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The limited availability of human heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig heart slice biomimetic culture systems that preserve the viability and functionality of 300 μm heart slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, heart slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1-1 μM. These results indicate that heart slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.

Continuous flow ventricular assist device (CFVAD) support in advanced heart failure patients causes diminished pulsatility, which has been associated with adverse events including gastrointestinal bleeding, end organ failure, and arteriovenous malformation. Recently, pulsatility augmentation by pump speed modulation has been proposed as a means to minimize adverse events. Pulsatility primarily affects endothelial and smooth muscle cells in the vasculature. To study the effects of pulsatility and pulse modulation using CFVADs, we have developed a microfluidic co-culture model with human aortic endothelial (ECs) and smooth muscle cells (SMCs) that can replicate physiologic pressures, flows, shear stresses, and cyclical stretch. The effects of pulsatility and pulse frequency on ECs and SMCs were evaluated during (1) normal pulsatile flow (120/80 mmHg, 60 bpm), (2) diminished pulsatility (98/92 mmHg, 60 bpm), and (3) low cyclical frequency (115/80 mmHg, 30 bpm). Shear stresses were estimated using computational fluid dynamics (CFD) simulations. While average shear stresses (4.2 dynes/cm2) and flows (10.1 mL/min) were similar, the peak shear stresses for normal pulsatile flow (16.9 dynes/cm2) and low cyclic frequency (19.5 dynes/cm2) were higher compared to diminished pulsatility (6.45 dynes/cm2). ECs and SMCs demonstrated significantly lower cell size with diminished pulsatility compared to normal pulsatile flow. Low cyclical frequency resulted in normalization of EC cell size but not SMCs. SMCs size was higher with low frequency condition compared to diminished pulsatility but did not normalize to normal pulsatility condition. These results may suggest that pressure amplitude augmentation may have a greater effect in normalizing ECs, while both pressure amplitude and frequency may be required to normalize SMCs morphology. The co-culture model may be an ideal platform to study flow modulation strategies. [ABSTRACT FROM AUTHOR]

Mechanical circulatory support (MCS) device therapy is one of the primary treatment options for end-stage heart failure (HF), whereby a mechanical pump is integrated with the failing heart to maintain adequate tissue perfusion. The ISO 14708-5:2020 standard prescribes generic guidelines for nonclinical device evaluation and system performance testing of MCS devices using a mock circulatory loop (MCL). However, the utility of MCLs in premarket regulatory submissions of MCS devices is ambiguous, and the specific disease states that the device is intended to treat are not usually simulated. Hence, we aim to outline the potential of MCLs as a valuable regulatory science tool for characterizing MCS device systems by adequately representing target clinical-use HF conditions on the bench. Target pathophysiologic hemodynamics of HF conditions (i.e., cardiogenic shock (CS), left ventricular (LV) hypertrophy secondary to hypertension, and coronary artery disease), along with a healthy adult at rest and a healthy adult during exercise are provided as recommended test conditions. The conditions are characterized based on LV, aorta, and left atrium pressures using recommended cardiac hemodynamic indices such as systolic, diastolic, and mean arterial pressure, mean cardiac output (CO), cardiac cycle time, and systemic vascular resistance. This study is a first step toward standardizing MCLs to generate well-defined target HF conditions used to evaluate MCS devices., (Copyright © 2024 by ASME.)