Altered Left Ventricular Rat Gene Expression Induced by the Myosin Activator Omecamtiv Mecarbil.

To explore the impact of omecamtiv mecarbil (OM) on the gene expression profile in adult male rats. Fourteen male Wistar rats were randomly assigned to a single OM (1.2 mg/kg/h; n = 6) or placebo (n = 8) 30-min infusion. Echocardiography was performed before and after OM infusion. Seven days after infusion, rats were euthanized, and left ventricular (LV) tissues were removed for real-time quantitative polymerase chain reaction (RTq-PCR) experiments. After OM infusion, pro-apoptotic Bax-to-Bcl2 ratio was decreased, with increased Bcl2 and similar Bax gene expression. The gene expression of molecules regulating oxidative stress, including glutathione disulfide reductase (Gsr) and superoxide dismutases (Sod1/Sod2), remained unchanged, whereas the expression of antioxidant glutathione peroxidase (Gpx) increased. While LV gene expression of key energy sensors, peroxisome proliferator activator (Ppar) α and γ, AMP-activated protein kinase (Ampk), and carnitine palmitoyltransferase 1 (Cpt1) remained unchanged after OM infusion, and the expression of pyruvate dehydrogenase kinase 4 (Pdk4) increased. The LV expression of the major myocardial glucose transporter Glut1 decreased, with no changes in Glut4 expression, whereas the LV expression of oxidized low-density lipoprotein receptor 1 (Olr1) and arachidonate 15-lipoxygenase (Alox15) increased, with no changes in fatty acid transporter Cd36. An increased LV expression of angiotensin II receptors AT1 and AT2 was observed, with no changes in angiotensin I-converting enzyme expression. The Kalikrein-bradykinin system was upregulated with increased LV expression of kallikrein-related peptidases Klk8, Klk1c2, and Klk1c12 and bradykinin receptors B1 and B2 (Bdkrb1 and Bdkrb2), whereas the LV expression of inducible nitric oxide synthase 2 (Nos2) increased. LV expression in major molecular determinants involved in calcium-dependent myocardial contraction remained unchanged, except for an increased LV expression of calcium/calmodulin-dependent protein kinase II delta (Cacna1c) in response to OM. A single intravenous infusion of OM, in adult healthy rats, resulted in significant changes in the LV expression of genes regulating apoptosis, oxidative stress, metabolism, and cardiac contractility.

Detection of soluble suppression of tumorigenicity 2 and N-terminal B-type natriuretic peptide in a rat model of aortic regurgitation: differential responses to omecamtiv mecarbil.

OBJECTIVES: Both N-terminal fragment of B-type natriuretic peptide (NT-proBNP) and soluble isoform of ST2 (sST2) have been identified as biomarkers of heart failure. We evaluated the plasma levels of NT-proBNP and sST2 in a rat model of severe aortic valve regurgitation (AR) and correlated these findings with echocardiographic measurements. We also examined the impact of omecamtiv mecarbil (OM) on these parameters. METHODS: The plasma levels of NT-proBNP and sST2 were measured in 18 rats both before and 2 months after surgical induction of AR, and at these same time points, in six rats assigned to a sham-procedure control group. Plasma biomarkers were then measured again after infusion of OM or placebo in rats with AR (n=8 and 10, respectively) and OM alone in the sham control rats (n=6). Echocardiographic measurements were collected before and 2 months after induction of AR. RESULTS: Our results revealed increased levels of plasma NT-proBNP (219 ± 34 pg/mL vs. 429 ± 374 pg/mL; p<0.001) in rats with AR at day 7 after infusion of placebo, whereas plasma levels of sST2 were higher in this cohort after infusion of either OM or placebo. We identified a significant positive correlation between plasma sST2 with posterior wall thickness in diastole (r=0.34, p<0.05) and total body weight (r=0.45, p<0.01) in rats with surgically induced AR. CONCLUSIONS: Because sST2 increased markedly, whereas NT-proBNP remained unchanged, when OM was administered, we hypothesize that sST2 has a distinct capability to detect deleterious effects of passive muscle tension, not reliably assessed by NT-proBNP, in the setting of AR.

