Francesco Fallani

Prophylaxis Versus Preemptive Anti-cytomegalovirus Approach for Prevention of Allograft Vasculopathy in Heart Transplant Recipients

BACKGROUND Cytomegalovirus (CMV) infection may influence the development of cardiac allograft vasculopathy (CAV). Prophylactic or preemptive administration of anti-CMV agents effectively prevents acute CMV manifestations. However, studies comparing allograft-related outcomes between these anti-CMV approaches are lacking. Herein we report a longitudinal observational study comparing CAV development between prophylactic and preemptive approaches. METHODS The 1-year change in maximal intimal thickening (MIT) assessed by intravascular ultrasound at 1 and 12 months after heart transplantation (the major surrogate for late survival) was compared in groups of patients routinely assigned to a preemptive strategy (from November 2004 to October 2005; n = 21) or receiving valganciclovir prophylaxis (from November 2005 to October 2006; n = 19). CMV infection was monitored with pp65 antigenemia. RESULTS The 1-year increase in MIT was significantly lower in patients receiving prophylaxis compared with those managed preemptively (0.15 +/- 0.17 vs 0.31 +/- 0.20 mm; p = 0.01). Prophylaxed recipients presented less frequently with MIT change > or =0.3 mm (p = 0.03) and > or =0.5 mm (p = 0.10) than those managed preemptively. Prophylaxis was also associated with later onset of CMV infection (p = 0.01), lower peak CMV detection (p < 0.01) and reduced incidence of CMV disease/syndrome (p = 0.04). After adjusting for metabolic risk factors and other possible confounders, prophylaxis remained independently associated with lower risk for MIT change > or =0.3 mm (odds ratio = 0.09, 95% confidence interval 0.01 to 0.93; p = 0.04). CONCLUSIONS Universal prophylaxis was associated with delayed onset of CMV infection, lower viral burden, reduced CMV disease/syndrome and less intimal thickening, as compared with a preemptive anti-CMV approach. Randomized studies are required to confirm the potential benefits of prophylaxis vs a preemptive approach in heart transplant recipients.

Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients: Long-term follow-up of the SHIRAKISS randomized, prospective study

BACKGROUND Cyclosporine nephrotoxicity negatively impacts long-term outcome after heart transplantation (HT). We previously reported 1-year results from a randomized study showing that cyclosporine-lowering strategies based on everolimus or mycophenolate mofetil (MMF) are equally effective for reducing progression of renal dysfunction. It is unknown whether this efficacy could be maintained over the long term. METHODS Thirty-four recipients 1 to 4 years after HT and with 25 to 60 ml/min of creatinine clearance (CrCl) were randomized to everolimus with a very low dose (C(0): 50 to 90 ng/ml, n = 17) or MMF with low dose of cyclosporine (C(0): 100 to 150 ng/ml, n = 17). Follow-up was prolonged up to 3 years, and calculated CrCl was the main efficacy measure. RESULTS Cyclosporine was maintained at 70% and 30% lower than baseline in the everolimus and MMF arms, respectively, throughout the 3-year study period. CrCl remained stable in the everolimus patients (+7% from baseline; p = 0.7), but improved in the MMF patients (+20% from baseline; p < 0.01), with a trend toward improved values compared with everolimus patients (46 ± 12 vs 56 ± 15 ml/min; p = 0.06). Subgroup analysis revealed that baseline proteinuria markedly influenced the renal function response to everolimus: whereas in patients with baseline proteinuria CrCl significantly worsened (-20%; p = 0.04), it improved in those without (+15%; p = 0.03). Safety was comparable between the two study arms. CONCLUSIONS Cyclosporine nephrotoxicity improved after a prolonged dose reduction in patients receiving MMF. The everolimus-based strategy provided a similar benefit only to patients without baseline proteinuria. While raising caution against the universal use of everolimus for kidney protection, our long-term results support the need for customized approaches in the management of drug toxicities in maintenance HT recipients.

