Anna Catino

Myocardial Atrophy and Chronic Mechanical Unloading of the Failing Human Heart : Implications for Cardiac Assist Device–Induced Myocardial Recovery

BACKGROUND In animal models of heterotopic transplantation, mechanical unloading of the normal, nonhypertrophic heart results in atrophy. Primarily on the basis of these animal data, the notion that chronic left ventricular assist device (LVAD)-induced unloading will result in atrophy has dominated the clinical heart failure field, and anti-atrophic drugs have been used to enhance the cardiac recovery potential observed in some LVAD patients. However, whether unloading-induced atrophy in experimental normal heart models applies to failing and hypertrophic myocardium in heart failure patients unloaded by continuous-flow LVADs has not been studied. OBJECTIVES The study examined whether mechanical unloading by continuous-flow LVAD leads to myocardial atrophy. METHODS We prospectively examined myocardial tissue and hemodynamic and echocardiographic data from 44 LVAD patients and 18 untransplanted normal donors. RESULTS Cardiomyocyte size (cross-sectional area) decreased after LVAD unloading from 1,238 ± 81 μm(2) to 1,011 ± 68 μm(2) (p = 0.001), but not beyond that of normal donor hearts (682 ± 56 μm(2)). Electron microscopy ultrastructural evaluation, cardiomyocyte glycogen content, and echocardiographic assessment of myocardial mass and left ventricular function also did not suggest myocardial atrophy. Consistent with these findings, t-tubule morphology, cytoplasmic penetration, and distance from the ryanodine receptor were not indicative of ongoing atrophic remodeling during LVAD unloading. Molecular analysis revealed no up-regulation of proatrophic genes and proteins of the ubiquitin proteasome system. CONCLUSIONS Structural, ultrastructural, microstructural, metabolic, molecular, and clinical functional data indicated that prolonged continuous-flow LVAD unloading does not induce hypertrophy regression to the point of atrophy and degeneration. These findings may be useful in designing future investigations that combine LVAD unloading and pharmaceutical therapies as a bridge to recovery of the failing heart.

Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma

Purpose: To prospectively evaluate cardiotoxicity risk with sunitinib in metastatic renal cell carcinoma (mRCC) routine clinical practice using comprehensive echocardiography and biomarker phenotyping. Experimental Design: In a multicenter prospective study of 90 patients with mRCC, echocardiography and biomarkers of cardiovascular injury and stress were quantified at baseline, 3.5, 15, and 33 weeks following sunitinib initiation. These “on-drug” visits corresponded to cycles 1, 3, and 6, respectively. Left ventricular (LV) dysfunction was defined as an absolute decline in LV ejection fraction (LVEF) by ≥10% to a value of <50%. Conditional survival analyses predicted the risk of LV dysfunction. Linear mixed-effects models estimated changes in LVEF, high-sensitivity Troponin I (hsTnI), and B-type natriuretic peptide (BNP) over time. Results: The predicted risk of LV dysfunction by cycle 6 was 9.7% (95% confidence interval, 3%–17%). The majority of events occurred in the first treatment cycle. This risk diminished to 5% and 2% in patients who had not experienced dysfunction by the completion of cycles 1 and 3, respectively. All evaluable patients who experienced LV dysfunction had subsequent improvement in LVEF with careful management. Six patients (6.7%) developed hsTnI elevations >21.5 pg/mL, and 11 additional patients (12.2%) developed BNP elevations >100 pg/mL. These elevations similarly tended to occur early and resolved over time. Conclusions: On average, patients with mRCC receiving sunitinib exhibit modest declines in LVEF and nonsignificant changes in hsTnI and BNP. However, approximately 9.7% to 18.9% of patients develop more substantive abnormalities. These changes occur early and are largely recoverable with careful management. Clin Cancer Res; 23(14); 3601–9. ©2017 AACR.

Clinical and histopathological effects of heart failure drug therapy in advanced heart failure patients on chronic mechanical circulatory support

Adjuvant heart failure (HF) drug therapy in patients undergoing chronic mechanical circulatory support (MCS) is often used in conjunction with a continuous‐flow left ventricular assist device (LVAD), but its potential impact is not well defined. The objective of the present study was to examine the effects of conventional HF drug therapy on myocardial structure and function, peripheral organ function and the incidence of adverse events in the setting of MCS.

Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma

Background: Sunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood. Methods and Results: In a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e′), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0–17.1; P=0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3–10.0; P<0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid–femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all P<0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time. Conclusions: In patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function.

Cardiac Rotational Mechanics As a Predictor of Myocardial Recovery in Heart Failure Patients Undergoing Chronic Mechanical Circulatory Support: A Pilot Study

Background: Impaired qualitative and quantitative left ventricular (LV) rotational mechanics predict cardiac remodeling progression and prognosis after myocardial infarction. We investigated whether cardiac rotational mechanics can predict cardiac recovery in chronic advanced cardiomyopathy patients. Methods and Results: Sixty-three patients with advanced and chronic dilated cardiomyopathy undergoing implantation of LV assist device (LVAD) were prospectively investigated using speckle tracking echocardiography. Acute heart failure patients were prospectively excluded. We evaluated LV rotational mechanics (apical and basal LV twist, LV torsion) and deformational mechanics (circumferential and longitudinal strain) before LVAD implantation. Cardiac recovery post-LVAD implantation was defined as (1) final resulting LV ejection fraction ≥40%, (2) relative LV ejection fraction increase ≥50%, (iii) relative LV end-systolic volume decrease ≥50% (all 3 required). Twelve patients fulfilled the criteria for cardiac recovery (Rec Group). The Rec Group had significantly less impaired pre-LVAD peak LV torsion compared with the Non-Rec Group. Notably, both groups had similarly reduced pre-LVAD LV ejection fraction. By receiver operating characteristic curve analysis, pre-LVAD peak LV torsion of 0.35 degrees/cm had a 92% sensitivity and a 73% specificity in predicting cardiac recovery. Peak LV torsion before LVAD implantation was found to be an independent predictor of cardiac recovery after LVAD implantation (odds ratio, 0.65 per 0.1 degrees/cm [0.49–0.87]; P=0.014). Conclusions: LV rotational mechanics seem to be useful in selecting patients prone to cardiac recovery after mechanical unloading induced by LVADs. Future studies should investigate the utility of these markers in predicting durable cardiac recovery after the explantation of the cardiac assist device.

Vascular Complications of Cancer and Cancer Therapy

Thromboembolism is an important cause of morbidity and mortality in cancer patients. Risk factors for venous thromboembolism include hospitalization, advanced age, comorbidities, type of cancer, and certain cancer therapies, including endocrine-based treatments and immunomodulating therapies. Chemotherapy and newer targeted biological agents, particularly anti-angiogenesis agents, are associated with an increased risk of arterial vascular complications. Due to the complex interaction of the coagulation system and cancer growth, angiogenesis, and metastases, a potential role of anticoagulants in improving cancer patient survival exists. This chapter discusses risk of and indications for thromboprophylaxis for venous thromboembolism in cancer patients and explores the epidemiologic and mechanistic relationship between certain cancer therapies and risk of vascular complications including venous thromboembolism and arterial thrombosis.