Long-Term Outcome After Venoarterial Extracorporeal Membrane Oxygenation as Bridge to Left Ventricular Assist Device Preceding Heart Transplantation.

OBJECTIVES: To determine if venoarterial extracorporeal membrane oxygenation (VA ECMO) as a bridge to left ventricular assist device (LVAD) in heart transplant (HT) candidates (ie, double bridge to HT) was associated with increased morbidity and mortality when compared to LVAD bridging to HT (ie, single bridge to HT). DESIGN: A retrospective analysis of patients undergoing LVAD support from 2011 to 2020. A Kaplan-Meier survival curve and Cox-Mantel hazard ratios (HR) were calculated during LVAD support and after HT. Postoperative complications were collected. SETTING: University Hospital Erasme. PARTICIPANTS: HT candidates requiring LVAD. INTERVENTIONS: VA ECMO bridging to LVAD (ECMO-LVAD group [n = 24]) versus LVAD (LVAD group [n = 64]). MEASUREMENTS AND MAIN RESULTS: Eighty-eight patients underwent HeartWare LVAD (HVAD, Medtronic) placement. Survival to hospital discharge and during the entire study period were lower in the ECMO-LVAD group (66.7% v 92.2%; p = 0.0027, and 37.5% v 62.5%; p = 0.035, respectively). Overall HR of death was 2.46 (95% confidence interval [CI]: 1.13-5.37; p = 0.005) in the ECMO-LVAD group and remained elevated throughout their time on LVAD support (HR 3.24 [95% CI: 1.15-9.14]; p = 0.0036). However, in patients who underwent HT (n = 50), mortality was similar between groups (HR 1.33 [95% CI: 0.33-5.31]; p = 0.66). Postoperative complications were more frequent in the ECMO-LVAD group (infection = 83.3% v 51.6%, p = 0.007; renal replacement therapy = 45.8% v 9.4%, p = 0.0001; post-LVAD ECMO = 25.0% v 1.6%; p = 0.0003). CONCLUSIONS: VA ECMO as a bridge to LVAD support before HT was associated with increased morbidity and mortality during LVAD support. However, in patients who underwent HT, outcomes were similar regardless of VA ECMO bridging.

The myosin activator omecamtiv mecarbil improves wall stress in a rat model of chronic aortic regurgitation.

In patients with chronic aortic regurgitation (AR), excessive preload and afterload increase left ventricle wall stress, leading to left ventricular systolic dysfunction. Thus, the objective of the present study was to evaluate the effects of the myosin activator omecamtiv mecarbil (OM) on left ventricle wall stress in an experimental rat model of severe chronic AR. Forty adult male Wistar rats were randomized into two experimental groups: induction of AR (acute phase) by retrograde puncture (n = 34) or a sham intervention (n = 6). Rats that survived the acute phase (n = 18) were randomized into an OM group (n = 8) or a placebo group (n = 10). Equal volumes of OM (1.2 mg/kg/h) or placebo (0.9% NaCl) were continuously infused into the femoral vein over 30 min. OM significantly decreased end-systolic and end-diastolic and maximum wall stress in this experimental rat model of chronic severe AR (p < 0.001) and increased systolic performance assessed by fractional shortening and left ventricle end-systolic diameter; both p < 0.05). These effects were correlated with decreased indices of global cardiac function (cardiac output and stroke volume; p < 0.05) but were not inferior to baseline pump indices. Infusion with placebo did not affect global cardiac function but decreased end-systolic wall stress (p < 0.05) and increased systolic performance (all p < 0.001). In the sham-operated (control) group, OM decreased diastolic wall stress (p < 0.05). Based on these results, OM had a favorable effect on left ventricle wall stress in an experimental rat model of severe chronic AR.

Proximal pressure reducing effect of wave reflection in the pulmonary circulation disappear in obstructive disease: insight from a rabbit model.

