Miguel Llano

Plasma Levels of Transforming Growth Factor-β1 Reflect Left Ventricular Remodeling in Aortic Stenosis

Background TGF-β1 is involved in cardiac remodeling through an auto/paracrine mechanism. The contribution of TGF-β1 from plasmatic source to pressure overload myocardial remodeling has not been analyzed. We investigated, in patients with valvular aortic stenosis (AS), and in mice subjected to transverse aortic arch constriction (TAC), whether plasma TGF-β1 relates with myocardial remodeling, reflected by LV transcriptional adaptations of genes linked to myocardial hypertrophy and fibrosis, and by heart morphology and function. Methodology/Principal Findings The subjects of the study were: 39 patients operated of AS; 27 healthy volunteers; 12 mice subjected to TAC; and 6 mice sham-operated. Myocardial samples were subjected to quantitative PCR. Plasma TGF-β1 was determined by ELISA. Under pressure overload, TGF-β1 plasma levels were significantly increased both in AS patients and TAC mice. In AS patients, plasma TGF-β1 correlated directly with aortic transvalvular gradients and LV mass surrogate variables, both preoperatively and 1 year after surgery. Plasma TGF-β1 correlated positively with the myocardial expression of genes encoding extracellular matrix (collagens I and III, fibronectin) and sarcomeric (myosin light chain-2, β-myosin heavy chain) remodelling targets of TGF-β1, in TAC mice and in AS patients. Conclusions/Significance A circulating TGF-β1-mediated mechanism is involved, in both mice and humans, in the excessive deposition of ECM elements and hypertrophic growth of cardiomyocytes under pressure overload. The possible value of plasma TGF-β1 as a marker reflecting preoperative myocardial remodeling status in AS patients deserves further analysis in larger patient cohorts.

Virtual Histology Intravascular Ultrasound Assessment of Cardiac Allograft Vasculopathy From 1 to 20 Years After Heart Transplantation

BACKGROUND Cardiac allograft vasculopathy (CAV) is the main cause of graft loss and death in heart transplant (HTx) recipients surviving >1 year. There is a dual etiology for coronary disease in HTx: classic atherosclerosis and an immunologically mediated disease. Intravascular ultrasound (IVUS) is highly sensitive for CAV detection; however, gray-scale IVUS is of limited value for identification of specific plaque components. We sought to characterize graft coronary artery disease by means of IVUS-virtual histology (IVUS-VH) at different time-points of follow-up and to correlate plaque composition with clinical factors. METHODS In our study we included 67 patients, who were 7.6 +/- 5.7 years post-HTx. IVUS gray-scale evaluation was performed on all patients. IVUS-VH analysis was done in those patients showing intimal thickening >0.5 mm at the three more significant lesions (three cross-sections for each) of the left anterior descending artery. RESULTS IVUS-VH analysis was obtained done on 58 patients (86.5%). We found a significant correlation between time of HTx and IVUS gray-scale parameters (plaque area and plaque burden), with both increasing over time. We also found a significant correlation between time and IVUS-VH-derived plaque components, necrotic core and calcium, which increased with time, and fibrous and fibrofatty components, both decreased at follow-up. IVUS-VH results were also related to donor age and cardiovascular risk factors. CONCLUSIONS We observed a time-related change in IVUS-VH-derived plaque composition. Necrotic core and calcium, typical atheromatous components, become more prevalent with time after HTx, especially when influenced by cardiovascular risk factors. The presence of a necrotic core in the early stages was linked to older donor age.

Impact of aortic regurgitation after transcatheter aortic valve implantation: results from the REVIVAL trial.

