Ziad Taimeh

Vascular endothelial growth factor in heart failure

Heart failure is a devastating condition, the progression of which culminates in a mismatch of oxygen supply and demand, with limited options for treatment. Heart failure has several underlying causes including, but not limited to, ischaemic heart disease, valvular dysfunction, and hypertensive heart disease. Dysfunctional blood vessel formation is a major problem in advanced heart failure, regardless of the aetiology. Vascular endothelial growth factor (VEGF) is the cornerstone cytokine involved in the formation of new vessels. A multitude of investigations, at both the preclinical and clinical levels, have garnered valuable information on the potential utility of targeting VEGF as a treatment option for heart failure. However, clinical trials of VEGF gene therapy in patients with coronary artery disease or peripheral artery disease have not, to date, demonstrated clinical benefit. In this Review, we outline the biological characterization of VEGF, and examine the evidence for its potential therapeutic application, including the novel concept of VEGF as adjuvant therapy to stem cell transplantation, in patients with heart failure.

Incidence, predictors, and temporal trends of sudden cardiac death after heart transplantation.

BACKGROUND Sudden cardiac death (SCD) has been reported to be a significant mode of death after heart transplantation (HT) in small case series. However, the incidence, timing, and predictors of SCD have not been examined in a large multicenter HT cohort. OBJECTIVE The purpose of this study was to examine the incidence, timing, predictors, and temporal trends of SCD after HT. METHODS Adults (≥18 years) who underwent first-time HT in the United States between 1987 and 2012 were retrospectively identified from the United Network for Organ Sharing (UNOS) registry. Patients with sudden cardiac arrest as the primary cause of death constituted the SCD group. RESULTS Data on 37,492 HT recipients (mean age 51.9 ± 11.7 years, 77% male, 78% Caucasian) were analyzed. During mean follow-up of 6.5 ± 5.7 years, there were 17,324 (46%) deaths, of which 1659 (9.6%) were SCD. On multivariate Cox regression analysis, left ventricular ejection fraction (LVEF) ≤40% (hazard ratio [HR] 3.67, 95% confidence interval [CI] 3.23-4.17, P < .0001), allograft rejection (HR 1.51, 95% CI 1.35-1.70, P < .0001), and donor age (HR 1.17, 95% CI 1.13-1.23, P < .0001) were associated with increased risk of SCD, whereas recipient age (HR 0.90, 95% CI 0.86-0.95, P < .0001) and Caucasian race (HR 0.61, 95% CI 0.54-0.69, P < .0001) were associated with reduced risk. The incidence of SCD has shown no significant temporal improvement since 1987 (log-rank P = .84). CONCLUSION Approximately 10% of deaths after HT are due to SCD. Allograft rejection and LVEF ≤40% are strong predictors of SCD in adult HT patients. Whether implantable cardioverter-defibrillators would reduce mortality in these patients with a relative higher risk of non-SCD remains to be determined.

Impact of pre-transplant pulmonary hypertension on survival after heart transplantation: a UNOS registry analysis.

INTRODUCTION Severe pre-transplant pulmonary hypertension (PH) has been associated with adverse short-term clinical outcomes after heart transplantation in relatively small single-center studies. The impact of pre-transplant PH on long-term survival after heart transplantation has not been examined in a large, multi-center cohort. METHODS Adults (≥18 years) who underwent first time heart transplantation in the United States between 1987 and 2012 were retrospectively identified from the United Network for Organ Sharing registry. Pre-transplant PH was classified as mild, moderate, or severe based on pulmonary vascular resistance (PVR), trans-pulmonary gradient (TPG), and pulmonary artery (PA) mean pressure. Primary outcome was all-cause mortality. RESULTS Data from 26,649 heart transplant recipients (mean age 52±12 years; 76% male; 76% Caucasian) were analyzed. During a mean follow-up of 5.7±4.8 years, there were 10,334 (39%) deaths. Pre-transplant PH (PVR≥2.5 WU) was a significant predictor of mortality (hazard ratio 1.10, 95% confidence interval 1.05-1.14, p<0.0001) in multivariable analysis. However, the severity of pre-transplant PH (mild/moderate vs. severe) did not affect short or long-term survival. Similarly, even in patients who were supported with either a left ventricular assist device or a total artificial heart prior to transplant, severe pre-transplant PH was not associated with worse survival when compared to patients with mild/moderate pre-transplant PH. CONCLUSION Pre-transplant PH (PVR≥2.5 WU) is associated with a modest increase in mortality when compared to patients without pre-transplant PH. However, the severity of pre-transplant PH, assessed by PVR, TPG, or mean PA pressure, is not a discriminating factor for poor survival in patients listed for heart transplantation.

