Do cardiovascular risk factors influence cardiac allograft vasculopathy?

BACKGROUND: Cardiac allograft vasculopathy (CAV) is the leading cause of heart transplant failure after the first year. The etiological factors involved are currently a controversial matter. Intravascular ultrasound (IVUS) is considered the diagnostic procedure of choice. We assessed the relationship of cardiovascular risk factors with CAV. MATERIALS: We analyzed prospectively 22 patients. We conducted a first study with coronary angiography and IVUS at 36 +/- 3 days and a second at 598 +/- 49 days. We performed an average of 5.6 clinical revisions per patient, assessing the effect of the classic cardiovascular risk factors, the cause of heart failure, and the age of the patient and donor. The statistics used were chi(2), Fisher exact test, and Student t test. RESULTS: CAV was found in 10 subjects (45.5%). Univariate analysis showed statistically significant differences in the assessment of the presence of diabetes and dyslipidemia posttransplantation, but not pretransplantation. Among the patients with CAV there was a higher percentage of diabetics (32.8% vs 12%, P < .01). The patients with CAV also had higher levels of total cholesterol (211 +/- 40 mg/dL vs 195 +/- 35 mg/dL, P = .02), triglycerides (172 +/- 108 mg/dL vs 136 +/- 66 mg/dL, P = .03), low-density lipoprotein (133 +/- 35 mg/dL vs 117 +/- 30 mg/dL, P = .01), and lower high-density lipoprotein levels (46 +/- 15 mg/dL vs 52 +/- 12 mg/dL, P = .03). CONCLUSIONS: Only the diabetes and dyslipidemia present in the posttransplantation period were associated with CAV, which highlights the fact that it is a condition that both shares and has different features with atherosclerosis and probably requires a different diagnostic-therapeutic approach.     

Cardiac allograft vasculopathy after cardiac transplantation and hormone therapy: positive effects?

BACKGROUND: There is a great deal of controversy surrounding the issue of hormone replacement therapy after transplantation. The question whether or not this therapy has effects in cardiac allograft vasculopathy (CAV), the Achilles heel of cardiac transplantation or other unique aspects of allograft function is still unknown. METHODS: We investigated the long-term effect of 17beta-estradiol as well as phytoestrogen Coumestrol, a synthetically produced phytoestrogen, on the development of CAV and the degree of fibrosis in an ovariectomized female heterotopic chronic allograft model (LEW-F344). RESULTS: We found that, 150 days after transplantation, no significant effect of estrogen application on intimal thickening of coronary arteries was observed. 17beta-estradiol and phytoestrogen Coumestrol did significantly reduce the perivascular immune reaction. However, the immune effect had no consequence on the intensity of CAV. Although neither 17beta-estradiol nor phytoestrogen Coumestrol revealed a positive effect on CAV, the group of animals treated with 17beta-estradiol showed the highest decline in heart function and the most distinct fibrosis. CONCLUSIONS: 17beta-estradiol does not affect CAV positively, but worsens cardiac allograft function and leads to increased fibrosis. This is the first study showing a negative effect of 17-beta-estradiol after heart transplantation in the long term.     

Uraemic vasculopathy in children with chronic kidney disease: prevention or damage limitation?

Since the inception of pediatric dialysis programmes nearly 50 years ago, there have been vast improvements in both the technology and expertise in the care of children with chronic kidney disease (CKD). Nevertheless, children on dialysis continue to have a significantly higher mortality than their healthy peers and cardiovascular disease (CVD) is the most common cause of death in this group. Chronic kidney disease is described as the “perfect storm” of risk factors for CVD development, and vascular calcification is a highly regulated cell-mediated process with several promoters and inhibitors of calcification. CVD begins early in the course of CKD and there is an independent and graded association between cardiovascular morbidity and renal decline. Also, it is shown that once vascular damage and calcification begin, they progress inexorably in the uraemic milieu and may only be partially reversed after successful transplantation. Thus, preventing the development of CVD is key, and early identification and management of specific CVD-related risk factors should begin from the early stages of CKD. While the vasculopathy of childhood CKD is clearly multifactorial, clinical, epidemiological and cell biology studies provide converging evidence pointing to the role of dysregulated mineral metabolism as an important modifiable risk factor in the development of vascular calcification. In this review we focus on the role of calcium, phosphate, parathyroid hormone and vitamin D in ectopic vascular calcification, and discuss the role of screening, early intervention and management of established vascular calcification.     

Is all intimal proliferation created equal in cardiac allograft vasculopathy? The quantity-quality paradox.

