Association of coronary artery disease in cardiac transplant recipients with cytomegalovirus infection

Coronary artery disease (CAD) is now the major limitation to long-term survival after cardiac transplantation. Its etiology remains unclear. The possible role of viral infection in the genesis of CAD stimulated the review of 102 patients transplanted since the introduction of triple drug immunosuppression (cyclosporine, azathioprine and prednisone) to assess the importance of posttransplant cytomegalovirus infection in the development of CAD in the cardiac graft. CAD occurred in 16 patients (16%). Recipient age and sex, donor age, pretransplant diagnosis, frequency of acute rejection episodes, HLA mismatch, cytomegalovirus infection, incidence of posttransplant systemic hypertension and diabetes mellitus, and mean triglyceride, cholesterol and cyclosporine levels were analyzed to assess their influence on the development of CAD. Only the occurrence of cytomegalovirus infection was found to be a significant factor (p = 0.007): infection occurred in 62% of patients with CAD and in only 25% of those without. These data support the existence of an association between cytomegalovirus infection and CAD after cardiac transplant. It is possible that the virus contributes to the initial injury to the coronary endothelium.     

Repeated intravascular ultrasound imaging in cardiac transplant recipients does not accelerate transplant coronary artery disease

OBJECTIVES: This study was designed to examine the impact of repeated intravascular ultrasound (IVUS) examinations on transplant coronary artery disease (CAD). BACKGROUND: Serial IVUS is the most accurate method for early detection and surveillance of transplant CAD. However, the long-term safety of serial IVUS exams is not well described. Accordingly, we examined the impact of repeated IVUS examinations on transplant CAD. METHODS: We examined 226 transplant recipients who underwent one or more IVUS examinations and coronary angiography at least one year after the last IVUS exam. The coronary angiograms were analyzed using quantitative coronary angiography. Vessel diameters, frequency, and severity of stenoses in IVUS-imaged and nonimaged coronary arteries were compared. In a subgroup analysis of 31 patients, angiographic lumen diameters were measured at baseline (within eight weeks of transplantation) and during follow-up (after two, three, or four IVUS studies). RESULTS: In the 226 patients, 548 coronary arteries were previously imaged by IVUS and 130 arteries were not imaged by IVUS. On subsequent angiograms, stenoses were observed in 16.2% (21/130) of nonimaged arteries and 19.5% (107/548) of imaged arteries (p = 0.38). The arterial diameters of nonimaged and imaged arteries were not significantly different (p = 0.07), regardless of the number of IVUS exams and duration of follow-up. Subgroup analysis revealed a significant decrease in vessel lumen diameter over time in nonimaged as well as imaged arteries. The magnitude of the diameter decrease was not significantly different between the two groups. CONCLUSIONS: Repeated IVUS examinations following heart transplantation do not result in angiographically evident acceleration of transplant CAD. Therefore, serial IVUS imaging is a safe method for the detection and surveillance of transplant CAD.     

Chlamydia pneumoniae infection is associated with coronary artery disease but not implicated in inducing plaque instability

BACKGROUND: Many authors have shown an association between Chlamydia pneumoniae (C. pneumoniae) infection and coronary artery disease. However, whether C. pneumoniae infection plays an important role in triggering an acute coronary event remains to be elucidated. METHODS: Sixty-four consecutive patients with unstable angina (group A), 56 consecutive patients with stable exertional angina (group B) and 74 control subjects (group C) were studied. The IgM, IgG and IgA anti-C. pneumoniae titers were assessed (microimmunofluorescence test Labsystem), values > or =1:16, > or =1:32 and > or =1:16 being respectively considered positive. RESULTS: IgM antibodies were found in 10.9% of group A and 12.5% of group B patients, whereas no subject of group C showed IgM titers (A vs. B, p=ns; C vs. A and B, p<0.05). Positive IgG titers were found in 76.6%, 82% and 44.6% in groups A, B and C, respectively (A vs. B, p=ns; C vs. A and B, p<0.05). Positive IgA titers were found in 62.5%, 61% and 31.1% in groups A, B and C, respectively (A vs. B, p=ns; C vs. A and B, p<0.05). Acute infection was observed in 10.9% and 12.5% of patients in groups A and B, respectively (p=ns); reinfection in 17% and 11%; no patient of the control group had signs of acute infection or reinfection. Chronic infection was observed in 34.4% and 37.5% in group A and B, respectively (p=ns). CONCLUSION: C. pneumoniae infection is associated with coronary artery disease, but no difference in serology is present between unstable and stable angina. Therefore, it does not seem implicated in triggering an acute coronary event.     