Lung transplantation for pulmonary sarcoidosis. Twenty-five years of experience in the USA

Objective Lung transplantation is the ultimate treatment for end-stage pulmonary sarcoidosis. Post-transplant survival outcomes remain unclear. Methods Survival models were used to assess survival and graft outcomes in patients with sarcoid among 20 896 lung transplants performed in the USA. Results 695 lung recipients were transplanted for pulmonary sarcoidosis. Sarcoid lung recipients had similar median survival rate (69.7 months (IQR 60.2–79.3)) compared with the non-sarcoid lung recipients (63.1 months (IQR 61.4–64.8), p=0.88). In multivariate Cox regression, sarcoidosis was not independently associated with worse mortality (HR 0.96 (95% CI 0.85 to 1.08), p=0.51). Among the sarcoid lung recipients, double lung transplantation (HR 0.76 (0.58 to 0.99), p=0.04) and lung allocation score era (HR 0.74 (0.56 to 0.97), p=0.03) were associated with improved survival. Conclusions Recipients of lung transplants for pulmonary sarcoidosis had similar outcomes compared with non-sarcoid lung recipients.

Primary myelodysplastic syndrome in Jordan: A single-centre experience

Objective: Study of the disease patterns and clinical evaluation of myelodysplastic syndrome (MDS). Subjects and Methods: A retrospective analysis was carried out on 85 patients, with MDS who were followed up over a period of 23 years at Jordan University Hospital, Amman, Jordan. Cases were analyzed according to the French, American and British Classification. Results: Of the 85 patients, 42 (49.4%) were females and 43 (50%) males; mean age was 59 ± 19 years (range 18–88). Most subtypes found in patients were refractory anemia (RA) in 27 (31.8%) and RA with excess blasts (RAEB) in 28 (32.9%). Adverse prognostic indicators were RAEB subtype and requirement for blood transfusion. Conclusion: Our findings showed that MDSs appeared at a younger age and tended to be of the aggressive subtype. Chronic myelomonocytic leukemia subtype seemed to appear dominantly in men.

Heart Failure Prevention

Heart failure takes a tremendous toll on patients and the health-care system. According to the National Heart, Lung, and Blood Institute (NHLBI), 5.7 million adult Americans had heart failure in 2012, and that number is expected to rise by 46 % by 2030. Despite significant advancements in therapies with improved morbidity, the 1-year mortality rate is 29.6 %, and cumulative mortality is almost 50 % within the first 5 years after initial diagnosis. More than 1.8 million office visits and 676,000 emergency room visits were attributed to heart failure in 2010. In 2012, the direct medical costs of heart failure exceeded

Erythrocyte aging as a mechanism of anemia and a biomarker of device thrombosis in continuous-flow left ventricular assist devices