Differential Effect of Everolimus on Progression of Early and Late Cardiac Allograft Vasculopathy in Current Clinical Practice

Randomized trials showed that mTOR inhibitors prevent early development of cardiac allograft vasculopathy (CAV). However, the action of these drugs on CAV late after transplant is controversial, and their effectiveness for CAV prevention in clinical practice is poorly explored. In this observational study we included 143 consecutive heart transplant recipients who underwent serial intravascular ultrasound (IVUS), receiving either everolimus or mycophenolate as adjunctive therapy to cyclosporine. Ninety‐one recipients comprised the early cohort, receiving IVUS at weeks 3–6 and year 1 after transplant, and 52 the late cohort, receiving IVUS at years 1 and 5 after transplant. Everolimus independently reduced the odds for early CAV (0.14 [0.01–0.77]; p = 0.02) but it did not appear to influence late CAV progression. High‐dose statins were found to be associated with reduced CAV progression both early and late after transplant (p ≤ 0.05). Metabolic abnormalities, such as high triglycerides, were associated with late, but not with early CAV progression. By highlighting a differential effect of everolimus and metabolic abnormalities on early and late changes of graft coronary morphology, this observational study supports the hypothesis that everolimus may be effective for CAV prevention but not for CAV treatment, and that risk factors intervene in a time‐dependent sequence during CAV development.

Non-invasive detection of coronary artery stenosis: a comparison among power-Doppler contrast echo, 99Tc-sestamibi SPECT and echo wall-motion analysis

Background Power‐Doppler imaging is a recently developed method for myocardial contrast echocardiography (MCE). It can selectively evaluate the signal coming from an ultrasound contrast agent, allowing myocardial perfusion studies. Objective To compare the ability of power‐Doppler MCE with stress‐echo wall‐motion and nuclear scan imaging (SPECT) to assess myocardial ischaemia during pharmacological stress, using coronary angiography as reference. Methods In 25 patients the three non‐invasive imaging modalities were acquired during a single dipyridamole stress test (so as to avoid stress variations). Power‐Doppler MCE was acquired using continuous intravenous infusion of Levovist. Echo wall‐motion was acquired too. At peak stress 99Tc‐Sestamibi was injected; stress SPECT images were acquired 30 min after injection. Results Power‐Doppler MCE and SPECT showed 84% concordance (21 of 25 patients; &kgr; = 0.67) for detection of ischaemia. Concordance based on coronary artery territories for normal perfusion versus fixed defects versus reversible defects was 92% (69 of 75; &kgr; = 0.81), with 100% for left anterior descending, 92% for right coronary artery and 84% for circumflex. Power‐Doppler MCE had lower sensitivity than SPECT (89 versus 100%) but higher specificity (100 versus 88%) for identification of stenotic (≥ 70%) coronary arteries as assessed by angiography. Echo wall‐motion analysis showed the lowest sensitivity (68%) with 100% specificity. Accuracy was 94% for both power‐Doppler MCE and SPECT, and 83% for wall‐motion analysis. Conclusion Power‐Doppler MCE is a sensitive and specific method for identification of myocardial perfusion during pharmacological stress. Accuracy of power‐Doppler MCE for stenotic coronary arteries appears to be slightly higher than stress‐echo wall‐motion and similar to SPECT. Coron Artery Dis 14:239‐245

A comparison of rest sestamibi and rest-redistribution thallium single photon emission tomography: possible implications for myocardial viability detection in infarcted patients.

Thirty patients (26 men, 4 women, mean age 61 ± 8 years) who had suffered myocardial infarction 15 ± 6 months previously, were submitted to (1) standard stress-redistribution thallium-201 single photon emission tomography (SPET), (2) rest-redistribution201Tl SPET and (3) stress-rest technetium-99m sestamibi SPET. Uptake modifications in relation to exercise-induced defects were evaluated in a total of 390 myocardial segments. Tracer uptake was scored as normal (=0), mildly reduced (=1), apparently reduced (=2), severely reduced (=3) or absent (=4). Comparison of stress studies failed to show any statistical difference (58% segmental abnormalities with sestamibi vs 61% with thallium). Uptake abnormalities (score 1–4) were detected in 55% of the segments wiliest sestamibi, 55% with standard thallium redistribution, 55% with early imaging after thallium injection at rest and 54% with 3-h delayed rest imaging (P = NS). Absence of tracer uptake (score = 4) under resting conditions was recorded in 75 (19%) segments with standard201Tl redistribution, 75 (19%) with rest sestamibi, 70 (18%) with rest201Tl imaging and 62 (16%) with rst-rdistruion201Tl (P<0.05 vs other imaging modalities). Thus, 3-h delayed rest thallium imaging detected reversibility of uptake defects in a significantly higher number of myocardial segments. This finding might have important implications for both tracer and technique selection when myocardial viability is the main clinical issue.