Rhabdomyolysis associated with cytomegalovirus infection in kidney transplant recipients

Rhabdomyolysis is a pathological syndrome caused by skeletal muscle cell damage that affects the integrity of the cellular membrane and leads to the release of toxic intracellular constituents into the bloodstream. Although cytomegalovirus (CMV) has rarely been reported as a cause of rhabdomyolysis, CMV infection could be considered as a possible cause because of its clinical significance in kidney transplant recipients (KTRs). We report 2 cases of rhabdomyolysis associated with CMV infection in KTRs. A 64‐year‐old woman (Case 1) and a 65‐year‐old man (Case 2), who had each received a kidney from a living unrelated donor, were admitted with complaints of weakness in both legs and myalgia. Laboratory findings revealed highly increased creatine phosphokinase and myoglobinuria. In both cases, no recent alterations of medications had occurred, and other causes of rhabdomyolysis—such as trauma, alcohol, drugs, and electrolyte abnormalities – were excluded. CMV pp65 antigen was positive, and patients were diagnosed with rhabdomyolysis associated with CMV infection. Both patients recovered without complications after ganciclovir treatment. In conclusion, CMV infection should be considered as a possible cause of rhabdomyolysis in KTRs.     

Effect of simvastatin on ejection fraction in cardiac transplant recipients

Our study suggests that simvastatin treatment is associated with improved EF in cardiac transplant recipients independent of effects attributable to the lipid profile.     

Impairment of coronary flow reserve in orthotopic cardiac transplant recipients with minor coronary occlusive disease

Objective—Coronary occlusive disease is the major long-term complication after cardiac transplantation. The relation between minor angiographic abnormalities and myocardial perfusion has not been previously assessed in a large number of cardiac transplant patients.

Design—Prospective study. Coronary flow reserve was measured with an intracoronary Doppler flow probe in the proximal left anterior descending coronary artery in each patient. A dose of intracoronary papaverine producing maximal vasodilation was then administered.

Setting—A regional cardiothoracic centre and a supraregional transplant unit.

Patients—Seven patients with chest pain but normal coronary anatomy (controls), and 61 cardiac transplant patients between three months and 10 years after operation (median 4·5 years). Twenty one cardiac transplant patients had angiographic evidence of minor coronary occlusive disease (mean (SD) percentage stenosis diameter 23% (6%)) in a primary or secondary coronary vessel (group 1), with 12 of these in the left anterior descending coronary artery (stenosis diameter (mean (SD) 24% (8%)). The remaining 40 transplant patients had normal coronary angiograms (group 2).

Main outcome measure—Coronary flow reserve was defined as the ratio of the peak flow velocity after papaverine to the resting flow velocity.

Results—Group 1 patients had a noticeably impaired coronary flow reserve (2·6 (1·1)) compared with control patients (3·9 (0·4), p = 0·05) and, after adjusting for year after operation, compared with group 2 patients (3·8 (1·0), p < 0·001). No other variables were associated with a reduction in coronary flow reserve. Mean resting flow velocity was similar in all three groups (controls, 7·4 (4·6) cm/s; group 1, 7·5 (5·9) cm/s; and group 2, 7·3 (3·9) cm/s). Mean peak flow velocity response to papaverine was reduced in group 1 patients (18·1 (13·5) cm/s) relative to group 2 patients (27·5 (15·4) cm/s, p = 0·05) but not controls (28·4 (15·1) cm/s, p = 0·1).

Conclusions—Coronary flow reserve and the peak flow response to the coronary vascular smooth muscle relaxant papaverine are impaired in cardiac transplant patients with minor coronary occlusive disease. This disturbance of cardiac microvascular function may contribute to the late morbidity and mortality seen in cardiac transplant patients with coronary occlusive disease.

     

Chlamydia pneumoniae , the heart, and coronary artery disease: Is there a cause and effect relationship?

The possibility that infection with Chlamydia pneumoniae may somehow contribute to the pathogenesis of atherosclerosis continues to be explored by researchers worldwide. A direct cause-and-effect relationship between the bacterium and subsequent development of atherosclerosis has yet to be proved. However, compelling indirect evidence continues to mount in favor of this association. In this article the most recent information on this topic is reviewed. Seroepidemiologic and histopathologic evidence will be highlighted, as well as recent animal models of infection and atherosclerosis. In addition, current studies looking at the association of antichlamydial antibiotic use and risk of adverse cardiovascular outcomes will be detailed.     