Locating the site of increased resistance within the vascular tree in pulmonary arterial hypertension could assist in both patient diagnosis and tailoring treatment. Wave intensity analysis (WIA) is a wave analysis method that may be capable of localizing the major site of reflection within a vascular system. We investigated the contribution of WIA to the analysis of the pulmonary circulation in a rabbit model with animals subjected to variable occlusive pulmonary disease. Animals were embolized with different sized microspheres for 6 wk ( n = 10) or underwent pulmonary artery (PA) ligation for 6 wk ( n = 3). These animals were compared with a control group ( n = 6) and acutely embolized animals ( n = 4). WIA was performed and compared with impedance-based methods to analyze wave reflections. The control group showed a relatively high extent of reflected waves (15.7 ± 10.6%); reflections had a net effect of pressure reduction during systole, suggesting an open-end reflector. The pattern of wave reflection was not different in the group with partial PA ligation (12.4 ± 4.1%). In the chronically embolized group, wave reflection was not observed (3.6 ± 1.5%). In the acute embolization group, wave reflection was more prominent (37.3 ± 12.6%), with the appearance of a novel wave increasing pressure, suggesting the appearance of a closed-end reflector. Wave reflections of an open-end type are present in the normal rabbit pulmonary circulation. However, the pattern and nature of reflections vary according to the extent of pulmonary vascular occlusion. NEW & NOTEWORTHY The study proposes an original framework of a complementary analysis of wave reflections in the time domain and in the frequency domain. The methodology was used in the pulmonary circulation with different forms of chronic obstructions. The results suggest that the pulmonary vascular tree generates a reflection pattern that could actually assist the heart during ejection, and chronic obstruction significantly modifies the pattern.

Effects of the cardiac myosin activator Omecamtiv-mecarbil on severe chronic aortic regurgitation in Wistar rats.

BACKGROUND: Aortic regurgitation (AR) is a valvular disease that can lead to systolic heart failure. Treatment options besides cardiac surgery are limited and consequently severe AR is associated with higher mortality and morbidity when not operated. In this investigation, we examined the effects of a novel cardiac myosin activator, Omecamtiv-mecarbil (OM), in rats with chronic severe AR. METHODS: AR was created by retrograde puncture of the aortic valve leaflets in 20 adults Wistar rats. 12 animals survived the acute AR phase and were randomized 2 months thereafter into OM (n = 7) or placebo groups (n = 5). Two rats underwent a sham operation and served as controls. Equal volumes of OM or placebo (NaCl 0.9%) were perfused in the femoral vein by continuous infusion (1.2 mg/kg/hour) during 30 min. Doppler-echocardiography was performed before and at the end of the infusion periods. RESULTS: OM increased indices of global cardiac function (cardiac output, stroke volume), and increased systolic performance (fractional shortening, ejection fraction, left ventricular end systolic diameter) (all p < 0.05). These effects concurred with decreases in indices of LV preload (left atrial size, left ventricular end diastolic diameter) as well in the aortic pre-ejection period / left ventricular ejection time ratio (all p < 0.05). The severity score of the regurgitant AR jet did not change. Placebo infusion did not affect these parameters. CONCLUSION: The cardiac myosin activator OM exerts favorable hemodynamic effects in rats with experimental chronic AR.

How to cope with a temporarily aborted transplant program: solutions for a prolonged waiting period.

BACKGROUND: Due to budgetary restrictions our university heart transplant program came to a standstill to be gradually restarted early 2011. Consequently waiting-times for transplantation increased dramatically beyond the usual 10-15 months. We reviewed the clinical results of this peculiar transplant program over the past 4 years. METHODS: Since March 2011 until February 2015, 65 patients (age 48±23 years) were listed for heart transplantation. Eight patients (11%) of whom three in high emergency were transplanted without any form of mechanical assistance. Fifty-one patients required a left ventricular assist device (LVAD) Heartware (Heartware Inc., Miami Lakes, FL, USA) as a bridge-to-transplant due to terminal heart failure. Merely 5 listed patients remain without assistance. RESULTS: One patient without assistance and 11 LVAD patients (22%) died on the waiting-list. Meanwhile 10 LVAD patients were transplanted after a 2-year waiting time (770±717 days). Four transplanted patients died of early graft failure none after LVAD explantation. Survival at 1 and 3 years was respectively 78 (72%) and 83 (78%) for transplanted and assisted patients (log-rank P=0.056). Cox multivariable regression analysis identified crash-to-burn patients (P=0.002) and waiting-times over 2 years (P=0.044) as risk factors for early death, while age above 60 (P=0.008) and ischemic aetiology (P=0.029) and pulmonary hypertension (P=0.092) were risk factors for survival. CONCLUSIONS: In times of donor shortage mechanical assistance proves very effective as bridge-to-transplant in patients for whom candidacy follows the standard inclusion procedures. In our settings, a steep increase in LVAD implantation served to salvage patients for whom transplantation became jeopardized due to an ever increasing waiting-time. Circulatory LVAD support could be considered as primary therapy in the future.

