Methods and systems for utilizing myocardial strain imaging in an inverse framework to identify mechanical properties of the heart and to determine structural and functional milestones for the development and progression to heart failure.
Elevation in left ventricular (LV) myocardial stiffness is a key remodeling-mediated change that underlies the development and progression of heart failure (HF). Despite the potential diagnostic value of quantifying this deterministic change, there is a lack of enabling techniques that can be readily incorporated into current clinical practice. To address this unmet clinical need, we propose a simple protocol for processing routine echocardiographic imaging data to provide an index of left ventricular myocardial stiffness, with protocol specification for patients at risk for heart failure with preserved ejection fraction. We demonstrate our protocol in both a preclinical and clinical setting, with representative findings that suggest sensitivity and translational feasibility of obtained estimates.
Standardized exercise protocols have been shown to improve overall cardiovascular fitness, but direct effects on left ventricular (LV) function, particularly diastolic function and relation to post-transcriptional molecular pathways (microRNAs (miRs)) are poorly understood. This project tested the central hypothesis that adaptive LV remodeling resulting from a large animal exercise training protocol, would be directly associated with specific miRs responsible for regulating pathways relevant to LV myocardial stiffness and geometry.
Pigs (n = 9; 25 Kg) underwent a 4 week exercise training protocol (10 degrees elevation, 2.5 mph, 10 min, 5 days/week) whereby LV chamber stiffness (KC) and regional myocardial stiffness (rKm) were measured by Doppler/speckle tracking echocardiography. Age and weight matched non-exercise pigs (n = 6) served as controls. LV KC fell by approximately 50% and rKm by 30% following exercise (both p < 0.05). Using an 84 miR array, 34 (40%) miRs changed with exercise, whereby 8 of the changed miRs (miR-19a, miR-22, miR-30e, miR-99a, miR-142, miR-144, miR-199a, and miR-497) were correlated to the change in KC (r ≥ 0.5 p < 0.05) and mapped to matrix and calcium handling processes. Additionally, miR-22 and miR-30e decreased with exercise and mapped to a localized inflammatory process, the inflammasome (NLRP-3, whereby a 2-fold decrease in NLRP-3 mRNA occurred with exercise (p < 0.05).
Chronic exercise reduced LV chamber and myocardial stiffness and was correlated to miRs that map to myocardial relaxation processes as well as local inflammatory pathways. These unique findings set the stage for utilization of myocardial miR profiling to identify underlying mechanisms by which exercise causes changes in LV myocardial structure and function.
Drug-coated balloon (DCB) therapy is a promising endovascular treatment for obstructive arterial disease. The goal of DCB therapy is restoration of lumen patency in a stenotic vessel, whereby balloon deployment both mechanically compresses the offending lesion and locally delivers an antiproliferative drug, most commonly paclitaxel (PTX) or derivative compounds, to the arterial wall. Favorable long-term outcomes of DCB therapy thus require predictable and adequate PTX delivery, a process facilitated by coating excipients that promotes rapid drug transfer during the inflation period. While a variety of excipients have been considered in DCB design, there is a lack of understanding about the coating-specific biophysical determinants of essential device function, namely, acute drug transfer. We consider two hydrophilic excipients for PTX delivery, urea (UR) and poly(ethylene glycol) (PEG), and examine how compositional and preparational variables in the balloon surface spray-coating process impact resultant coating microstructure and in turn acute PTX transfer to the arterial wall. Specifically, we use scanning electron image analyses to quantify how coating microstructure is altered by excipient solid content and balloon-to-nozzle spray distance during the coating procedure and correlate obtained microstructural descriptors of coating aggregation to the efficiency of acute PTX transfer in a one-dimensional ex vivo model of DCB deployment. Experimental results suggest that despite the qualitatively different coating surface microstructures and apparent PTX transfer mechanisms exhibited with these excipients, the drug delivery efficiency is generally enhanced by coating aggregation on the balloon surface. We illustrate this microstructure–function relation with a finite element-based computational model of DCB deployment, which along with our experimental findings suggests a general design principle to increase drug delivery efficiency across a broad range of DCB designs.
Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV Kc) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus will alter posttranscriptional regulation, specifically microRNAs (miRs). LVPO was induced in pigs (n = 9) by sequential ascending aortic cuff and age- and weight-matched pigs (n = 6) served as controls. LV function was measured by echocardiography and LV Kc by speckle tracking. LV myocardial miRs were quantified using an 84-miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed (n = 10, n = 9, respectively). LV samples from LVPO and controls (n = 6, respectively) were subjected to RNA sequencing. LV mass and Kc increased by over 40% with LVPO (P < 0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV Kc (P < 0.05) that mapped to functional domains relevant to Kc such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by fourfold (P < 0.05). RNA analysis identified several genes that mapped to specific miRs that were altered with LVPO. In conclusion, a specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties, and several miRs mapped to molecular pathways that may hold relevance in terms of prognosis and therapeutic targets.
Strategic delivery of hydrogels to the newly formed myocardial infarction (MI) is an area of active investigation and offers high target specificity for releasing a small molecule therapeutic payload. This study examined the effects of delayed post-MI delivery (pigs, 3 days post-MI) of a shear-thinning hydrogel which encapsulated and released a small molecule matrix metalloproteinase inhibitor. The results demonstrated the feasibility and efficacy of targeted delivery of a shear-thinning injectable hydrogel containing a small molecule matrix metalloproteinase inhibitor to attenuate post-MI remodeling.
Described herein are devices and methods for performing automated and minimally invasive intramyocardial injections for cardiac repair that eliminate the need for opening the chest cavity for injections of therapeutics to the heart muscle to address heart attack, cardiomyopathy or myocardial diseases and can detect diseased tissue and deliver a specified volume of a therapeutic injectate to the region of interest.
