Michelle Frank

Statins and the Risk of Cancer After Heart Transplantation

Background— Although newer immunosuppressive agents, such as mTOR (mammalian target of rapamycin) inhibitors, have lowered the occurrence of malignancies after transplantation, cancer is still a leading cause of death late after heart transplantation. Statins may have an impact on clinical outcomes beyond their lipid-lowering effects. The aim of the present study was to delineate whether statin therapy has an impact on cancer risk and total mortality after heart transplantation. Methods and Results— A total of 255 patients who underwent heart transplantation at the University Hospital Zurich between 1985 and 2007 and survived the first year were included in the present study. The primary outcome measure was the occurrence of any malignancy; the secondary end point was overall survival. During follow-up, a malignancy was diagnosed in 108 patients (42%). The cumulative incidence of tumors 8 years after transplantation was reduced in patients receiving a statin (34% versus 13%; 95% confidence interval, 0.25–0.43 versus 0.07–0.18; P<0.003). Statin use was associated with improved cancer-free and overall survival (both P<0.0001). A Cox regression model that analyzed the time to tumor formation with or without statin therapy, adjusted for age, male sex, type of cardiomyopathy, and immunosuppressive therapy (including switch to mTOR inhibitors or tacrolimus), demonstrated a superior survival in the statin group. Statins reduced the hazard of occurrence of any malignancy by 67% (hazard ratio, 0.33; 95% confidence interval, 0.21–0.51; P<0.0001). Conclusions— Although it is not possible to adjust for all potential confounders because of the very long follow-up period, this registry suggests that statin use is associated with improved cancer-free and overall survival after cardiac transplantation. These data will need to be confirmed in a prospective trial.

Congenital coronary anomalies detected by coronary computed tomography compared to invasive coronary angiography

BackgroundAs coronary computed tomography angiography (CCTA) has emerged as a non-invasive alternative for evaluation of coronary anatomy with a lower referral threshold than invasive coronary angiography (ICA), the prevalence of coronary anomalies in CCTA may more closely reflect the true prevalence in the general population. Morphological features of coronary anomalies can be evaluated more precisely by CCTA than by ICA, which might lead to a higher identification of congenital coronary anomalies in CCTA compared to ICA.To evaluate the incidence, clinical and morphological features of the anatomy of patients with coronary anomalies detected either by coronary computed tomography angiography (CCTA) with prospective ECG-triggering or invasive coronary angiography (ICA).MethodsConsecutive patients underwent 64-slice CCTA (n = 1′759) with prospective ECG-triggering or ICA (n = 9′782) and coronary anatomy was evaluated for identification of coronary anomalies to predefined criteria (origin, course and termination) according to international recommendations.ResultsThe prevalence of coronary anomalies was 7.9% (n = 138) in CCTA and 2.1% in ICA (n = 203; p < 0.01). The most commonly coronary anomaly detected by CCTA was myocardial bridging 42.8% (n = 59) vs. 21.2% (n = 43); p < 0.01, while with ICA an absent left main trunk was the most observed anomaly 36.0% (n = 73; p < 0.01). In 9.4% (n = 13) of identified coronary anomalies in CCTA 9.4% were potentially serious coronary anaomalies, defined as a course of the coronary artery between aorta and pulmonary artery were identified.ConclusionThe prevalence of coronary anomalies is substantially higher with CCTA than ICA even after exclusion of patients with myocardial bridging which is more frequently found with CCTA. This suggests that the true prevalence of coronary anomalies in the general population may have been underestimated based on ICA.

