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.

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.

Progress in Clinical Gene Therapy for Cardiac Disorders.

Despite significant advances in novel treatments and approaches, cardiovascular disease remains the leading cause of death globally. Gene therapy is a promising option for many diseases, including cardiovascular diseases. In the last 30 years, gene therapy has slowly proceeded towards clinical translation and recently reached US Food and Drug Administration approval for several diseases such as Leber congenital amaurosis and spinal muscular atrophy, among others. Previous attempts at developing gene therapies for cardiovascular diseases have yielded promising results in preclinical studies and early-phase clinical trials. However, larger trials failed to demonstrate consistent benefits in patients with ischemic heart disease and heart failure. In this review, we summarize the history and current status of clinical cardiac gene therapy. Starting with angiogenic gene therapy, we also cover more recent gene therapy trials for heart failure and cardiomyopathies. New programs are actively vying to be the first to get Food and Drug Administration approval for a cardiac gene therapy product by taking advantage of novel techniques.

Elevated Lipoprotein(a) Levels and Atrial Fibrillation: A Systematic Review.

Objective: The role of lipoprotein(a) (Lp[a]) as a possibly causal risk factor for atherosclerotic cardiovascular disease has been well established. However, the clinical evidence regarding the association between Lp(a) levels and atrial fibrillation (AF) remains limited and inconsistent. This study aimed to analyze the association between elevated Lp(a) levels or single-nucleotide polymorphisms (SNPs) related to high levels of Lp(a) and AF. Methods: This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A literature search was performed to identify studies that evaluated the association between Lp(a) levels or SNPs related to high levels of Lp(a) and AF. Observational studies with a cross-sectional, case-control, or cohort design were included in this systematic review, without limitations according to language, country, or publication type. Results: Eleven observational studies including 1,246,817 patients were eligible for this systematic review. Two cross-sectional studies, 5 prospective/retrospective cohort studies, and 4 Mendelian randomization studies were analyzed. Two cross-sectional studies that compared Lp(a) levels between patients with and without AF showed conflicting results. Cohort studies that evaluated the incidence of AF according to Lp(a) levels showed different results: no association (3 studies), a positive association (1 study), and an inverse relationship (1 study). Finally, Mendelian randomization studies also showed heterogeneous results (positive association: 2 studies; inverse association: 1 study; no association: 1 study). Conclusion: Although there could be an association between Lp(a) levels and AF, the results of the studies published to date are contradictory and not yet definitive. Therefore, further research should clarify this issue.

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.

Updates on Cardiac Gene Therapy Research and Methods: Overview of Cardiac Gene Therapy.

Gene therapy has made a significant progress in clinical translation over the past few years with several gene therapy products currently approved or anticipating approval for clinical use. Cardiac gene therapy lags behind that of other areas of diseases, with no application of cardiac gene therapy yet approved for clinical use. However, several clinical trials for gene therapy targeting the heart are underway, and innovative research studies are being conducted to close the gap. The second edition of Cardiac Gene Therapy in Methods in Molecular Biology provides protocols for cutting-edge methodologies used in these studies. In this chapter, we discuss recent updates on cardiac gene therapy studies and provide an overview of the chapters in the book.

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.

Long-term outcomes of percutaneous or surgical treatment in left main disease.

INTRODUCTION: Long-term efficacy and safety of either surgical or percutaneous treatment left main coronary artery disease treatment is lacking. EVIDENCE ACQUISITION: We conducted a systematic review and meta-analysis of the most updated randomized clinical trials that compared the efficacy of coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) for the Left Main Coronary Artery (LMCA) disease. It was also conducted a systematic search of PubMed, Google Scholar, reference lists of relevant articles, and Medline. The search utilized the following terms: "left main PCI versus CABG," "drug-eluting stents," "bypass surgery" and "left main stenting." The search of articles compatible with our inclusion and exclusion criteria was performed from inception through April 2020 and returned a combined total of 304 articles. EVIDENCE SYNTHESIS: We identified 6 studies, providing data on 5812 patients. The mean follow-up was 6.7 years. PCI was associated with an increased risk of major vascular events (MACE) (IRR 1.24, 95% CI [1.03-1.67], P<0.01), and coronary revascularization (IRR 1.69, 95% CI [1.42-2.03], P<0.01) compared to CABG. Furthermore, all-cause death, MI and stroke events were not statistically different between the two therapeutic revascularization methodologies (IRR 1.06, 95% CI [0.90-1.24], P=0.47, IRR 1.35, 95% CI [0.84-2.16], P=0.03 and IRR 0.66, 95% CI [0.43-1.01], P=0.05, respectively). CONCLUSIONS: LMCA PCI has an overall same survival compared to CABG in the long term follow-up. Nevertheless, MACE and revascularization events were more frequent in PCI compared to CABG.

Balloon rupture during aortic valvuloplasty with compliant balloon: predictors and outcomes.

