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.

Lung diffusion capacity correlates with pre-implant pulmonary hypertension and predicts outcome after LVAD implantation.

AIMS: Diffusing capacity of the lung for carbon monoxide (DLCO ) reduction is common in heart failure (HF) and is associated with a worse prognosis. Correlations between DLCO and pulmonary hypertension (PH) are unclear, and published data are conflicting; it has been shown that DLCO impairment may persist or even worsen after normalization of pulmonary pressures following left ventricle assist device (LVAD) implantation, maybe reflecting persistent pulmonary damage. We aimed to investigate the impact of pre-implant DLCO and central haemodynamics on outcome in patients with advanced HF implanted with a LVAD. METHODS AND RESULTS: We retrospectively analysed pre-implant and post-implant data from 42 patients implanted with a LVAD at our institution. Out of 42 patients, 35 had post-capillary PH before implantation, including 17 with combined post- and pre-capillary PH (Cpc-PH). Median DLCO was 59% (IQR 47-68%), and it inversely correlated with pulmonary vascular resistance (PVR) (P 0.037) and diastolic pulmonary gradient (DPG) (P 0.042). Compared with baseline, LVAD resulted in improvement in LV diameter (LVDd, P < 0.001), mitral regurgitation (P 0.022), and PH (mPAP 24 vs. 36 mmHg, P < 0.001; PAWP 12 vs. 23 mmHg, P 0.001; pulmonary artery compliance, CPA 3.1 vs. 1.9 mL/mmHg, P 0.021). Lower DLCO and Cpc-PH at baseline were associated with a better LV reverse remodelling post-implantation (P 0.027 for LVDd) but also with a smaller gain in CPA (P 0.049). CONCLUSIONS: Before LVAD implantation, DLCO impairment is associated with higher PVR and DPG, suggesting that it might be an expression of persistent pulmonary damage occurring in Cpc-PH. After LVAD implantation, both LV dimension and haemodynamics improve. Lower pre-implant DLCO is associated with better LV reverse remodelling.

A novel metrics to predict right heart failure after left ventricular assist device implantation.

BACKGROUND: Right Heart Failure (RHF) is a severe complication that can occur after left ventricular assist device (LVAD) implantation, increasing early and late mortality. Although numerous RHF predictive scores have been developed, limited data exist on the external validation of these models. We therefore aimed at comparing existent risk score models and identifying predictors of severe RHF at our center. METHODS: In this retrospective, single-center analysis, clinical, biological and functional data were collected in patients implanted with a LVAD between 2011 and 2020. Early severe RHF was defined as the use of inotropes for ≥ 14 days, nitric oxide use for ≥ 48 h or unplanned right-sided circulatory support. Risk models were evaluated for the primary outcome of RHF or RVAD implantation by means of logistic regression and receiver operating characteristic curves. RESULTS: Among 92 patients implanted, 24 (26%) developed early severe RHF. The EUROMACS-RHF risk score performed the best in predicting RHF (C = 0.82-95% CI: 0.68-0.90), compared with the other scores (Michigan, CRITT). In addition, we developed a new model, based on four variables selected for the best reduced logistic model: the INTERMACS level, the number of inotropes used, the ratio of right atrial/pulmonary capillary wedge pressure and the ratio of right ventricle/left ventricle diameters by echocardiography. This model demonstrated significant discrimination of RHF (C = 0.9-95% CI: 0.76-0.96). CONCLUSION: Amongst available risk scores, EUROMACS-RHF performs best to predict the occurrence of RHF after LVAD implantation. Our model's performance compares well to the EUROMACS-RHF score, adding a more objective parameter to RV function evaluation.

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.

Gonococcal ascending aortic aneurysm with penetrating ulcer and bovine arch.

We describe a patient with ascending aorta aneurysm and bovine aortic arch who initially presented with fever. A 65-year-old man with a 2-month history of intermittent fever was referred to our hospital and diagnosed as having a gonococcal ascending aorta aneurysm with penetrating ulcers. He was successfully treated by resection of the ascending aorta and ulcers, replacement of the aortic valve, and prolonged postoperative antibiotic therapy.

The role of biventricular assistance in primary graft failure after heart transplantation.

A 37-year-old man suffered from systolic heart failure as a result of idiopathic dilated cardiomyopathy since 1995 and was followed up in our cardiology department. In June 2006, the patient arrived at our outpatient clinic with an acute renal impairment and all manifestations of acute heart failure. He was already registered on the waiting list for heart transplantation (Eurotransplant) as a highly urgent request. The patient underwent heart transplantation but the reperfused allograft was totally akinetic and we decided to place a biventricular assist device immediately. The patient fully recovered after seven days of biventricular circulatory support and was discharged on the 38th day after the transplantation. Three years later, he is in good general condition without any manifestation of rejection. We conclude that biventricular assist device implantation is a good indication after post-cardiotomy failure and it should be started as early as possible before shock and possible irreversible organ damage.

