Clinical and Functional Correlates of Early Microvascular Dysfunction After Heart Transplantation

1 Stanford University, Stanford, CA
Circulation Heart Failure (Impact Factor: 5.89). 08/2012; 5(6). DOI: 10.1161/CIRCHEARTFAILURE.111.962787
Source: PubMed


Microvascular dysfunction is emerging as a strong predictor of outcome in heart transplant recipients. At this time, the determinants and consequences of early microvascular dysfunction are not well established. The objective of the study was to determine the risk factors and functional correlates associated with early microvascular dysfunction in heart transplant recipients.

Methods and results:
Sixty-three heart transplant recipients who had coronary physiology assessment, right heart catheterization, and echocardiography performed at the time of their first annual evaluation were included in the study. Microvascular dysfunction was assessed using the recently described index of microcirculatory resistance. The presence of microvascular dysfunction, predefined by an index of microcirculatory resistance >20, was observed in 46% of patients at 1 year. A history of acute rejection and undersized donor hearts were associated with microvascular dysfunction at 1 year, with odds ratio of 4.0 (1.3-12.8) and 3.6 (1.2-11.1), respectively. Patients with microvascular dysfunction had lower cardiac index (3.1±0.7 versus 3.5±0.7 L/min per m(2); P=0.02) and mild graft dysfunction measured by echocardiography-derived left and right myocardial performance indices ([0.54±0.09 versus 0.43±0.09; P<0.01] and [0.47±0.14 versus 0.32±0.05; P<0.01], respectively). Microvascular dysfunction was also associated with a higher likelihood of death, graft failure, or allograft vasculopathy at 5 years after transplant (hazard ratio, 2.52 [95% CI, 1.04-5.91]).

A history of acute rejection during the first year and smaller donor hearts were identified as risk factors for early microvascular dysfunction. Microvascular dysfunction assessed using index of microcirculatory resistances at 1 year was also associated with worse graft function and possibly worse clinical outcomes.

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    ABSTRACT: To evaluate the diagnostic performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting cardiac allograft vasculopathy (CAV) using contemporary invasive epicardial artery and microvascular assessment techniques as reference standards, and to compare the performance of CMR with that of angiography. CAV continues to limit the long-term survival of heart transplant recipients. Coronary angiography has a class I recommendation for CAV surveillance and annual or biannual surveillance angiography is performed routinely in most centers. All transplant recipients referred for surveillance angiography at a single UK center over a 2-year period were prospectively screened for study eligibility. Patients prospectively underwent coronary angiography followed by coronary intravascular ultrasound, fractional flow reserve and index of microcirculatory resistance. Within one month patients underwent multiparametric CMR, including assessment of regional and global ventricular function, absolute myocardial blood flow quantification and myocardial tissue characterization. In addition, 10 healthy volunteers underwent CMR. Forty-eight patients were recruited; median 7.1 years (IQR 4.6-10.3) since transplantation. CMR myocardial perfusion reserve was the only independent predictor of both epicardial (β = -0.57, p<0.001) and microvascular disease (β = -0.60, p<0.001) on stepwise multivariable regression. CMR myocardial perfusion reserve significantly outperformed angiography for detecting moderate CAV (AUC 0.89 (0.79-1.0) v 0.59 (0.42-0.77), p=0.01) and severe CAV (AUC 0.88 (0.78-0.98) v 0.67 (0.52-0.82), p=0.05). CAV, including epicardial and microvascular components, can be detected more accurately using non-invasive CMR-based absolute myocardial blood flow assessment than with invasive coronary angiography, the current clinical surveillance technique.
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    ABSTRACT: Opinion statement: The central event in the development of allograft vasculopathy is the inflammatory response to immune-mediated and nonimmune-mediated endothelial damage. This response is characterized by the release of inflammatory cytokines, upregulation of cell-surface adhesion molecules, and subsequent binding of leukocytes. Growth factors stimulate smooth muscle cell proliferation and circulating progenitor cells are recruited to sites of arterial injury leading to neointima formation. Because of its diffuse nature, intravascular ultrasound is more sensitive than angiography for early diagnosis. Proliferation signal inhibitors (PSIs) have the capacity to slow vasculopathy progression by inhibiting smooth muscle cell proliferation, but its side effects profile makes its use as a first line agent difficult. Retransplantation is still the only definitive therapy but is available only in selected cases. The current hope is that immunomodulation at the time of transplant could induce long-term tolerance and graft accommodation, leading to less vasculopathy.
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    ABSTRACT: Background Implementation of reliable noninvasive testing for screening cardiac allograft vasculopathy (CAV) is of critical importance. The most widely used modality, dobutamine stress echocardiography (DSE), has moderate sensitivity and specificity. The aim of this study was to assess the potential role of serial coronary flow reserve (CFR) assessment together with DSE for predicting CAV. Methods A total of 90 studies were performed prospectively over 5 years in 23 consecutive heart transplant recipients who survived >1 year after transplantation. Assessment of CFR with transthoracic Doppler echocardiography, DSE, coronary angiography, and endomyocardial biopsy was performed annually. Results of CFR assessment and DSE were compared with angiographic findings of CAV. Results Acute cellular rejections were excluded by endomyocardial biopsies. CAV was detected in 17 of 90 angiograms. Mean CFR was similarly lower in both mild (CAV grade 1) and more severe (CAV grades 2 and 3) vasculopathy, but wall motion score index became higher in parallel with increasing grades of vasculopathy. Any CAV by angiography was detected either simultaneously with or later than CFR impairment, yielding 100% sensitivity for CFR. The combination of CFR and DSE increased the specificity of the latter from 64.3% to 87.2% without compromising sensitivity (77.8%). Conclusions CFR is very sensitive for detecting CAV and increases the diagnostic accuracy of DSE, raising the potential for patient management tailored to risk modification and to avoid unnecessary angiographic procedures.
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