在MS组为277.11±122.99,显著低于非MS组,318.47±143.84,P＜0.05.结论 MS对OPCABG的病死率、房颤发生率、脑卒中、IABP和ECMO、透析的使用率无影响,但在术后当天和术后第1天,MS可以对OPCABG病人的呼吸和循环系统产生短暂的负面影响.

Abstract：

Objective Metabolic syndrome ( MS), a disorder involving multiple metabolic abnormalities such obesity,hypertension, diabetes or abnormal glucose tolerance and dyslipidemia, has been observed in many patients receiving coronary artery bypass procedures. In this study we try to examine the perioperative effects of metabolic syndrome on the off-pump coronary artery bypass (OPCABG). Methods A prospective study was conducted in 1060 consecutive OPCABG patients who were admited to Beijing Anzhen Hospital from July 2009 to March 2010. The patients were grouped as MS group and non-MS group according to the diagnostic criteria for Chinese metabolic syndrome. The outcomes such as mortality, atrial fibrillation,stroke, staying in ICU for more than three days, use of IABP, ECMO, dialysis, multiple organ dysfunction score ( MOOS) ,postoperative score for cardiac surgery (PSCS), PaO2/FiO2 , heart rate x central venous pressure/mean artery pressure(pressure-adjusted heart rate, PAHR) ,renal and liver function, platelets, and the dosage of vasoactive agents were analyzed and compared between the two groups by x2 test or t test. Results Three hundred and eighty-nine cases were diagnosed with MS among 1060 cases with OPCABG. In the MS group, 17 cases stayed in ICU for more than 3 days, 2 cases died, 76 had atrial fibrillation, 3 had stroke, 18 cases were treated with intra-aortic balloon counterpulsation (IABP). In the non-MS group, 47 cases stayed in ICU for more than 3 days, 12 cases died, 148 had atrial fibrillation, 3 had stroke, 48 cases were treated withIABP, 3 cases received ECMO and 4 cases received dialysis. No significant difference between MS group and non-MS group was identified in the aspects of mortality, atrial fibrillation, stroke, duration of more than three days in ICU, the use of IABP,ECMO, dialysis after OPACBG based on the x2 test(P＞0.05). However, on the operative days, the MODS and PSCS in MS group were significantly higher than that in non-MS group (P ＜ 0.05). MODS 2. 57 ± 1. 62 in MS group vs. 2. 15 ± 1.65 in non-MS group, PSCS 4.27 ±2.15 in MS group vs. 3.92 ±2.29 in non-MS group. PaO2/FiO2 in MS group was significantly lower than that in non-MS group (249.23 ± 110.99 vs. 283. 33 ± 114. 35), P ＜ 0. 01. PAHR in MS group was significantly higher than that in non-MS group (9.98 ±3.54 vs. 9.23 ±3. 88), P ＜0.05. On the first postoperative days, the MODS in MS group was also significantly higher than that in non-MS group (3.05 ±1.64 vs. 2.82 ± 1.72), P＜0.05. PaO2/FiO2 in MS group was significantly lower than that in non-MS group (277.11 ±122.99 vs.318.47 ±143.84), P＜0.05. Conclusion MS was not a predictor for death, atrial fibrillation, stroke, duration of more than three days in 1CU, the use of IABP, ECMO, dialysis after OPACBG. However, MS had a temporary adverse effect on the respiratory and circulatory systems on the operative day and the first postoperative day after OPCABG.     

Diabetes and coronary artery disease impose similar cardiovascular morbidity and mortality on renal transplant candidates.

BACKGROUND: In renal transplant candidates (RTC), diabetes and coronary artery disease (CAD) are commonly observed. However, whether diabetes imparts a cardiovascular risk equivalent to that of CAD and whether CAD adds to the cardiovascular risk associated with diabetes is unknown. METHODS: To assess the interplay between diabetes and CAD as a determinant of major adverse cardiovascular events (MACE), 288 high-risk RTC (56.4+/-8.1 years old, 72% males) underwent a comprehensive cardiovascular evaluation including coronary angiography. Patients were divided into four groups based on the diagnoses of diabetes and CAD (>70% narrowing), and followed up for 1-60 months (median, 17). The primary endpoint was the composite incidence of fatal/non-fatal MACE. RESULTS: During follow-up, 80 MACE occurred. Patients with diabetes (P=0.03) or CAD (P<0.0001) had a worse long-term prognosis. However, only in patients without diabetes was CAD associated with an increased incidence of MACE (10.6% vs 45.9%, P<0.0001). In patients with diabetes, the endpoints were not different between those with and without CAD. No difference occurred in the long-term prognosis of patients with diabetes (with or without CAD) and patients without diabetes with CAD. CONCLUSIONS: We concluded that in high-risk RTC, diabetes confers a cardiovascular risk comparable to that of CAD in patients without diabetes, independent of coronary obstruction. In patients with diabetes, concomitant CAD does not add to the already very high cardiovascular risk of this population.     