Endothelial function and sympathetic nervous system activity in patients with Takotsubo syndrome

BACKGROUND Takotsubo syndrome (TTS) is an acute cardiomyopathy associated with intense physical or emotional stress. The precise mechanisms of the disease remain unclear. The aim of this study was to study alterations in endothelial function, vascular compliance and structure and muscle sympathetic activity in the stable phase of the disease. METHODS In this prospective observational study, patients with TTS and controls matched for age, sex, cardiovascular risk factors and medications were recruited. Flow-mediated vasodilatation (FMD) as a measure of endothelial dysfunction was the primary endpoint. Secondary endpoints included measurements of arterial stiffness, carotid atherosclerosis, quality of life and laboratory parameters. In a subset of patients, muscle sympathetic activity was measured before and after stress tests. RESULTS The study included 22 TTS patients and 21 matched controls. A significant increase in endothelial dysfunction was seen in TTS compared to controls (FMD 3.4±2.4% vs. 4.8±1.9%, p=0.016). No significant differences in arterial stiffness, intima-media thickness, quality of life and laboratory markers including endothelin-1 were noted. TTS patients showed a reduced carotid total plaque area compared to controls (TPA 17.3±15.1 vs 24.7±12.8mm2, p=0.02). A trend of increased muscle sympathetic activity at rest was observed in TTS patients vs. controls (53.5±28.4 vs. 29.4±16.5 bursts/100 heart beats, p=0.09) with no significant differences in muscle sympathetic activity in response to stress. CONCLUSIONS Our findings underscore the importance of endothelial dysfunction in patients with TTS which may be involved in the pathophysiology of this syndrome. CLINICALTRIALS. GOV IDENTIFIER NCT01249599.

Turbulent Kinetic Energy Assessed by Multipoint 4-Dimensional Flow Magnetic Resonance Imaging Provides Additional Information Relative to Echocardiography for the Determination of Aortic Stenosis Severity

Background— Turbulent kinetic energy (TKE), assessed by 4-dimensional (4D) flow magnetic resonance imaging, is a measure of energy loss in disturbed flow as it occurs, for instance, in aortic stenosis (AS). This work investigates the additional information provided by quantifying TKE for the assessment of AS severity in comparison to clinical echocardiographic measures. Methods and Results— Fifty-one patients with AS (67±15 years, 20 female) and 10 healthy age-matched controls (69±5 years, 5 female) were prospectively enrolled to undergo multipoint 4D flow magnetic resonance imaging. Patients were split into 2 groups (severe and mild/moderate AS) according to their echocardiographic mean pressure gradient. TKE values were integrated over the aortic arch to obtain peak TKE. Integrating over systole yielded total TKEsys and by normalizing for stroke volume, normalized TKEsys was obtained. Mean pressure gradient and TKE correlated only weakly (R2=0.26 for peak TKE and R2=0.32 for normalized TKEsys) in the entire study population including control subjects, while no significant correlation was observed in the AS patient group. In the patient population with dilated ascending aorta, both peak TKE and total TKEsys were significantly elevated (P<0.01), whereas mean pressure gradient was significantly lower (P<0.05). Patients with bicuspid aortic valves also showed significantly increased TKE metrics (P<0.01), although no significant difference was found for mean pressure gradient. Conclusions— Elevated TKE levels imply higher energy losses associated with bicuspid aortic valves and dilated ascending aortic geometries that are not assessable by current echocardiographic measures. These findings indicate that TKE may provide complementary information to echocardiography, helping to distinguish within the heterogeneous population of patients with moderate to severe AS.

The value of ECG parameters as markers of treatment response in Fabry cardiomyopathy

Objective Best treatment outcomes in Fabry disease (FD) associated cardiomyopathy can be obtained when treatment is started as early as possible. The rationale of this study was to assess the role of ECG changes for identification of cardiac involvement and patients at an earlier stage of the disease more likely deriving a benefit from enzyme replacement therapy (ERT). Methods A retrospective analysis of patient data was performed from an observational, longitudinal, prospective cohort. Treatment response was defined as absence or presence of disease progression, defined as new onset or increase in left ventricular (LV) mass >10%. Demographic, clinical, ECG and echocardiographic parameters at baseline were tested for their value in determining absence or presence of disease progression under ERT at 5-year follow-up. Results The study population consisted of a total of 38 patients (25 men, mean age 36±13 years, overall median follow-up duration 6.4±1.2 years). Patients in the progression group (14 men, 4 women) had a longer QRS duration (99±11 ms vs 84±13 ms, p<0.05 for men, 93±9 years vs 81±5 years, p<0.05 for women) and QTc interval (401±15 ms vs 372±10 ms, p<0.005 for men) and a higher amount of ECG abnormalities (86% vs 18%, p<0.005 for men and 100% vs 0%, p<0.005 for women) at the time of ERT initiation. An abnormal baseline ECG was significantly associated with disease progression (sensitivity 94.1%, specificity 88.9%, positive likelihood ratio of 8.47, p<0.005). Conclusions An abnormal ECG at the time of treatment initiation is significantly associated with cardiac disease progression in FD. This effect seems to be independent of age, gender or LV mass at baseline and suggests maximal treatment benefit when ERT is initiated before ECG abnormalities develop.

