Reduction of left ventricular diastolic pressure as a key regulator of infarct coronary flow under mechanical left ventricular support.

Restoring ischaemic myocardial tissue perfusion is crucial for minimizing infarct size. Acute mechanical left ventricular (LV) support has been suggested to improve infarct tissue perfusion. However, its regulatory mechanism remains unclear. We investigated the physiological mechanisms in six Yorkshire pigs, which were subjected to 90-min balloon occlusion of the left anterior descending artery. During the acute reperfusion phase, LV support using an Impella heart pump was initiated. LV pressure, coronary flow and pressure of the infarct artery were simultaneously recorded to evaluate the impact of LV support on coronary physiology. Coronary wave intensity was calculated to understand the forces regulating coronary flow. Significant increases in coronary flow velocity and its area under the curve were found after mechanical LV support. Among the coronary flow-regulating factors, coronary pressure was increased mainly during the late diastolic phase with less pulsatility. Meanwhile, LV pressure was reduced throughout diastole resulting in significant and consistent elevation of coronary driving pressure. Interestingly, the duration of diastole was prolonged with LV support. In the wave intensity analysis, the duration between backward suction and pushing waves was extended, indicating that earlier myocardial relaxation and delayed contraction contributed to the extension of diastole. In conclusion, mechanical LV support increases infarct coronary flow by extending diastole and augmenting coronary driving pressure. These changes were mainly driven by reduced LV diastolic pressure, indicating that the key regulator of coronary flow under mechanical LV support is downstream of the coronary artery, rather than upstream. Our study highlights the importance of LV diastolic pressure in infarct coronary flow regulation. KEY POINTS: Restoring ischaemic myocardial tissue perfusion is crucial for minimizing infarct size. Although mechanical left ventricular (LV) support has been suggested to improve infarct coronary flow, its specific mechanism remains to be clarified. LV support reduced LV pressure, and elevated coronary pressure during the late diastolic phase, resulting in high coronary driving pressure. This study demonstrated for the first time that mechanical LV support extends diastolic phase, leading to increased infarct coronary flow. Future studies should evaluate the correlation between improved infarct coronary flow and resulting infarct size.

Negative Impact of Acute Reloading after Mechanical Left Ventricular Unloading.

Mechanical LV unloading for acute myocardial infarction (MI) is a promising supportive therapy to reperfusion. However, no data is available on exit strategy. We evaluated hemodynamic and cellular effects of reloading after Impella-mediated LV unloading in Yorkshire pigs. First, we conducted an acute study in normal heart to observe effects of unloading and reloading independent of MI-induced ischemic effects. We then completed an MI study to investigate optimal exit strategy on one-week infarct size, no-reflow area, and LV function with different reloading speeds. Initial studies showed that acute reloading causes an immediate rise in end-diastolic wall stress followed by a significant increase in cardiomyocyte apoptosis. The MI study did not result in any statistically significant findings; however, numerically smaller average infarct size and no-reflow area in the gradual reloading group prompt further examination of reloading approach as an important clinically relevant consideration.

Cell-Based Determination of Neutralizing Antibodies Against Adeno-Associated Virus in Cardiac Gene Therapy.

The field of cardiac gene therapy has seen the rising use of adeno-associated viral (AAV) vectors as a promising therapeutic option for cardiac diseases and heart failure. To achieve intended results of AAV delivery, a majority of clinical studies screen patients for existing neutralizing antibodies that could inhibit the effects of the administered AAV and confound treatment efficacy. The cell-based neutralizing antibody assay offers a method of quantifying and identifying a patient's existing neutralizing antibodies against specific serotypes. Combined with the luciferase assay, the neutralizing antibody assay tests the ability of patient antibodies in the blood to prevent gene transduction of AAV-encoded luciferase gene at ranging serial dilutions. This chapter provides a protocol and experimental techniques to determine the presence of neutralizing antibodies against AAV in the blood.

Assessing the Effect of Cardiac Gene Therapy Using Catheter-Based Pressure-Volume Measurement in Large Animals.

Gene therapy for heart failure targets various pathways that modulate cardiac function. Its detailed evaluation is crucial for proving the efficacy of cardiac gene therapies. Parameters that can be obtained by noninvasive approaches are generally influenced by loading conditions of the heart. In contrast, catheter-based left ventricular pressure-volume assessment provides a unique option to minimally invasively assess intrinsic myocardial function in a load-insensitive manner. In this chapter, we describe procedural steps for performing pressure-volume measurements and analysis in a preclinical large animal model.

Impact of ischemia on left atrial remodeling and dysfunction in swine models of mitral regurgitation.

Left atrial (LA) dysfunction is one of the predictive factors of worse outcomes after mitral valve surgery for mitral regurgitation (MR). We aimed to investigate the effect of MR etiology on progression of LA remodeling in swine MR models. MR was induced in 14 Yorkshire pigs using catheter-based procedures. Seven pigs underwent simultaneous occlusions of the left circumflex artery and the diagonal branch, which resulted in ischemic mitral regurgitation (IMR group). The other seven pigs underwent chordal severing to induce leaflet prolapse simulating degenerative mitral regurgitation (DMR group). Changes in LA volume and function were assessed at baseline, 1 mo, and 3 mo using echocardiography and hemodynamic evaluations. Histopathological assessments were conducted to evaluate LA hypertrophy and fibrosis. At 3 mo, quantitative MR severity was comparable and severe in both groups. Despite the similar degree of MR, minimum LA volume index increased significantly more in the IMR group (IMR: 11.9 ± 6.4 to 73.2 ± 6.4 mL/m2, DMR: 10.7 ± 6.4 to 29.5 ± 6.4 mL/m2, Pinteraction = 0.004). Meanwhile, increase in maximum LA volume index was similar between the groups, resulting in lower LA emptying function in the IMR group (IMR: 60.1 ± 3.1 to 29.4 ± 3.1%; DMR: 62.4 ± 3.1 to 58.2 ± 3.1%, Pinteraction = 0.0003). LA reservoir strain assessed by echocardiography was also significantly lower in the IMR group. Histological analyses revealed increased LA cellular hypertrophy and fibrosis in the IMR group. In conclusion, ischemic MR is associated with aggressive remodeling and reduced emptying function compared with the MR due to leaflet prolapse. Earlier intervention might be necessary for ischemic MR to prevent LA remodeling.NEW & NOTEWORTHY We show different LA structural and functional remodeling patterns between ischemic MR and MR due to leaflet prolapse. Severe ischemic MR was accompanied by extensive LA remodeling, which may be associated with poor clinical outcomes. Our data suggest that detailed structural and functional LA remodeling assessment is important for managing IMR and to determine the presence of LA ischemia.