Endocarditis of bovine jugular vein conduit due to Q fever.

Contegra (Medtronic, Minneapolis, MN) conduits are routinely used in cases of right ventricular outflow tract reconstruction during congenital heart surgery. We report two cases of Q fever endocarditis involving Contegra conduits. Surgical treatment and distinct aspects of both unusual cases are described.

Continuous mixed venous and central venous oxygen saturation in cardiac surgery with cardiopulmonary bypass.

BACKGROUND AND OBJECTIVE: Replacing mixed venous oxygen saturation (SvO2) monitoring by central venous oxygen saturation (ScvO2) monitoring in order to avoid the use of a pulmonary artery catheter and its related complications is still controversial in the setting of cardiac surgery. The influence of surgery, cardiopulmonary bypass and anaesthesia drugs on the relationship between SvO2 and ScvO2 has never been studied. METHODS: Fifteen patients scheduled for cardiac surgery with cardiopulmonary bypass were included in the study. SvO2 (from the pulmonary artery) and ScvO2 (from the superior vena cava) were continuously measured with fibre-optic catheters from induction of anaesthesia to 24 h postoperatively. RESULTS: A total of 9267 pairs of measurements were recorded. Mean bias between SvO2 and ScvO2 was 4.4% with limits of agreement of -13.6 and +22.5%, respectively. Trends of SvO2 and ScvO2 values followed very different patterns for some patients. Surgery, cardiopulmonary bypass and anaesthesia drugs did not influence the relationship between the two methods. CONCLUSION: Because of the large interindividual variability in the difference between SvO2 and ScvO2, the measure of ScvO2 should not replace the measure of SvO2 with a pulmonary artery catheter for the management of patients undergoing cardiac surgery with cardiopulmonary bypass.

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.

Oxidative stress produced by circulating microparticles in on-pump but not in off-pump coronary surgery.

OBJECTIVE: This study was undertaken to assess whether plasmas isolated during off-pump coronary surgery trigger less oxidative stress than those isolated during on-pump surgery. METHODS AND RESULTS: Plasmas were sampled from patients before (TO), just after (TI) and 24 hours after (T2) cardiac surgery (n=24 on-pump and n=10 off-pump). Rings of rat thoracic aortas were incubated for 20 hours with these different plasmas (100 microl + 4 ml medium) or saline (control). Thereafter, superoxide anion production was assessed by chemiluminescence and the mean signal was expressed as percent of that in the control ring. In rat aorta exposed to plasmas from on-pump CABG patients (n=6), the signal was enhanced by 210 +/- 29% at T1 (P < 0.05) and by 174 +/- 29% at T2 (P < 0.05) versus 53 +/- 12% at T0. Moreover, at T1 and T2, there was an upregulation of p22(phox), the key subunit of NADPH oxidase, the main enzyme involved in oxidative stress of the vascular wall. In contrast, off-pump plasmas did not induce this superoxide production. Incubation with microparticles obtained by ultracentrifugation also markedly enhanced the signal at T1 and T2 (vs. T0) in the on-pump group (but not in the off-pump group). Selective removal of CD34, CD105, CD59, CD146, CD42 microparticles using flow cytometry did not abolish the signal. CRP and SAA plasma levels were enhanced only at T2 in both groups. CONCLUSIONS: Plasmas isolated after on-pump but not off-pump coronary bypass surgery can induce superoxide generation by the vascular wall which seems related to circulating microparticles remaining present at least 24 hours after the procedure that might be of endothelial origin.

Esophageal stents for iatrogenic esophageal perforations during cardiac surgery.

The usefulness and safety of transesophageal echocardiography during cardiac surgery have been well described in the literature. However, rare complications of this procedure can occur and should be familiar to surgeons and anesthesiologists. A series of two cases of esophageal perforation by echoprobe during cardiac surgery treated successfully by endoscopic stenting are reported.

Recurrent endocarditis of a bicuspid aortic valve due to Q fever.

A 46-year-old man was referred to our institution for a recurrent endocarditis with negative blood culture. Clinical examination and complementary investigations confirmed the diagnosis of aortic valve endocarditis with left ventricular fistula. Blood culture was negative but serological tests were positive for Coxiella burnetti. Aortic valve replacement and fistula repair were done. A combination of Doxycycline and Chloroquine antibiotics was given postoperatively with a clinical improvement. Coxiella burnetti should be systemically searched for in all cases of endocarditis even with negative blood cultures. This case is interesting because of its rarity, diagnosis, therapeutic problems and its severe complication.

10-year experience with the ATS mechanical valve in the mitral position.