OBJECTIVES Understanding the severity of aortic regurgitation (AR) after transcatheter aortic valve implantation, its impact on left ventricular (LV) structure and function, and the structural factors associated with worsening AR could lead to improvements in patient selection, implantation technique, and valve design. BACKGROUND Initial studies in patients at high risk of surgical aortic valve replacement have reported both central valvular and paravalvular AR after transcatheter aortic valve implantation. METHODS Transthoracic echocardiograms were quantified from 95 patients in the REVIVAL (TRanscatheter EndoVascular Implantation of VALves) trial. Transthoracic echocardiograms were obtained before implantation of the Edwards-Sapien valve (Edwards Lifesciences, Irvine, California) and thereafter at selected intervals. Measurements included LV internal diameters and volumes, ejection fraction, aortic valve area, and the degree of aortic regurgitation. Measures of degree of native leaflet mobility, thickness, and calcification, as well as left ventricular outflow tract, aortic annulus, and aortic root diameters were also made. RESULTS Eighty-four patients remained after 11 were excluded; 26 (29.8%) died over a period of 3 years. At 24 h post-implantation, 75% had some degree of AR, mostly paravalvular. By 1 year, the mean AR grade increased slightly, but not significantly (1.1 ± 0.8 to 1.3 ± 0.9), and all measures of LV structure and function improved (LV ejection fraction, 50.7 ± 16.1% to 59.4 ± 14.0%). Native aortic leaflet calcification and annulus diameter correlated significantly with the severity of AR at 1 year (p < 0.05). CONCLUSIONS AR after transcatheter aortic valve implantation is frequent but is rarely more than mild. Although AR progresses, it is not associated with a harmful impact on LV structure and function over the first year. Native valve calcification and aortic annulus diameter influence the degree of AR at 6 months.

Avoidance of Calcineurin Inhibitors With Use of Proliferation Signal Inhibitors in De Novo Heart Transplantation With Renal Failure

BACKGROUND This study describes our experience with proliferation signal inhibitors in de novo heart transplant recipients with significant renal impairment. To circumvent further nephrotoxicity, calcineurin inhibitors were avoided in the peri-operative period. METHODS Immunosuppression in 20 patients was with a proliferation signal inhibitor (sirolimus, 14; everolimus, 6), an anti-mitotic drug, and corticosteroids from the time of transplantation. Induction was used in 9 patients (45%). All patients had preoperative significant renal dysfunction (mean glomerular filtration rate <30 ml/min/1.73 m(2)), and 4 patients required dialysis. RESULTS Post-operatively, the glomerular filtration rate significantly increased (>65 ml/min/1.73 m(2) at Month 1, remaining stable thereafter). No patients required dialysis after the first month of transplantation. Mean follow-up was 500 days. Rejection episodes occurred in 11 patients (55%), and 4 patients died (2 of rejection, although 1 death occurred 48 days after conversion to conventional treatment with tacrolimus). Half of the patients were eventually converted to conventional calcineurin-inhibitor therapy because of proliferation signal inhibitor adverse events. CONCLUSION Although this immunosuppressive approach was associated with a somewhat high rate of rejection and frequent side effects, it represents an attractive alternative in the complicated peri-operative setting of patients with significant renal impairment. This approach could serve as a temporary bridge to a conventional treatment.

Predictors of long-term renal function after conversion to proliferation signal inhibitors in long-term heart transplant recipients

BACKGROUND The purpose of this study was to evaluate the change in renal function and its determinants after replacement of calcineurin inhibitors with a proliferation signal inhibitor (sirolimus or everolimus) in long-term heart transplant recipients. METHODS We studied 49 consecutive patients in whom a switch to a proliferation signal inhibitor was carried out 9 ± 4 years after transplantation. Evolutive glomerular filtration rate was assessed at a mean of 28 months after conversion by the simplified MDRD equation. RESULTS Pre-conversion glomerular filtration rate (40 ± 22 ml/min/1.73 m(2)) remained stable at 1 year after conversion (41 ± 22 ml/min/1.73 m(2)), but decreased significantly by the end of follow-up (35 ± 22 ml/min/1.73 m(2); p = 0.008 and p = 0.002 vs pre-conversion and 1-year values, respectively). In a multivariate model, including age, time from transplantation to conversion, pre-conversion glomerular filtration rate, presence of diabetes and use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) therapy, the rate of decline in renal function was related only to the presence of diabetes (p = 0.017) and inversely related to the use of ACEI/ARB therapy (p = 0.003). There were no significant differences with respect to age, time between transplantation and replacement and baseline glomerular filtration rate. CONCLUSION In long-term heart transplant recipients, late substitution of a calcineurin inhibitor for a proliferation signal inhibitor does not preclude a decrease in renal function in the long-term setting. We identified the presence of diabetes as the main clinical predictor of renal function deterioration. In contrast, we found that the use of ACEI/ARB therapy could exert a protective effect.

