Statins affect human iPSC-derived cardiomyocytes by interfering with mitochondrial function and intracellular acidification.

Statins are effective drugs in reducing cardiovascular morbidity and mortality by inhibiting cholesterol synthesis. These effects are primarily beneficial for the patient's vascular system. A significant number of statin users suffer from muscle complaints probably due to mitochondrial dysfunction, a mechanism that has recently been elucidated. This has raised our interest in exploring the effects of statins on cardiac muscle cells in an era where the elderly and patients with poorer functioning hearts and less metabolic spare capacity start dominating our patient population. Here, we investigated the effects of statins on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-derived CMs). hiPSC-derived CMs were exposed to simvastatin, atorvastatin, rosuvastatin, and cerivastatin at increasing concentrations. Metabolic assays and fluorescent microscopy were employed to evaluate cellular viability, metabolic capacity, respiration, intracellular acidity, and mitochondrial membrane potential and morphology. Over a concentration range of 0.3-100 µM, simvastatin lactone and atorvastatin acid showed a significant reduction in cellular viability by 42-64%. Simvastatin lactone was the most potent inhibitor of basal and maximal respiration by 56% and 73%, respectively, whereas simvastatin acid and cerivastatin acid only reduced maximal respiration by 50% and 42%, respectively. Simvastatin acid and lactone and atorvastatin acid significantly decreased mitochondrial membrane potential by 20%, 6% and 3%, respectively. The more hydrophilic atorvastatin acid did not seem to affect cardiomyocyte metabolism. This calls for further research on the translatability to the clinical setting, in which a more conscientious approach to statin prescribing might be considered, especially regarding the current shift in population toward older patients with poor cardiac function.

Mycotic aortic aneurysms: characteristic macroscopic findings in a case series.

Infected or mycotic aortic aneurysms (MAAs) are a rare type of aneurysms. Due to the high risk of rupture, MAAs are life-threatening conditions. Early diagnosis and treatment are necessary, yet MAAs are usually found coincidentally. We report 10 patients with MAAs in whom macroscopically, similar coined-sized lesions of the inner aortic wall were seen in all cases. When a coin-sized lesion in the inner aortic wall is seen during open surgical repair of an aortic aneurysm, the surgeon should consider an infectious cause. Microbiological tissue samples should be collected, and additional targeted antibiotic therapy should be started.

Safety and Efficacy of Human Chorionic Gonadotropin Hormone-Derivative EA-230 in Cardiac Surgery Patients: A Randomized Double-Blind Placebo-Controlled Study.

OBJECTIVES: To determine the safety and efficacy of human chorionic gonadotropin hormone-derivative EA-230 in cardiac surgery patients. Cardiac surgery induces systemic inflammation and may impair renal function, affecting patient outcome. EA-230 exerted immunomodulatory and renoprotective effects in preclinical models and was safe and showed efficacy in phase I and II human studies. DESIGN: Double-blinded, placebo-controlled, randomized study. SETTING: Collaboration of the Cardiothoracic Surgery, Anesthesiology, and the Intensive Care departments of a tertiary hospital in the Netherlands. PATIENTS: One hundred eighty patients undergoing an on-pump coronary artery bypass procedure with or without concomitant valve surgery. INTERVENTIONS: Ninety mg/kg/hr EA-230 or placebo administered during surgery. MEASUREMENTS AND MAIN RESULTS: During the study, no safety concerns emerged. EA-230 did not modulate interleukin-6 plasma concentrations (area under the curve 2,730 pg/mL × hr [1,968-3,760] vs 2,680 pg/mL × hr [2,090-3,570] for EA-230 and placebo group, respectively; p = 0.80). Glomerular filtration rate increased following surgery (mean ± sem increase in the EA-230 vs placebo groups: glomerular filtration rateiohexol measured using iohexol plasma clearance: 19 ± 2 vs 16 ± 2 mL/min/1.73 m2; p = 0.13 and estimated glomerular filtration rate with the Modification of Diet in Renal Disease equation using creatinine: 6 ± 1 vs 2 ± 1 mL/min/1.73 m2; p = 0.01). The "injury" stage of the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease criteria for acute kidney injury was 7% in the EA-230 group versus 18% in the placebo group (p = 0.07). In addition, EA-230-treated patients had a less positive fluid balance compared with placebo-treated patients (217 ± 108 vs 605 ± 103 mL; p = 0.01), while the use of vasoactive agents was similar in both groups (p = 0.39). Finally, hospital length of stay was shorter in EA-230 treated patients (8 d [7-11] vs 10 d [8-12]; p = 0.001). Efficacy results were more pronounced in patients that had longer duration of surgery and thus longer duration of study drug infusion. CONCLUSIONS: EA-230 was safe in patients undergoing on-pump cardiac surgery. It did not modulate interleukin-6 plasma concentrations but appeared to exert beneficial renal and cardiovascular effects and shortened in-hospital length of stay.