Cyclosporine lowering with everolimus or mycophenolate to preserve renal function in heart recipients: a randomized study.

Doppler imaging: A new technique to assess orbital blood flow in patients with diabetic retinopathy. Invest Ophthalmol Vis Sci 1995;36:864. 3. Gracner T. Ocular blood flow velocity determined by color Doppler imaging in diabetic retinopathy. Ophthalmologica 2004; 218:237. 4. Lieb WE, Cohen SM, Merton DA, et al. Color Doppler imaging of the eye and orbit. Technique and normal vascular anatomy. Arch Ophthalmol 1991;109:527. 5. Venturini M, Zaganelli E, Angeli E, et al. Color-Doppler flow imaging: Examination technique, detectability and flow analysis of orbital vessels. Radiol Med 1996;91:60. 6. Parving HH, Hommel E, Mathiesen E , et al. Prevalence of microalbuminuria, arterial hypertension, retinopathy, and neuropathy in patients with insulin-dependent diabetes. BMJ 1988;296:156. 7. Step henson JM, Fuller JH, Viberti GC, et al; the EURODIAB IDDM Complications Study Group. Blood pressure, retinopathy and urinary albumine excretion in IDDM: The EURODIAB IDDM Complications Study. Diabetologia 1995;38:599. 8. Porta M, Bandello F. Diabetic retinopathy. A clinical update. Diabetologia 2002;45: 1617. 9. Rajagopalan S, Harrison DG. Reversing endothelial dysfunction with ACE inhibitors. A new trend. Circulation 1996;94: 258. 10. Fiorina P, Folli F, Maffi P, et al. Islet transplantation improves vascular diabetic complications in patients with diabetes who underwent kidney transplantation: A comparison between kidney-pancreas and kidney-alone transplantation. Transplantation 2003; 75: 1296. 11. Thomson DM, Begg IS, Harris C, et al. Reduced progression of diabetic retinopathy after islet cell transplantation compared with intensive medical therapy. Transplantation 2008; 85: 1400. 12. Diem P, Abid M, Redmon JB, et al . Systemic venous drainage of pancreas allograft as independent cause of hyperinsulinemia in type I diabetic recipients. Diabetes 1990; 39:534. 13. Parving HH. Impact of blood pressure and antihypertensive treatment on incipient and overt nephropathy, retinopathy , and endothelial permeability in diabetes mellitus. Diabetes Care 1991;14:260.

Cardiac resynchronization therapy : Effects on left and right ventricular ejection fraction during exercise

In patients with heart failure and wide QRS complex, cardiac resynchronization therapy (CRT) is associated with improvement of symptoms and cardiac function. This study examined the effects of a 3‐month period of CRT on left ventricular (LV) and right ventricular (RV) ejection fraction (EF) and on LV volumes, both at rest and during exercise. A CRT system was implanted in 15 patients with severe heart failure and wide QRS. Before implant and 3 months later, all patients underwent assessment of cardiac performance with equilibrium Tc99 radionuclide angiography with imaging in the best septal left anterior oblique view. Exercise was performed on a bicycle ergometer. At 3 months, a significant improvement in New York Heart Association functional class was observed, and radionuclide angiography showed a significant decrease in LV volumes and a significant increase in LVEF at rest, as well as a significant increase in LVEF during exercise. The remodeling processes associated with CRT did not appear to include RV function, since RVEF did not improve, and changes in RVEF did not correlate with changes in LVEF, neither at rest nor during exercise.