Utility of implantable loop recorders for diagnosing unexplained syncope in clinical practice.

Establishing a symptom–rhythm correlation in patients with unexplained syncope is complicated because of its sporadic, infrequent, and unpredictable nature. Prolonged monitoring with an implantable loop recorder (ILR) allows the recording of electrocardiogram (ECG) data from a spontaneous syncopal event.

Health Care and Nonhealth Care Costs in the Treatment of Patients With Symptomatic Chronic Heart Failure in Spain

INTRODUCTION AND OBJECTIVES Chronic heart failure is associated with high mortality and utilization of health care and social resources. The objective of this study was to quantify the use of health care and nonhealth care resources and identify variables that help to explain variability in their costs in Spain. METHODS This prospective, multicenter, observational study with a 12-month follow-up period included 374 patients with symptomatic heart failure recruited from specialized cardiology clinics. Information was collected on the socioeconomic characteristics of patients and caregivers, health status, health care resources, and professional and nonprofessional caregiving. The monetary cost of the resources used in caring for the health of these patients was evaluated, differentiating among functional classes. RESULTS The estimated total cost for the 1-year follow-up ranged from € 12,995 to € 18,220, depending on the scenario chosen (base year, 2010). The largest cost item was informal caregiving (59.1%-69.8% of the total cost), followed by health care costs (26.7%- 37.4%), and professional care (3.5%). Of the total health care costs, the largest item corresponded to hospital costs, followed by medication. Total costs differed significantly between patients in functional class II and those in classes III or IV. CONCLUSIONS Heart failure is a disease that requires the mobilization of a considerable amount of resources. The largest item corresponds to informal care. Both health care and nonhealth care costs are higher in the population with more advanced disease.

Experimental modelling of cardiac pressure overload hypertrophy: Modified technique for precise, reproducible, safe and easy aortic arch banding-debanding in mice

Pressure overload left ventricular hypertrophy is a known precursor of heart failure with ominous prognosis. The development of experimental models that reproduce this phenomenon is instrumental for the advancement in our understanding of its pathophysiology. The gold standard of these models is the controlled constriction of the mid aortic arch in mice according to Rockman’s technique (RT). We developed a modified technique that allows individualized and fully controlled constriction of the aorta, improves efficiency and generates a reproducible stenosis that is technically easy to perform and release. An algorithm calculates, based on the echocardiographic arch diameter, the intended perimeter at the constriction, and a suture is prepared with two knots separated accordingly. The aorta is encircled twice with the suture and the loop is closed with a microclip under both knots. We performed controlled aortic constriction with Rockman’s and the double loop-clip (DLC) techniques in mice. DLC proved superiority in efficiency (mortality and invalid experiments) and more homogeneity of the results (transcoarctational gradients, LV mass, cardiomyocyte hypertrophy, gene expression) than RT. DLC technique optimizes animal use and generates a consistent and customized aortic constriction with homogeneous LV pressure overload morphofunctional, structural, and molecular features.

TCT-436 Impact of a Mechanical Circulatory Support Program in the Survival of Patients with Cardiogenic Shock Undergoing Primary Angioplasty.

Patients in cardiogenic shock benefit from mechanical reperfusion, but their mortality remains high even using intra-aortic balloon. It is not well known if a Mechanical Circulatory Support Program (MCSP) might improve the long term outcome of these patients. We have compared in-hospital and 1 year