Recycling of internal thoracic arteries in reoperative coronary surgery: in-hospital and midterm results.

BACKGROUND: Selected patients, presenting for reoperative coronary surgery with patent internal thoracic arteries (ITAs), may benefit from techniques to salvage and reuse these ITA grafts. We have termed this practice the recycling of ITAs. The purpose of this study is to report our short-term and midterm results using various recycling techniques. METHODS: Between April 1996 and February 2009, 60 patients underwent ITA recycling at our institution. Information regarding survival and cardiac events was obtained from a prospectively maintained, institutional database. Survival and freedom from major adverse cardiac events were calculated using Kaplan-Meier analysis. Mean follow-up duration was 60 ± 36 months. RESULTS: Mean age was 64 ± 9 years and the mean time to reoperation was 117 ± 68 months. The patent ITA served as an inflow for a composite Y graft in 39 patients and was distally reimplanted on the same coronary vessel in 9 patients. A combination of these two techniques was used in 8 patients. Other techniques were used in the remaining 4 patients. Freedom from cardiac death was 93% ± 7% and 85% ± 9% at 1 and 5 years and freedom from major adverse cardiac events was 93% ± 7% and 81% ± 11% at 1 and 5 years, respectively. CONCLUSIONS: Recycling of ITA grafts during reoperative coronary artery bypass grafting is safe and feasible in selected patients. These techniques can be useful in selected young patients to avoid saphenous vein graft or in patients with a lack of graft conduits.

Reoperation for ascending aorta false aneurysm using deep hypothermia and circulatory arrest.

OBJECTIVES: Ascending aorta false aneurysms after cardiac surgery are uncommon. Resternotomy is hazardous and may result in massive and uncontrollable hemorrhage if the false aneurysm is entered. Here we report our experience with the use of deep hypothermia and circulatory arrest to avoid this risk. METHODS: From March 2000 to December 2007, seven patients (mean age 50 years) were reoperated for an ascending aorta false aneurysm. Three patients had undergone an aortic valve replacement (n=2) or an aortic valve repair (n=1). Three had undergone an ascending aorta replacement with a valved conduit (n=2) or an aortic valve repair (n=1) for type A dissection. One had undergone a coronary artery bypass grafting. Mean delay to reoperation was 133 months (range 22-324 months). Two patients had positive blood cultures (Staphylococcus species). Cardiopulmonary bypass was established by extramediastinal access. Patients were cooled to 18 °C. RESULTS: Resternotomy was performed uneventfully under total circulatory arrest in all patients. Four patients underwent an ascending aorta replacement with a valved conduit (n=2) or a dacron conduit (n=2) associated with a mitral valve replacement in one patient. Direct suture was performed in two patients and in one patient the aorta was repaired using a saphenous vein patch. There was one hospital death. Mean follow-up was 53 months (range 14-90 months). CONCLUSION: Resternotomy under circulatory arrest and deep hypothermia is a safe technique well-adapted to patients with an ascending aorta false aneurysm.

Ventricular-arterial uncoupling in heart failure with preserved ejection fraction after myocardial infarction in dogs - invasive versus echocardiographic evaluation.