Interplay of coronary angiography and intravascular ultrasound in predicting long-term outcomes after heart transplantation

BACKGROUND Cardiac allograft vasculopathy (CAV) remains the major cause of late graft-related death after heart transplantation (HT). Identification of patients at risk of cardiovascular events has relevant implications in appropriately guiding resources and intensity of follow-up. In this context, the prognostic relevance of serial coronary imaging long-term after HT is unexplored. METHODS Recipients with intravascular ultrasound (IVUS) and coronary angiography performed 1 and 5 years after HT were monitored for subsequent 1 to 10 years to analyze the association of serial coronary imaging with cardiovascular death and major cardiovascular events (MACEs). RESULTS Included were 131 patients. The MACE incidence was 31.8 per 1,000 patient-years, and cardiovascular mortality was 17.4 per 1,000 patient-years. Progression of coronary lesions detected by angiography and changes in IVUS-defined parameters, including an increase in maximal intimal thickness (MIT) ≥0.35 mm and vascular remodeling, predicted MACE occurrence. However, only MIT change ≥0.35 mm also predicted cardiovascular mortality. Among patients with normal or stable angiography, an MIT change ≥0.35 mm identified those with a significantly higher MACE rate (80 vs 13 events/1,000 patient-years). Worsening metabolic parameters appeared associated with the increasing severity of CAV development. CONCLUSIONS Combined imaging analysis of progression of angiographic lesions and IVUS-detected MIT between 1 and 5 years post-HT allows discriminating patients at high, intermediate, and low risk for adverse long-term cardiovascular outcomes. The metabolic syndrome milieu is confirmed as a key risk factor for long-term CAV progression and adverse prognosis.

Safety and efficacy of ezetimibe with low doses of simvastatin in heart transplant recipients.

Although statins have proven efficacy in lowering lipids and improving survival in heart transplantation (HT) recipients, potential drug interactions may limit efficacy and reduce tolerability. This observational study explored the efficacy and tolerability of ezetimibe (10 mg/day) combined with simvastatin (10 or 20 mg/day) prescribed to HT recipients with intolerance to statins (n = 11) or inadequate lipid control despite high-dose statins (n = 14). Substantial reductions in lipid levels were apparent after 2 months (total cholesterol, -22%; low-density lipoproteins, -28%; triglycerides, -31%) and were maintained at 6 months. Reductions were significant in both subgroups of recipients; the vast majority (12 of 14, 85%) of recipients with a history of statins intolerance were able to tolerate ezetimibe plus low-dose simvastatin. This study provides suggestive evidence that treatment with ezetimibe plus low-dose simvastatin is well tolerated by HT recipients and may be effective for treatment of dyslipidemia in HT recipients with statins intolerance or resistance.

Safety and efficacy of early aggressive versus cholesterol-driven lipid-lowering strategies in heart transplantation: a pilot, randomized, intravascular ultrasound study.

BACKGROUND Statins are recommended in heart transplantation regardless of lipid levels. However, it remains unknown whether dosing should be maximized or adjusted toward a pre-defined cholesterol threshold. METHODS This pilot, randomized, open-label study compares an early maximal dose of fluvastatin (80 mg/day) with a strategy based on 20 mg/day subsequently titrated to target low-density lipoproteins (LDL) <100 mg/dl. Efficacy outcomes consisted of achieving an LDL level of <100 mg/dl at 12 months after transplant, and change in intracoronary ultrasound parameters. RESULTS Fifty-two patients were randomized. Overall safety, and efficacy in achieving LDL targets (13 [50%] vs 14 [54%]; p = 0.8) were comparable between study arms, but 17 (65%) patients needed a dose increase in the titrated-dosing arm. Early LDL levels and average LDL burden were lower in the maximal-dosing arm (p < 0.05). Few patients developed an increase in maximal intimal thickness of >0.5 mm, with numerical prevalence in the titrated-dosing arm (3 [12.5%] vs 1 [5%]; p = 0.3). Intimal volume increased in the titrated-dosing (p < 0.01) but not in the maximal-dosing arm (p = 0.1), which accordingly showed a higher prevalence of negative remodeling (p = 0.02). CONCLUSIONS Despite being as effective as the titrated-dosing approach in achieving LDL <100 mg/dl at 12 months after transplant, the maximal-dose approach was associated with a more rapid effect and with potential advantages in preventing pathologic changes in graft coronary arteries.