Clinical Criteria Replenish High-Sensitive Troponin and Inflammatory Markers in the Stratification of Patients with Suspected Acute Coronary Syndrome

Objectives In patients with suspected acute coronary syndrome (ACS), rapid triage is essential. The aim of this study was to establish a tool for risk prediction of 30-day cardiac events (CE) on admission. 30-day cardiac events (CE) were defined as early coronary revascularization, subsequent myocardial infarction, or cardiovascular death within 30 days. Methods and Results This single-centre, prospective cohort study included 377 consecutive patients presenting to the emergency department with suspected ACS and for whom troponin T measurements were requested on clinical grounds. Fifteen biomarkers were analyzed in the admission sample, and clinical parameters were assessed by the TIMI risk score for unstable angina/Non-ST myocardial infarction and the GRACE risk score. Sixty-nine (18%) patients presented with and 308 (82%) without ST-elevations, respectively. Coronary angiography was performed in 165 (44%) patients with subsequent percutaneous coronary intervention – accounting for the majority of CE – in 123 (33%) patients, respectively. Eleven out of 15 biomarkers were elevated in patients with CE compared to those without. High-sensitive troponin T (hs-cTnT) was the best univariate biomarker to predict CE in Non-ST-elevation patients (AUC 0.80), but did not yield incremental information above clinical TIMI risk score (AUC 0.80 vs 0.82, p = 0.69). Equivalence testing of AUCs of risk models and non-inferiority testing demonstrated that the clinical TIMI risk score alone was non-inferior to its combination with hs-cTnT in predicting CE. Conclusions In patients presenting without ST-elevations, identification of those prone to CE is best based on clinical assessment based on TIMI risk score criteria and hs-cTnT.

Vascular Effects of Eplerenone in Coronary Artery Disease With Preserved Ejection Fraction: A Double-Blind, Randomized, Placebo-Controlled Trial

Mineralocorticoid receptor antagonists (MRAs) reduce morbidity and mortality in heart failure with reduced ejection fraction (HFrEF). Their role in patients without heart failure, particularly in patients with coronary artery disease (CAD) and preserved EF, is still a matter of debate.

Robot-assisted training for heart failure patients - a small pilot study.

Objective The objective of this study was assess robot-assisted gait therapy with the Lokomat® system in heart failure patients. Methods Patients (n = 5) with stable heart failure and a left ventricular ejection fraction of less than 45% completed a four-week aerobic training period with three trainings per week and an integrated dynamic resistance training of the lower limbs. Patients underwent testing of cardiac and inflammatory biomarkers. A cardiopulmonary exercise test, a quality of life score and an evaluation of the muscular strength by measuring the peak quadriceps force was performed. Results No adverse events occurred. The combined training resulted in an improvement in peak work rate (range: 6% to 36%) and peak quadriceps force (range: 3% to 80%) in all participants. Peak oxygen consumption (range: –3% to + 61%) increased in three, and oxygen pulse (range: –7% to + 44%) in four of five patients. The quality of life assessment indicated better well-being in all participants. NT-ProBNP (+233 to –733 ng/ml) and the inflammatory biomarkers (hsCRP and IL6) decreased in four of five patients (IL 6: +0.5 to –2 mg/l, hsCRP: +0.2 to –6.5 mg/l). Conclusions Robot-assisted gait therapy with the Lokomat® System is feasible in heart failure patients and was safe in this trial. The combined aerobic and resistance training intervention with augmented feedback resulted in benefits in exercise capacity, muscle strength and quality of life, as well as an improvement of cardiac (NT-ProBNP) and inflammatory (IL6, hsCRP) biomarkers. Results can only be considered as preliminary and need further validation in larger studies. (ClinicalTrials.gov number, NCT 02146196)