BACKGROUND: Heart failure with preserved left ventricular ejection fraction and abnormal diastolic function is commonly observed after recovery from an acute myocardial infarction. The aim of this study was to investigate the physiopathology of heart failure with preserved ejection fraction in a model of healed myocardial infarction in dogs. METHODS: Echocardiography, levels of neurohormones and conductance catheter measurements of left ventricular pressure-volume relationships were obtained in 17 beagle dogs 2 months after a coronary artery ligation, and in 6 controls. RESULTS: Healed myocardial infarction was associated with preserved echocardiographic left ventricular ejection fraction (0.57 +/- 0.01, mean +/- SEM) and altered Doppler mitral indices of diastolic function. NT-proBNP was increased, aldosterone was decreased, and norepinephrine was unchanged. Invasive measurements showed a markedly decreased end-systolic elastance (2.1 +/- 0.2 vs 6.1 +/- 0.8, mmHg/ml, p < 0.001) and end-systolic elastance to effective arterial elastance ratio (0.6 +/- 0.1 vs 1.4 +/- 0.2, p < 0.001), with altered active relaxation (dP/dtmin -1992 +/- 71 vs -2821 +/- 305, mmHg/s, p < 0.01) but preserved left ventricular capacitance (70 +/- 6 vs 61 +/- 3, ml at 20 mmHg, p = NS) and stiffness constant. Among echocardiographic variables, the wall motion score index was the most reliable indicator of cardiac contractility while E', E/A and E'/A' were correlated to dP/dtmin. CONCLUSIONS: In the canine model of healed myocardial infarction induced by coronary ligation, heart failure is essentially characterized by an altered contractility with left ventricular-arterial uncoupling despite vascular compensation rather than by abnormal diastolic function.

Five years follow-up after Y-graft arterial revascularization: on pump versus off pump; prospective clinical trial.

OBJECTIVES: We report our comparative experience of on-pump and off-pump full arterial coronary artery bypass grafting (CABG) using both internal mammary arteries (IMAs) anastomosed as a Y-graft. METHODS: A single-center clinical study was conducted prospectively between January 2003 and May 2008. It compared the short- and mid-term clinical outcomes of on- and off-pump arterial revascularization where the left internal mammary artery (LIMA) was anastomosed to the left anterior descending (LAD) artery while the free right internal mammary artery (RIMA) graft taking off from the LIMA was used to bypass different coronary targets. RESULTS: One hundred and ninety-two patients were divided into 77 on-pump and 115 off-pump procedures based on the intention to treat. The mean age in both groups was 60.2+/-11.7 and 68.1+/-10.6 years, respectively (P<0.05). Mean predictive logistic EuroSCORE was 3.5+/-6.7% for the on-pump group and 7.3+/-8.6% for the off-pump group (P<0.0001). Mean number of distal anastomoses were 2.7+/-0.6 (group ON) and 2.5+/-0.6 (group OFF) (P=NS). Postoperative mortality was two patients (2.6%) in the on-pump group and four patients (3.4%) in the off-pump group (P=0.63). No major adverse cardiac event, no stroke and no late death were reported during the follow-up that averaged 36.5+/-18.6 months. Angina recurrence was three patients (2.6%) in off-pump and two patients (3.5%) in on-pump group (P=NS). CONCLUSIONS: The use of a free RIMA as Y-graft from the LIMA performed off pump eradicates aortic manipulations and provides complete revascularization to high-risk patients with mortality similar to the one of a lower risk population operated on pump. The morbidity and cost was lower in the off-pump group. This advocates for the widespread usage of the technique in high-risk patients.

Cell therapy with autologous bone marrow mononuclear stem cells is associated with superior cardiac recovery compared with use of nonmodified mesenchymal stem cells in a canine model of chronic myocardial infarction.

OBJECTIVE: Stem cell therapy can facilitate cardiac repair in infarcted myocardium, but the optimal cell type remains uncertain. We conducted a randomized, blind, and placebo-controlled comparison of autologous bone marrow mononuclear cell and mesenchymal stem cell therapy in a large-animal model of chronic myocardial infarction. METHODS: Eleven weeks after coronary ligation, 24 dogs received intramyocardial injections of mononuclear cells (227.106 +/- 32.106 cells), mesenchymal stem cells (232.106 +/- 40.106 cells), or placebo (n = 8 per group). Cardiac performance and remodeling were assessed up to 16 weeks' follow-up. RESULTS: At echocardiographic analysis, the wall motion score index showed a sustained improvement after mononuclear cell transfer (from 1.8 +/- 0.1 to 1.5 +/- 0.07) and a moderate late improvement after mesenchymal stem cell transfer (from 1.9 +/- 0.08 to 1.7 +/- 0.1). After mononuclear cell transfer, end-systolic elastance increased (from 2.23 +/- 0.25 to 4.42 +/- 0.55 mm Hg/mL), infarct size decreased (from 13% +/- 0.67% to 10% +/- 1.17%), N-terminal B-type natriuretic propeptide level decreased (from 608 +/- 146 to 353 +/- 118 pmol/L), and relative wall area and arterial density increased. Vascular endothelial growth factor receptor 2 expression was upregulated in the border zone. No change in cardiac contractility or histologic parameters was noted in the mesenchymal stem cell group. CONCLUSION: In a canine model of chronic myocardial infarction, bone marrow mononuclear cell transfer is superior to mesenchymal stem cell transfer in improvement of cardiac contractility and regional systolic function and reduction in infarct size and plasma N-terminal B-type natriuretic propeptide level. Functional improvement is associated with a favorable angiogenic environment and neovascularization.