BACKGROUND: The ATS Medical Open Pivot mechanical heart valve was introduced in 1992. Previous reports have focused on the low rate of thromboembolic complications in the aortic position. The purpose of this retrospective study is to analyze the rate of midterm thromboembolic events and other valve-related complications when the ATS Open Pivot valve is implanted in the mitral position. METHODS: Between June 1992 and June 2002, 177 patients (63 male and 114 female; mean age 57.5 years) underwent mitral replacement with an ATS Open Pivot mechanical heart valve. Preoperatively, 17 patients (10%) were in New York Heart Association functional class II, 117 patients (66%) in class III, and 43 patients (24%) in class IV. Seventy-four patients (42%) were in chronic atrial fibrillation. Seventy-four mitral valve replacements (42%) were associated with other cardiac procedures. Etiologies included degenerative disease (56%), rheumatic disease (38%), and endocarditis (6%). On the second postoperative day, 100 mg acetylsalicylic acid and oral acenocoumarol (Sintrom) was introduced to obtain a target INR of 2.0 to 3.0. All patients were followed up by one cardiologist and underwent annual transthoracic echocardiographic examination. RESULTS: Percent follow-up was 90.4%. Data represent 724 total patient-years. Mean follow-up was 48 +/- 34 months (range, 1 to 119). Operative morbidity was 15%. Overall hospital mortality was 2.8% (5 patients). At hospital discharge, the mean INR for all the patients was 2.38 +/- 0.68 (range, 1.32 to 6.44). Five early neurologic complications occurred: 3 transient cerebrovascular accidents and 2 strokes. Three late transient cerebrovascular ischemic accidents occurred at 3, 4, and 6 years, respectively. No other complications such as paravalvular leak, valve dysfunction, thrombosis, or valve explant occurred. Postoperative echocardiographic data revealed low mean pressure gradient as related to the valvular size. CONCLUSIONS: The ATS Medical Open Pivot mitral valve demonstrates low rates of bleeding, thromboembolic, and other valve-related complications.

Early experience with a new aortic clamping system designed for port access cardiac surgery: the PortaClamp.

BACKGROUND: We report a clinical study to demonstrate the feasibility and safety of a new aortic crossclamping concept for use in port-access cardiac surgery. The limited access to the aorta in minimally invasive cardiac surgery mandates specific clamping modalities, which entail specific limitations, drawbacks, and costs. Therefore a new autoguided, extravascular, and atraumatic clamping system (PortaClamp) was developed to facilitate port-access surgery while potentially avoiding the complications and costs inherent to endoluminal clamping or "blind" crossclamping. METHODS: Twenty patients underwent various cardiac operations under cardiopulmonary bypass and aortic crossclamping with the PortaClamp between February and September 2003. The method of aortic clamping is described and the operative course and clinical outcome of the patients are reported as surrogates of feasibility and safety. RESULTS: The average time to position the clamp was 196 +/- 75 seconds. Crossclamping through a 10-mm port or incision was achieved successfully, enabling cardiac arrest throughout the procedure in every patient. No patient presented with cardiovascular accident or transient ischemic attack, aortic dissection, or hematoma. Intensive care unit times were 12 +/- 3 hours; length of stay was 7.2 +/- 1.1 days. CONCLUSION: From this early experience we conclude that the PortaClamp system is safe and can effectively be used to crossclamp the aorta inexpensively to facilitate port-access cardiac surgery. Further comparative studies with the existing systems are warranted to confirm that the atraumatic design provides further benefit.

Pulmonary vein isolation by robotic-enhanced thoracoscopy for symptomatic paroxysmal atrial fibrillation.

BACKGROUND: Pulmonary vein isolation (PVI) has been shown to be effective treatment of patients with symptomatic paroxysmal atrial fibrillation (PAF). The percutaneous approach is currently the technique of choice. Unfortunately, this procedure has limitations and complications that lead to fluctuating success rates. We explored an alternative technique of robotic-enhanced, closed-chest PVI with an endoscopic microwave-based catheter. METHODS: Seven symptomatic PAF patients were included in the study. The pulmonary veins were isolated through right (only) robotic-enhanced thoracoscopy on the beating heart. RESULTS: Six patients underwent successful endoscopic PVI. In 1 patient the operation was converted into small right thoracotomy. Operative assessment of the ablation line showed a successful electric block in every patient. Three months after the procedure, the first 5 patients were in permanent sinus rhythm. The 2 other patients had AF but had less frequent and less symptomatic episodes compared with the preoperative situation. CONCLUSIONS: On the basis of this preliminary experience, we believe that in the near future endoscopic right-chest robotic-enhanced PVI on the beating heart may become a valid option in the treatment of symptomatic PAF patients. This procedure allows for more-reproducible ablation lines and may avoid many of the pitfalls and drawbacks of the percutaneous approach. Therefore this technique deserves larger prospective evaluation in the treatment of AF.