BACKGROUND: Pre-angiographic detection of intimal proliferation using intravascular ultrasound in heart transplant recipients has focused investigators' attention on the prognostic utility of such early information. Not all heart transplant recipients who exhibit a "prognostically relevant" threshold of severe (>0.5 mm) intimal thickening experience cardiac events. We sought to contrast clinical characteristics of heart transplant recipients who have prognostically relevant, severe intimal proliferation and who experience cardiac events with those who remain event free. METHODS: We prospectively followed an inception cohort of 54 consecutive heart transplant recipients with severe intimal proliferation (intimal thickness >0.5mm) of the coronary arteries after index intravascular ultrasound examination to assess the development of cardiac events (sudden cardiac death, myocardial infarction) and/or the necessity for coronary revascularization with percutaneous techniques (angioplasty, atherectomy, stent implantation) or surgical bypass. RESULTS: Based on the occurrence of adverse cardiac events during the subsequent 24 months, we divided the study cohort into 2 groups: Group 1 (no event, n = 33) and Group 2 (cardiac event, n = 21). Both groups demonstrated similar intimal thickness at the index ultrasound (Group 1, 0.89 +/- 0.27 mm, vs Group 2, 0.94 +/- 0.36 mm; p = not significant). Those with cardiac events were more likely than those without events to have hyperlipidemia, to have greater exposure to cumulative and average daily prednisone, and to exhibit greater average biopsy rejection scores at follow-up. CONCLUSIONS: These observations underscore the importance of the quality and not merely the quantity of intimal proliferation in determining occurrence of morbid cardiac events and further emphasize the interaction of immunologic and non-immunologic factors in determining event vulnerability in cardiac allograft vasculopathy.     

Effects of mTOR inhibitor–related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients

We have previously described the use of sirolimus (SRL) as primary immunosuppression following heart transplantation (HT). The advantages of this approach include attenuation of cardiac allograft vasculopathy (CAV), improvement in glomerular filtration rate (GFR), and reduced malignancy. However, in some patients SRL may cause significant proteinuria. We sought to investigate the prognostic value of proteinuria after conversion to SRL. CAV progression and adverse clinical events were studied. CAV progression was assessed by measuring the Δ change in plaque volume (PV) and plaque index (PI) per year using coronary intravascular ultrasound. Proteinuria was defined as Δ urine protein ≥300 mg/24 h at 1 year after conversion to SRL. Overall, 137 patients were analyzed (26% with proteinuria). Patients with proteinuria had significantly lower GFR (P = .005) but similar GFR during follow-up. Delta PV (P < .001) and Δ PI (P = .001) were significantly higher among patients with proteinuria after adjustment for baseline characteristics. Multivariate Cox regression analysis showed higher all-cause mortality (hazard ratio 3.8; P = .01) with proteinuria but similar risk of CAV-related events (P = .61). Our results indicate that proteinuria is a marker of baseline renal dysfunction, and that HT recipients who develop proteinuria after conversion to SRL have less attenuation of CAV progression and higher mortality risk.     

High prevalence of small dense LDL as an underestimated component of heart transplantation-induced dyslipidemia: potential role in graft coronary vasculopathy?

Heart transplantation-induced dyslipidemia is a recognized risk factor for cardiac allograft vasculopathy that affects survival prognosis. Beyond increased lipids, low-density lipoprotein (LDL) size and systemic factors, including glucose intolerance, oxidative stress, and inflammation, must be taken into account as components of the atherosclerotic risk. The aim of this study was to explore the atherogenic profile of heart transplant recipients (HTR) by assessing lipid parameters, glycemia, oxidative stress status, and inflammation in 59 transplant patients (follow-up of 6 +/- 3 years) compared to 20 healthy volunteers. Classical hypercholesterolemia and hypertriglyceridemia were observed in HTR compared to controls, associated with increased apoCIII levels (0.13 +/- 0.6 vs 0.07 +/- 0.03 g/L, P < .01). Mean LDL size was reduced in HTR compared to controls (25.22 +/- 0.72 vs 26.06 +/- 0.54 nm, P < .001) with an abnormally high prevalence (69% vs 0%, P < .001) of small dense LDL (<25.5 nm). Hyperglycemia (7.3 +/- 3 vs 5.4 +/- 0.8 mmol/L, P < .05) and inflammation (high-sensitive CRP: 3.1 +/- 3 vs 1.6 +/- 0.9 mg/L, P < .001) were evidenced in HTR since no difference in oxidative stress parameters was observed. In conclusion, a high prevalence of small dense LDL is an important component of posttransplantation dyslipidemia.