Extending the scope of mitral valve repair in rheumatic disease.

BACKGROUND: Repair of rheumatic mitral valves has met with limited success because hemodynamic obstruction may persist after repair because of residual diseased leaflet tissue and lack of suppleness. Over the past decade, we have developed and implemented an aggressive approach to rheumatic mitral valve repair with radical excision of the diseased leaflets area, and subvalvular apparatus and subsequent reconstruction, with the objective of removing all diseased valvular tissue. METHODS: From July 1996 to June 2007, 78 patients underwent mitral valve repair for rheumatic valve disease. Over the same time interval, 54 patients underwent mitral valve replacement. Mean age was 56.4 +/- 16 years. Clinical follow-up (mean 60 +/- 36 months) was complete in 100% of patients, and echocardiographic follow-up (mean 52 +/- 37 months) was 96% complete. RESULTS: There was no hospital mortality or early reoperations. Overall survival was 94% +/- 6% at 8 years, and 95% of patients were in New York Heart Association functional class II or less. Three patients (4%) required reoperation for mitral restenosis and 2 underwent re-repair. At 8 years of follow-up, freedom from cardiac death and mitral valve reoperation were 98% +/- 2% and 94% +/- 5%, respectively. Freedom from valve-related events at 5 and 10 years was 90% +/- 8% and 86% +/- 11%, and freedom from significant mitral regurgitation was 98% +/- 2% at 5 years and 83% +/- 9% at 8 years. CONCLUSIONS: A more aggressive approach to resection of diseased valvular tissue with subsequent reconstruction is feasible, with good midterm results, and may extend the scope of valve repair in rheumatic disease patients.

Long-term follow-up after endocardial radiofrequency modified Nitta procedure for concomitant atrial fibrillation treatment.

In atrial fibrillation (AF) patients, the surgical restoration of sinus rhythm aims at restoring atrial contraction, hence to decrease thromboembolic events. We investigated the long-term outcome of radiofrequency (RF) ablation by a modified Nitta procedure, in patients with AF associated with operative structural heart diseases. Between September 2000 and April 2004, a total of 20 patients (63.7+/-13.34 years) with structural heart diseases due to surgery and chronic AF underwent endocardial RF ablation. Evaluation was achieved at discharge, at 6 months, 12 months and in November 2005. Echocardiography, 12-derivations electrocardiogram and 24-h electrocardiogram were obtained. At the mean follow-up of 43.25+/-13.4 months, 14 out of 20 patients (70%) were in sinus rhythm. Actuarial freedom from AF recurrence was 85% after 6 months, 75% after 12 months and 70% at the follow-up completion. Effective atrial contraction was present in 78.5% of patients with sinus rhythm. No hemodynamic pulmonary edema has been reported during the hospital stay, and no thromboembolic event has been reported during the follow-up period. The Nitta procedure, modified for RF ablation, is an easy procedure when performed in the setting of structural heart disease surgery. Further studies are warranted to evaluate this technique on a larger scale basis.

Off-pump treatment of coronary artery perforation after percutaneous intervention with a pericardial patch.

Coronary artery perforation is a rare complication of percutaneous coronary interventions, usually requiring surgical intervention. A case of perforation of the diagonal branch after stent deployment is reported. Off-pump surgery was performed with the use of a pericardial patch and surgical glue to close the perforation. Epidemiology and treatment are discussed.