21 billion, with a projected increase of almost 127 % by 2030. The good news is the impact of prevention on the reduction of heart failure. As one example, 75 % of heart failure cases had predisposing hypertension; the lifetime risk for people with a blood pressure (BP) > 160/90 mmHg is double that of those with a BP < 140/90 mmHg. The Coronary Artery Risk Development in Young Adults (CARDIA) study identified hypertension, obesity, and systolic dysfunction as important risk factors amenable to prevention. Thus, the “heart failure tide” is turning to a bigger focus on prevention, rather than a singular focus on treatment. As with other diseases, early detection is vital as is eliminating or reducing risk factors and treating them aggressively. Common, preventable risk factors include hypertension, dyslipidemia, obesity, and diabetes mellitus. This chapter also describes other areas where prevention can make a big difference, such as with heart failure’s association with social behaviors ranging from alcohol abuse to use of cocaine, androgenic steroids, and amphetamines (recreational use)—and heart failure’s relationship to the human immunodeficiency virus and chemotherapy. Eliminating or reducing risk factors and treating them adequately will not only reduce morbidity and mortality but can maintain patients’ quality of life and reduce health-care costs.

ORTHOTOPIC HEART TRANSPLANTATION & PSEUDORESTRICTIVE LV FILLING PATTERN: A STUDY OF TRANSMITRAL DOPPLER FLOW / TISSUE DOPPLER IMAGING AND COMPARATIVE INVASIVE HEMODYNAMICS IN PATIENTS WITH ORTHOTOPIC HEART TRANSPLANTATION

BACKGROUND Blood trauma caused by continuous-flow left ventricular assist devices (CF-LVADs) has been associated with device thrombosis and anemia. Accurate in vivo quantification of erythrocyte turnover and its contribution to CF-LVAD complications have yet to be elucidated. METHODS We investigated the age (lifespan) of circulating erythrocytes in subjects with CF-LVAD. Erythrocyte lifespan is a quantitative indicator of in vivo erythrocyte turnover that can be accurately derived from measurement of the exhaled carbon monoxide (CO) level. Sixty non-smoking subjects were prospectively enrolled: 25 had a CF-LVAD without thrombosis; 10 had a CF-LVAD with thrombosis; and 25 were normal controls. End-tidal breath CO levels were measured and used to calculate erythrocyte lifespan. RESULTS The mean erythrocyte lifespan was significantly shorter in CF-LVAD subjects with (29.7 ± 14.9 days) compared to those without (65.0 ± 17.3 days) device thrombosis (p < 0.0001). The lifespans in these 2 groups were significantly shorter compared with normal controls (96.0 ± 24.9 days, both p < 0.0001). A receiver operator curve demonstrated high sensitivity-specificity for use of erythrocyte lifespan to detect device thrombosis (AUC = 0.94). In addition, all CF-LVAD subjects had low hemoglobin (11.8 ± 2.0 g/dl), and their anemia was normochromic normocytic with elevated mean reticulocyte counts. Erythrocyte lifespan correlated significantly with mean corpuscular hemoglobin concentration (r = 0.56, p = 0.0005) and red cell distribution width (r = -0.65, p < 0.001), but not with reticulocyte count (r = 0.27, p = 0.32). CONCLUSIONS Erythrocyte lifespan is substantially reduced in subjects with a CF-LVAD, which was more pronounced in the presence of device thrombosis. The etiology of anemia in CF-LVAD was primarily due to accelerated erythrocyte aging. Further studies are needed to determine whether erythrocyte lifespan could provide a practical means of detecting subtle pre-clinical thrombosis.

Ventricular Assist Devices for Advanced Heart Failure

Echo studies in heart transplant patients often show elevated early diastolic filling (E) velocities and an E/A ratio > 2. Whether this represents left ventricular diastolic dysfunction or it is a benign finding is yet to be ascertained. In a retrospective study we analyzed echocardiographic and

Cardiac Transplantation: Immunobiology and Immunotherapy

The limited number of donor organs for orthotopic heart transplantation has boosted interest in alternative therapies, including mechanical circulatory support. Ventricular assist devices (VADs) were developed in the 1960s to help patients who could not be weaned from cardiopulmonary bypass following cardiac surgery. Since then, attention has focused on creating a safe, durable, and hemodynamically effective device for the patient with advanced heart failure.