Behfar, Atta

Introduction: Microaxial flow pumps reduce mortality in myocardial infarction (MI) related cardiogenic shock (CS). The Impella 5.5 generates increased flow to provide circulatory support, and optimization relies on mechanistic understanding of pressure-volume (PV) relationships. Aim: Using a porcine model of acute MI in tandem with biventricular (BiV) PV loop conductance catheters, this study aimed to understand the impact of Impella 5.5 on BiV hemodynamics in MI CS. Methods: In 6 Domestic Yorkshire Pigs, an Impella 5.5 (J&J MedTech, NJ) was inserted percutaneously under fluoroscopic guidance via carotid or aortic access. An angioplasty balloon catheter was advanced past the first diagonal and inflated to above nominal pressure with blood flow obstruction for 90 minutes. BiV PV loop conductance catheters (Sigma-M, CD Leycom, Hengelo, The Netherlands) were inserted via femoral venous access. The left ventricle (LV) PV loop catheter is positioned via transeptal puncture using intracardiac echocardiography. BiV PV loops are generated for each level of Impella support from P1 to P7. Results: With increasing Impella 5.5 support, LV PV loops shifted to the left and right ventricular (RV) loops to the right. Without statistical significance, LV end diastolic volume (EDV) decreased by a mean of 12.3 ± 10.7% from baseline and RV EDV increased by 32 ± 40%. Native LV function decreased with increasing Impella 5.5 support, demonstrated by a reduction in stroke volume (SV) (35±13 ml to 27±14 ml; p<0.001), cardiac output (CO) derived from SV&heart rate (2.0±0.5 ml/min to 1.7±0.7 ml/min; p<0.001), and ejection fraction (EF) (37±7% to 29±12%; p<0.001). Less consistent trends were noted in peak positive dP/dt and end-systolic pressure volume relationship. Native RV function increased with higher levels of Impella 5.5 support, noted by increasing SV (27±24 ml to 41±28 ml; p=0.004), CO (1.6±1.2 ml/min to 2.3±1.4 ml/min; p=0.001), and EF (42±16% to 45±9%; p=0.04). Arterial elastance and ventriculo-arterial coupling increased in the LV from baseline to P7 (2.2±1.4 mmHg/ml to 2.8±1.0 mmHg/ml and 1.8±0.5 to 3.2±1.9, respectively; p<0.001) and decreased in the RV (1.3±0.7 mmHg/ml to 0.9±0.7 mmHg/ml (p<0.001) and 2.1±2.2 to 1.3±0.6 (p=0.004)). Conclusions: Impella 5.5 speed modulation highlights significant ventricular interdependence in the setting of acute MI. PV loop derived parameters here visualized parameters that may be utilized to improve optimization of hemodynamic support in CS.

Abstract The expanding use of continuous‐flow left ventricular assist devices (CF‐LVADs) for end‐stage heart failure warrants familiarity with the physiologic interaction of the device with the native circulation. Contemporary devices utilize predominantly centrifugal flow and, to a lesser extent, axial flow rotors that vary with respect to their intrinsic flow characteristics. Flow can be manipulated with adjustments to preload and afterload as in the native heart, and ascertainment of the predicted effects is provided by differential pressure‐flow ( H ‐ Q ) curves or loops. Valvular heart disease, especially aortic regurgitation, may significantly affect adequacy of mechanical support. In contrast, atrioventricular and ventriculoventricular timing is of less certain significance. Although beneficial effects of device therapy are typically seen due to enhanced distal perfusion, unloading of the left ventricle and atrium, and amelioration of secondary pulmonary hypertension, negative effects of CF‐LVAD therapy on right ventricular filling and function, through right‐sided loading and septal interaction, can make optimization challenging. Additionally, a lack of pulsatile energy provided by CF‐LVAD therapy has physiologic consequences for end‐organ function and may be responsible for a series of adverse effects. Rheological effects of intravascular pumps, especially shear stress exposure, result in platelet activation and hemolysis, which may result in both thrombotic and hemorrhagic consequences. Development of novel solutions for untoward device‐circulatory interactions will facilitate hemodynamic support while mitigating adverse events. © 2021 American Physiological Society. Compr Physiol 12:1‐37, 2021.

ABSTRACT Background Addition of left heart catheterization (LHC) to exercise protocols allows for a unique focus on parameters of systolic and diastolic responses to increased activity in patients with left ventricular assist device (LVAD) support. Methods A retrospective review was conducted of all consecutive adult patients who underwent LHC with exercise for any indication from June 2017 to June 2023. For all patients, the relationship between exercise and parameters of LV systolic and diastolic response was assessed. Patients were divided into two cohorts based on the indication for testing: hemodynamic optimization (Optim, n = 5) or weaning consideration (Wean, n = 3). Results Eight patients (88% male, median age 57 years (IQR 44, 65)) were included. LVEF was 45% (IQR 45, 56) in Wean and 25% (IQR 20, 42) in Optim. LV systolic work index (LVSWI) increased more rapidly over levels of exercise in Wean vs. Optim (slope 46.3 vs. −0.625; p = 0.044) and LVSWI rose more quickly at lower levels of LV end diastolic pressure (LVEDP) in Wean vs. Optim (slope 219.5 vs. −2.008; p = 0.0026). Pulse power index was higher in Wean patients at baseline (0.046 (IQR 0.04, 0.07) vs. 0.016 (IQR 0.001, 0.04); p = 0.14) and peak exercise (0.12 (IQR 0.12, 0.12) vs. 0.06 (IQR 0.03, 0.1); p = 0.29). Conclusions Patients with favorable remodeling on LVAD support have significantly improved LV systolic and diastolic responses to exercise and a trend of higher systemic pulsatility. Improving our understanding of LV‐LVAD interactions with activity may aid in future efforts to improve exercise tolerance through speed modulation.

Introduction: Cardiac differentiation protocols enable derivation of cardiomyocytes (CM). from human induced pluripotent stem cell (iPS). However, limited tools are available to ensure enhanced iPS-CM maturation without the need for prolonged and complex culture. Research Question: This study assessed whether the mesodermal and cardiopoiesis inductor, Brachyury (T), complements standard cardiac differentiation and augments structural and functional maturation of iPS-CM. Aims: The impact of T mRNA introduction prior to initiation of cardiac differentiation was characterized on: i) cardiac transcription factor expression; ii) structural and functional hallmarks of maturity; and iii) cardiotoxicity. Methods: RT-qPCR was employed to monitor the expression of cardiac-specific transcription factors. Transmission electron microscopy enabled the assessment of cellular ultrastructure. Seahorse measurements were used to determine basal respiration. Fluo4 staining was used to measure calcium transients with external field stimulation. Cardiotoxicity was measured as the impact of doxorubicin on calcium handling and cell survival. Results: Transfection with T prompted early and sustained upregulation of the cardiac transcription factors Nkx2.5 (10-fold; FDR<0.001) and MEF2C (7.2-fold; FDR<0.001). Mitochondrial area was increased with T transfection (P<0.001) and T-transfected iPS-CM exhibited greater basal respiration (FDR<0.05), greater calcium handling resilience in response to field stimulation, and a more mature transient morphology. Following doxorubicin exposure T transfected iPS-CM exhibited a greater compromise in calcium handling (FDR<0.001), and exaggerated cell death. Conclusion: Induction of human iPS with T prior to initiation of cardiac differentiation enhanced signatures of structural and functional maturity, and provided more robust readouts of drug toxicity.