Vascular but not cardiac remodeling is associated with superoxide production in angiotensin II hypertension

OBJECTIVE: Angiotensin (Ang) II increases reactive oxygen species (ROS), decreases nitric oxide (NO) bioavailability and promotes cardiovascular remodeling. ROS have been identified as critical second messengers of the trophic responses by Ang II. In rats with Ang II-induced hypertension, we investigated the role of ROS in cardiac hypertrophy as well as the remodeling of aortas and mesenteric (resistance) arteries. METHODS: Sprague-Dawley rats received Ang II (0.7 mg/kg per day by mini-pump, n = 7) or vehicle (n = 7) for 5 days. Endothelium-dependent relaxation to acetylcholine (EDR) in aortas was determined in organ baths and in mesenteric resistance vessels in a pressurized myograph. Superoxide (O2) production was measured by lucigenin chemiluminescence, laser-confocal fluorescence microscopy (LCM) and NADPH oxidase assay. RESULTS: Ang II-treated rats developed hypertension (183 +/- 3 versus 138 +/- 4 mmHg, P < 0.05), increased aortic O2 (50%), aortic hypertrophy (12%) and impaired EDR. Mesenteric arteries manifested impaired EDR, increased NADPH oxidase activity (356%) and eutrophic inward remodeling (decreased lumen diameter and increased wall/lumen ratio). However, although Ang II-treated rats developed cardiac hypertrophy (13%), this was not accompanied by an increase in cardiac O2, as measured by lucigenin, LCM or NADPH oxidase assay. On the other hand, cardiac calcineurin, a molecule that promotes cardiac hypertrophy linked to Ang II, was increased by 40% (52 +/- 8 versus 33 +/- 5 pmol/min per mg protein, P < 0.05). CONCLUSION: These studies demonstrate that the role of ROS in Ang II-induced vascular remodeling differ across vascular territories. Although in conduit and resistance vessels, vascular hypertrophy and endothelial dysfunction are linked to increased ROS production, cardiac hypertrophy is not. Instead, cardiac hypertrophy is associated, at least in part, with an increase in calcineurin. These studies unveil novel mechanisms that may play an important role in the pathogenesis of cardiac and vascular injury in hypertension.     

Experience of percutaneous transluminal coronary angioplasty in orthotopic cardiac transplant recipients

We evaluated the role of percutaneous transluminal coronaryangioplasty (PTCA) in a series of orthotopic cardiac transplantrecipients with severe epicardial coronary occlusive disease.Ten ortho topic cardiac transplant patients treated by PTCAup to March 1990 were reviewed. All had significant epicardialcoronary artery lesions (>70% stenosis compared with theadjacent healthy artery) and exercise electrocardiogram or isotopeperfusion evidence of myocardial ischaemia in the relevant region.Primary angiographic PTCA success was achieved in 12 of the16 lesions attempted (75%). Mean stenosis improvement was from80% of adjacent healthy artery (range 70–90%) to 12% (range0–20%). Median angiographic follow-up of 9 months (2–25months) is available for all patients. The mean recurrence rateis 33% (4 of 12 successfully treated lesions) defined as >50%reduction in the original gain at the PTCA. We have shown thatPTCA is technically possible in a series of cardiac transplantrecipients. The primary success and recurrence rates are comparableto the use of PTCA in conventional atherosclerotic coronarydisease.     

Impairment of coronary flow reserve in orthotopic cardiac transplant recipients with minor coronary occlusive disease.