Impact of cardio-renal syndrome on adverse outcomes in patients with Fabry disease in a long-term follow-up

AIMS Fabry disease (FD) is a rare X-linked lysosomal storage disease with a deficiency of α-galactosidase A leading to progressive sphingolipid accumulation in different organs, among them heart and kidney. We evaluated the impact of cardio-renal syndrome (CRS) on the incidence of major cardiovascular complications and death in a prospective FD cohort. METHODS AND RESULTS A total of 104 genetically proven FD patients were annually followed at the University Hospitals Zurich and Bern. The main outcome was a composite of incident renal replacement therapy (RRT), hospitalisation due to decompensated Heart Failure, new onset atrial fibrillation, pacemaker/ICD implantation, stroke/TIA and death. Estimated glomerular filtration rate (eGFR) and left ventricular myocardial mass index (LVMMI) where explored as the primary exposure variables. During the median follow-up of 103 [59-155] months, events occurred in 27 patients. In a Cox regression analysis, both higher LVMMI and lower eGFR were independently associated with a greater risk of developing adverse events after adjustment for multiple confounders (HR 1.67 [1.04-2.73] P=0.03 per SD increase in LVMMI, HR 0.45 [0.25-0.83], P=0.01 per SD decrease in eGFR). In patients with CRS, the risk to develop events was significantly increased if adjusted for demographics and RRT (HR 4.46 [1.07-18.62], P=0.04), approaching significance if additionally adjusted for hypertension (HR 4.05 [0.95-17.29], P=0.06). In Kaplan-Meier-Analysis, the poorest event-free survival was observed among patients with CRS. CONCLUSIONS CRS was associated with a high risk to develop cardiovascular complications and death, emphasizing the importance of its prevention and early recognition. A focus on cardio-reno-protective therapies is crucial.

Prognostic value of mean pulmonary artery pressure in the stable phase after heart transplantation

OBJECTIVES In heart transplant recipients, elevated mean pulmonary artery pressure (mPAP) shortly before or after transplantation represents a powerful predictor for an adverse short‐term outcome. Less is known on cardiac and pulmonary pressures measured in the stable phase after heart transplantation. The aim of this study was to assess the predictive value of mPAP, mean pulmonary capillary wedge pressure and mean central venous pressure in the stable phase after transplantation. METHODS All patients (n = 260, mean age 47.4 ± 12.7 years, 224 males) who received a cardiac allograft at the University Hospital Zurich between September 1985 and August 2014 and who had undergone at least 1 right heart catheterization after transplantation (median 358 days after transplantation) were included and survival analysis was performed (median follow‐up 11.9 years). RESULTS The median mPAP, mean pulmonary capillary wedge pressure and mean central venous pressure were 15 mmHg (interquartile range 12‐19 mmHg), 8 mmHg (interquartile range 6‐11 mmHg) and 3 mmHg (interquartile range 1‐5 mmHg), respectively. In mPAP median split survival analysis, patients with an mPAP above the median had a significantly lower long‐term survival than patients with or below median mPAP (P = 0.012). mPAP but not mean central venous pressure or mean pulmonary capillary wedge pressure was independently associated with long‐term mortality in multivariable Cox‐hazard survival analysis (hazard ratio 1.10, confidence interval 1.04‐1.16, P = 0.001). Other factors independently associated with mortality were age at transplantation (hazard ratio 1.03 per year, confidence interval 1.01‐1.04, P = 0.002) and serum creatinine (&mgr;mol/l) (hazard ratio 1.003, confidence interval 1.001‐1.010, P = 0.021). CONCLUSIONS Our results demonstrate that mPAP measured in the stable phase after heart transplantation is an independent prognostic factor for long‐term mortality.