Objectives of the study were the prevalence and clinical consequences of balloon rupture with compliant balloons in balloon aortic valvuloplasty (BAV). Compliant low-profile balloons have been developed to reduce access site complications. Made by thinner materials, these balloons are more prone to rupture. This is a single-center retrospective analysis (2016-2018) of patients undergoing BAV with compliant balloons. Baseline echocardiography and computed tomography (CT) were analyzed. Best cutoff point for calcium score was assessed. Long-term mortality was analyzed with Kaplan-Maier. In vitro test was performed. Rupture occurred in 30/90 (33%) of BAVs independent of risk factors, surgical risk and frailty scores. Patients experiencing rupture had increased mean gradient [53.5 (44-64) vs 44 (35-49) mmHg, p < 0.05] and reduced aortic valve area [0.61 (0.46-0.76) vs 0.76 (0.64-0.83) mm2, p < 0.05]. Valve calcium score on CT > 2686 AU was more frequent in the rupture group (41% vs 10%, p < 0.05) and more patients in the third tertile of calcium score experienced rupture (75% vs 23% vs 41% for second and first tertile, p < 0.05). Median gradient reduction from baseline was similar among groups [30 (20-50) vs 30 (17-39) mmHg]. No patient with rupture had any complication. One-month and long-term mortality were similar (rupture 0% vs 3.5% no rupture from 1 month). In vitro test required more volume and strength to rupture the balloon than used in BAV. Balloon rupture is frequent in BAV using compliant balloons, occurs with more severe aortic stenosis, does not affect BAV efficacy and does not impair outcomes.

Prognostic impact of myocardial contraction fraction in patients undergoing transcatheter aortic valve replacement for aortic stenosis.

BACKGROUND: Myocardial contraction fraction (MCF), a volumetric measurement of myocardial shortening, may help to improve risk stratification in patients with severe aortic stenosis (AS) referred for transcatheter aortic valve replacement (TAVR) especially in those with preserved left ventricular ejection fraction (LVEF). We investigated the association between MCF and 1-year all-cause mortality in patients with severe AS who underwent TAVR. METHODS: MCF was calculated as the ratio of stroke volume (SV) to myocardial volume. Patients referred for TAVR from 2011 to 2015 were eligible for inclusion and were divided into two groups according to the estimated MCF (MCF ≤30% vs. MCF >30%). The primary endpoint was 1-year all-cause mortality. A Cox regression analysis was performed for independent risk factors of mortality. Receiver operating curve (ROC) was performed for assessing the best cut-off point of MCF for predicting the primary outcome [area under the curve (AUC) 0.60; 95% confidence interval (CI): 0.453-0.725]. Baseline patient and echo characteristics were included for multivariate analysis. RESULTS: Of 126 patients (mean age 82±5 years, 45.2% male), 44.4% showed MCF ≤30%. Patient with reduced MCF showed higher body mass index (28.1±5.8 vs. 26.0±4.5 kg/m2, P=0.031), higher surgical EuroScore II (6.2±4.5 vs. 4.7±3.2, P=0.032), lower LVEF (54.2%±11.9% vs. 58.5%±10.8%, P=0.042) and more severe AS (indexed aortic valve area 0.40±0.09 vs. 0.45±0.10 cm2/m2, P=0.030). The median follow-up was of 14 [3.5-33] months, and 16% of patients died. Patients with MCF ≤30% showed significantly increased all-cause mortality (Log-rank P=0.002). In a multivariate model adjusting for clinical and echo variables, MCF ≤30% was independently associated with increased risk for all-cause 1-year mortality [hazard ratio (HR) 2.76, 95% CI: 1.03-7.77, P=0.04]. CONCLUSIONS: In a population of patients undergoing TAVR, MCF ≤30% was independently associated with increased mortality.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as predictors of survival after heart transplantation.

AIMS: The aim of this study was to evaluate whether neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) predict outcome in heart failure (HF) patients undergoing heart transplantation (HTX). METHODS AND RESULTS: Data from 111 HF patients undergoing HTX 2010-2015 were retrospectively reviewed. NLR and PLR were calculated before HTX, immediately after HTX, and at 6 and 24 hours. Primary endpoint was in-hospital mortality, and secondary endpoints were 1 year mortality and renal replacement therapy (RRT). Prognostic factors were assessed by multivariate analysis, and the predictive values of NLR and PLR for mortality were compared. The discriminatory performance for predicting in-hospital mortality was better for NLR [area under the receiver operating characteristic curve (AUC) = 0.644, 95% confidence interval 0.492-0.797] than for PLR (AUC = 0.599, 95% confidence interval 0.423-0.776). Best cut-off value was 2.41 for NLR (sensitivity 86%, specificity 67%) and 92.5 for PLR (sensitivity 86%, specificity 68%). When divided according to best cut-off value, in-hospital mortality was significantly higher in the high NLR group (17.5% vs. 3.2%, P < 0.05), but not in the high PLR group (16.5% vs. 6.3%, P = ns). One year mortality was not significantly higher for either group (37.5% vs. 6.5% for NLR; 36.7% vs. 9.4% for PLR, P = ns for both), while RRT was significantly higher in both the NLR and PLR high groups (33.8% vs. 0%; 32.9% vs. 3.1%, respectively, P < 0.001). Multivariate analysis indicated that only high NLR (hazard ratio = 3.403, P < 0.05) and pre-transplant diabetes (hazard ratio = 3.364, P < 0.05) were independent prognostic factors for 1 year mortality. CONCLUSIONS: High NLR was a predictor for in-hospital mortality, and an independent prognostic factor for 1 year mortality. Both high NLR and high PLR were predictors for RRT.