OBJECTIVE--Coronary occlusive disease is the major long-term complication after cardiac transplantation. The relation between minor angiographic abnormalities and myocardial perfusion has not been previously assessed in a large number of cardiac transplant patients. DESIGN--Prospective study. Coronary flow reserve was measured with an intracoronary Doppler flow probe in the proximal left anterior descending coronary artery in each patient. A dose of intracoronary papaverine producing maximal vasodilation was then administered. SETTING--A regional cardiothoracic centre and a supraregional transplant unit. PATIENTS--Seven patients with chest pain but normal coronary anatomy (controls), and 61 cardiac transplant patients between three months and 10 years after operation (median 4.5 years). Twenty one cardiac transplant patients had angiographic evidence of minor coronary occlusive disease (mean (SD) percentage stenosis diameter 23% (6%)) in a primary or secondary coronary vessel (group 1), with 12 of these in the left anterior descending coronary artery (stenosis diameter (mean (SD) 24% (8%)). The remaining 40 transplant patients had normal coronary angiograms (group 2). MAIN OUTCOME MEASURE--Coronary flow reserve was defined as the ratio of the peak flow velocity after papaverine to the resting flow velocity. RESULTS--Group 1 patients had a noticeably impaired coronary flow reserve (2.6 (1.1)) compared with control patients (3.9 (0.4), p = 0.05) and, after adjusting for year after operation, compared with group 2 patients (3.8 (1.0), p < 0.001). No other variables were associated with a reduction in coronary flow reserve. Mean resting flow velocity was similar in all three groups (controls, 7.4 (4.6) cm/s; group 1, 7.5 (5.9) cm/s; and group 2, 7.3 (3.9) cm/s). Mean peak flow velocity response to papaverine was reduced in group 1 patients (18.1 (13.5) cm/s) relative to group 2 patients (27.5 (15.4) cm/s, p = 0.05) but not controls (28.4 (15.1) cm/s, p = 0.1). CONCLUSIONS--Coronary flow reserve and the peak flow response to the coronary vascular smooth muscle relaxant papaverine are impaired in cardiac transplant patients with minor coronary occlusive disease. This disturbance of cardiac microvascular function may contribute to the late morbidity and mortality seen in cardiac transplant patients with coronary occlusive disease.     

Circulating endothelial progenitor cell numbers are not associated with donor organ age or allograft vasculopathy in cardiac transplant recipients

IntroductionIncreasing age is associated with reduced numbers of circulating endothelial progenitor cells (EPCs). It is unclear whether this relates to depletion or impairment of bone marrow progenitors, or to deficient mobilization signals from aging tissues. In cardiac transplant patients, one previous study has reported an association between circulating EPCs and the risk of cardiac allograft vasculopathy (CAV). We investigated whether increased donor heart age, a strong risk factor for CAV, was associated with reduced circulating EPC numbers in a group of cardiac transplant recipients matched for factors which influence EPC numbers, but with maximally discordant donor heart ages.MethodsWe identified 32 patient pairs, matched for factors known to influence EPC numbers, but who had discordant donor heart ages by at least 20 years. EPCs were quantified using flow cytometry for absolute counts of cells expressing all the combinations of CD45, CD34, CD133 and the kinase domain receptor (KDR).ResultsThere were no significant differences in the numbers of circulating EPCs between patients with old or young donor heart age. There was no association between the presence of CAV and circulating EPC numbers.ConclusionsWe suggest that the increased susceptibility to CAV of older donor hearts is not mediated via circulating EPCs. Our results are consistent with the theory that the normal age-related decline in EPC numbers relates to bone marrow aging rather than failure of target tissues to induce EPC mobilization.     

Human herpesvirus-6 is associated with cytomegalovirus reactivation in liver transplant recipients

Human herpesvirus-6 (HHV-6) may be a risk factor for cytomegalovirus (CMV) disease in posttransplant patients, possibly through a direct interaction or through a general immunomodulatory effect. To examine this possibility, 88 liver transplant recipients were monitored with serial HHV-6 polymerase chain reaction (PCR), CMV antigenemia, and CMV plasma viral load. HHV-6 infection was defined by a positive PCR of peripheral blood lymphocytes. Forty-eight (54.4%) of 88 patients had at least 1 positive HHV-6 PCR. CMV recurrence was significantly more common in patients with HHV-6 infection (38/48 patients [79. 2%]), compared with recurrence in those without HHV-6 infection (18/40 patients [45%]; P=.001). Peak CMV viral load was 24, 147+/-6799 copies/mL in patients with HHV-6 infection versus 8391+/-4598 copies/mL in patients without HHV-6 infection (P=.001). Symptomatic CMV disease was more common in patients with HHV-6 infection than it was in those without infection (15/48 patients [31. 3%] vs. 4/10 patients [10.0%]; P=.013). In a multivariate analysis including other risk factors for CMV, HHV-6 infection remained an independent risk factor for CMV disease (P=.013; odds ratio, 7.26; 95% confidence interval, 1.52-34.72). HHV-6 is associated with CMV infection and disease, thus supporting an interaction between these viruses.