Prevalence of donor-transmitted coronary artery disease and its influence on heart transplant outcomes

Background

It is uncertain whether donor-transmitted coronary artery disease (DTCAD) affects heart transplant (HT) recipients.

Methods

This retrospective analysis includes records of all patients who underwent a HT at our center over an 8-year period, who survived for at least 1 month, and who were examined by coronary angiography within 2 months post-HT. We distinguished angiographically from keep ultrasonography (IVUS) detected DTCAD. Major adverse cardiovascular events (MACE) comprised death, myocardial infarction, unstable angina, coronary revascularization, and admission because of heart failure not due to an acute rejection episode.

Results

Among the 171 patients of mean age 53 ± 13 years and including 83% men, 65 (38%) were evaluated by IVUS. Donors were aged 40 ± 14 years (range = 14-73). Angiographic DTCAD affected seven patients (4.1%), and IVUS-detected DTCAD, 35 (53.8% of those examined by IVUS). DTCAD donors were older than non-DTCAD donors, by an average of 13 years (P = .001) for angiographic DTCAD and 18 years (P < .0001) for IVUS-detected DTCAD. Two patients underwent percutaneous revascularization upon detection of angiographic DTCAD. The angiographic- and IVUS-detected DTCAD groups did not differ significantly from the corresponding non-DTCAD groups as regards MACE incidence during 54 ± 41 and 38 ± 20 months follow-up, respectively. Cox regression analysis with adjustment for relevant confounders confirmed that IVUS-detected DTCAD was not a predictor of MACE (hazard ratio 1.2, 95% confidence interval 0.2-8.1).

Conclusions

Among HT patients surviving ≥ 1 month, angiographic- and IVUS-detected DTCAD showed prevalences of <10% and >50%, respectively. Neither detection method was associated with a greater long-term incidence of MACE.     

Early detection of left ventricular dysfunction related to transplant coronary artery disease

BACKGROUND: Transplant coronary artery disease (TxCAD) is a major limitation to the long-term success of cardiac transplantation. We assessed left ventricular (LV) function in relation to severity of coronary lesions to improve both early diagnosis of TxCAD and evaluation of the severity of myocardial damage. METHODS: Echocardiographic evaluation of LV function, including pulsed-wave tissue Doppler imaging (PW-TDI) wall motion analysis, was performed in 304 heart recipients before each of their follow-up cardiac catheterizations. LV systolic and diastolic parameters obtained both invasively and non-invasively were tested for their relation to angiographic and intravascular ultrasound (IVUS) findings. RESULTS: LV end-diastolic pressure and most of the PW-TDI parameters differed significantly (p < 0.001) between patients with and without TxCAD. In comparison to patients without the disease, even those with moderate, angiographically non-visible TxCAD showed significant differences for all systolic PW-TDI parameters. Wall motion alterations during angiographic TxCAD were almost always global and related mainly to diffuse Type B lesions. Systolic PW-TDI parameter changes showed highly predictive values for TxCAD. At systolic wall motion peak velocity (Sm) values constantly <10 cm/sec, we found a 97.37% likelihood of TxCAD (angiographically and/or IVUS-visible), whereas Sm values of > or =11 cm/sec excluded angiographic TxCAD with 90.41% probability. CONCLUSIONS: Among all parameters investigated for the evaluation of allograft LV function, PW-TDI systolic parameters were of the greatest diagnostic value. Wall motion assessment allows early detection of myocardial dysfunction and provides information on both local and global LV dysfunction linked to TxCAD, with potential usefulness for both timing of cardiac catheterizations and prognostic evaluation.