Recent developments on coronary microvasculopathy after heart transplantation: a new target in the therapy of cardiac allograft vasculopathy

Heart transplantation (HTx) is the treatment of choice for patients with refractory end-stage heart diseases. Although the procedure is considered effective in extending and improving quality of life, the onset of cardiac allograft vasculopathy (CAV) continues to limit the long-term success of HTx. Emerging data indicate that the endothelium plays a significant role in the onset, progression and complication of this multifactorial disease, with both immunologic and nonimmunologic risk factors contributing to its development. Improving our understanding of the integral role of the coronary microcirculation in CAV is of crucial clinical interest since it could provide further insights into the related pathophysiological mechanisms and possible new strategies for CAV prevention and therapy. Assessment of coronary microvasculopathy has been shown to be of predictive value after HTx. Predominant allograft microvascular dysfunction is detectable in 15-20% of patients after HTx. Very recently, stenotic microvasculopathy (detected in biopsy samples) has been characterized as a prognostic factor for long-term survival after HTx. The ability to detect and distinguish changes in epicardial and microvascular function may aid in identifying modifiable factors that lead to CAV. Improved immunosuppressive drugs, including mycophenolate mofetil and proliferation signal inhibitors, as well as statins (in part via immunomodulation), may have a beneficial effect on coronary microcirculation after HTx, although there is still a need to confirm the impact of vasodilators in improving the prognosis of HTx patients. We review the role of coronary microvasculopathy in HTx, its prevention and new potential pharmacological interventions.     

Everolimus Prevents Coronary Microvasculopathy in Heart Transplant Recipients With Normal Coronary Angiograms: An Anatomo-Functional Study

Background

Coronary allograft vasculopathy (CAV) involves both epicardial vessels and coronary microcirculation. Little is known about the effect of everolimus on coronary microvasculopathy in heart transplantation (HT). The aim of our study was to assess the pathological substrate of coronary flow reserve (CFR) impairment in HT patients and the effect of everolimus on microvascular remodeling and CFR.

Methods

We studied 28 HT patients with normal coronary angiograms (25 male, age at HT 54 ± 10 years). Immunosuppressive regimen consisted of cyclosporine and everolimus (10 patients) or mycophenolate mophetil (18 patients). They were evaluated with digital microscopy for morphometric analysis of fibrosis and microvascular remodeling. Coronary flow velocity in the left anterior descending coronary artery was detected using transthoracic Doppler echocardiography at rest and during adenosine infusion. CFR was the ratio of hyperaemic diastolic flow velocity (DFV) to resting DFV. A CFR ≤2.5 was considered abnormal and sign of coronary microvascular dysfunction.

Results

In patients with CFR ≤2.5 the thickness of the tunica media of intramyocardial arterioles was greater than in patients with CFR >2.5 (39 ± 2 vs 17 ± 3 μm; P = .02). Microvascular remodeling was significantly higher in patients with CFR ≤2.5 (72.7 ± 2.4 vs 50.4 ± 8.4%; P < .007). Capillary density and fibrosis were comparable between groups (157.2 ± 42.4 vs 175.7 ± 42.4 capillaries/mm²; P = .3; and 6.8 ± 5 vs 8.3 ± 4.9%; P = .4, respectively). The thickness of the tunica media of intramyocardial arterioles was lower in patients whose therapy included everolimus (15 ± 2 vs 32 ± 4 μm, P = .03) and CFR was higher (3.2 ± 0.5 vs 2.8 ± 0.9; P = .03).

Conclusion

The pathological substrate of reduced CFR in HT patients seems to be a hypertrophic remodeling of coronary arterioles. Everolimus appears to prevent such microvascular remodeling and preserve coronary flow reserve.     

Sperm telomere length in donor samples is not related to ICSI outcome

Purpose

Variations in sperm telomere length (STL) have been associated with altered sperm parameters, poor embryo quality, and lower pregnancy rates, but for normozoospermic men, STL relevance in IVF/ICSI is still uncertain. Moreover, in all studies reported so far, each man’s STL was linked to the corresponding female partner characteristics. Here, we study STL in sperm donor samples, each used for up to 12 women, in order to isolate and determine the relationship between STL and reproductive outcomes.

Methods

Relative STL was determined by qPCR in 60 samples used in a total of 676 ICSI cycles. Univariable and multivariable statistical analyses were used to study the STL effect on fertilization rate; embryo morphology; biochemical, clinical, and ongoing pregnancy rates; and live birth (LB) rates.

Results

The average STL value was 4.5 (relative units; SD 1.9; range 2.4–14.2). Locally weighted scatterplot smoothing regression and the rho-Spearman test did not reveal significant correlations between STL and the outcomes analyzed. STL was not different between cycles resulting or not in pregnancy and LB (Mann-Whitney U test, p?>?0.05). No significant effect of STL on reproductive outcomes was found, with the OR for each unit increase in STL (95% CI) of 0.94 (0.86–1–04), 0.99 (0.9–1.09), 0.98 (0.89–1.09), and 0.93 (0.8–1.06) for biochemical, clinical, and ongoing pregnancy and LB, respectively. The multilevel analysis confirmed that the effect of STL on fertilization; biochemical, clinical, and ongoing pregnancy; and LB was not significant (p?>?0.05).

Conclusion

After addressing STL independently from female variables, results show that STL measurement is not useful to predict reproductive outcomes in ICSI cycles using donor semen.

     

Coronary Microvascular Dysfunction Correlates With the New Onset of Cardiac Allograft Vasculopathy in Heart Transplant Patients With Normal Coronary Angiography

Coronary microvascular dysfunction is emerging as a strong predictor of outcome in heart transplantation (HT). We assessed the validity of microvascular dysfunction, defined by means of a reduced coronary flow reserve (CFR), as a factor associated with new onset epicardial cardiac allograft vasculopathy (CAV) or death. We studied 105 patients at 4 ± 1 years post‐HT with a normal coronary angiography (CA). New onset CAV was assessed by CA. CFR was assessed in the left anterior descending (LAD) coronary artery by transthoracic Doppler echocardiography and calculated as the ratio of hyperaemic to basal blood flow velocity. A CFR ≤ 2.5 was considered abnormal. Epicardial CAV onset or death was assessed during a follow‐up of 10 years. New onset CAV was diagnosed in 30 patients (28.6%) (Group A), and the CA was normal in the remaining 75 patients (71.4%) (Group B). Group A had reduced CFR compared with group B (2.4 ± 0.6 vs. 3.2 ± 0.7, p < 0.0001). A CFR ≤ 2.5 was independently associated with a higher probability of new onset CAV (p < 0.0001) and a higher probability of death, regardless of CAV onset (p < 0.01). Microvascular dysfunction is independently associated with the onset of epicardial CAV, and associated with a higher risk of death, regardless of CAV onset.     

Modification of poly[(3-hydroxybutyric acid)-co-(3-hydroxyvaleric acid)] film surfaces in an oxygen low pressure plasma

Poly[(3-hydroxybutyric acid)-co-(3-hydroxyvaleric acid)] (91:9 mass-%) (P(HB-co-9% HV)) film surfaces were modified by an oxygen plasma treatment (75 W, 50 Pa, 5 min). The number of oxygen atoms increases about 12–13% and the polar component of the surface energy increases from 6.3 to 21 mN · m^?1. However, the wettability is stable only after 60 days. Untreated and treated film surfaces are studied by means of X-ray photoelectron spectroscopy with two different depth analyses. With storage time, the oxygen contents of the modified film is constant at a take-off angle of 20° but decreases to the initial value at a take-off angle of 70°. The superficial layer of the polymer film between the top of the film to a depth of 10 nm is divided into three superimposing zones. The interpretation is supported by motions of modified macromolecular chains and buried polar groups, chain cleavage and the formation of low-molecular-weight molecules which leads to a decrease of the glass transition temperature (plasticizer effect) and migration of short chains from the lowest modified zone toward the surface.