Transcatheter aortic valve replacement during the COVID-19 pandemic-A Dutch single-center analysis.

BACKGROUND AND AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic has put an enormous strain on healthcare systems and intensive care unit (ICU) capacity, leading to suspension of most elective procedures, including transcatheter aortic valve replacement (TAVR). However, deferment of TAVR is associated with significant wait-time mortality in patients with severe aortic valve stenosis. Conversely, there is currently no data available regarding the safety and feasibility of a continued TAVR program during this unprecedented crisis. The aim of this study is to evaluate the safety and feasibility of patients undergoing TAVR during the COVID-19 pandemic in our center, with specific emphasis on COVID-19 related outcomes. METHODS: All patients who underwent TAVR in our center between February 27, 2020, and June 30, 2020, were evaluated. Clinical outcomes were described in terms of Valve Academic Research Consortium 2 definitions. Patient follow-up was done by chart review and telephone survey. RESULTS: A total of 71 patients have undergone TAVR during the study period. Median age was 80 years, 63% were men, and 25% were inpatients. Procedural success was 99%. After TAVR, 30% involved admission to the ICU, and 94% were ultimately discharged to the cardiac care unit on the same day. Two patients (3%) had confirmed COVID-19 a few days after TAVR, and both died of COVID-19 pneumonia within 2 weeks after hospital discharge. CONCLUSIONS: A continued TAVR program during the COVID-19 pandemic is feasible despite limited hospital resources. However, COVID-19 related mortality after TAVR is of concern.

Proof of principle of a novel co-pulsating intra-ventricular membrane pump.

In this proof of principle study, we investigated the effectiveness and safety of hemodynamic support with the Intra-Ventricular Membrane Pump (IVMP). The IVMP was implanted into the apex of the left ventricle. Hemodynamic assessment was performed in six ex vivo beating porcine hearts (PhysioHeart platform). The cardiac output (CO), mean arterial pressure (MAP), coronary flow (CF) and pulse pressure (PP) were obtained before and during IVMP support and reported as means ± standard deviations. In two additional visualization experiments, the integrity of the mitral valve was assessed during IVMP support. We found a significant increase of the CO (+1.4 ± 0.2 L/min, P < .001), MAP (+13 ± 6 mm Hg, P = .008), CF (+0.23 ± 0.1 L/min, P = .004), and PP (+15 ± 4 mm Hg, P = .002) during IVMP support, when compared to baseline. No interference of the IVMP with mitral valve function was observed. An increase of premature ventricular complexes (PVC) was observed during support with the IVMP (mean PVC-burden 4.3% vs. 0.7% at baseline), negatively influencing hemodynamic parameters. The IVMP is able to significantly improve hemodynamic parameters in a co-pulsatile fashion, without hampering the function of the mitral valve. These findings provide a basis for future development of a catheter-based IVMP.

Spontaneous leaflet fracture resulting in embolization from mechanical valve prostheses.

Spontaneous leaflet fracture of mechanical heart valve prostheses is very rare. We describe a case of spontaneous leaflet embolization 31 years after aortic valve replacement with an Edwards-Duromedics prosthesis (Baxter Healthcare Corp., Edwards Division, Santa Ana, CA). We review the literature on this subject to increase awareness and recognition for this potentially life-threatening complication.

Effect of statins on mitochondrial function and contractile force in human skeletal and cardiac muscle.

OBJECTIVES AND BACKGROUND: The success of statin therapy in reducing cardiovascular morbidity and mortality is contrasted by the skeletal muscle complaints, which often leads to nonadherence. Previous studies have shown that inhibition of mitochondrial function plays a key role in statin intolerance. Recently, it was found that statins may also influence energy metabolism in cardiomyocytes. This study assessed the effects of statin use on cardiac muscle ex vivo from patients using atorvastatin, rosuvastatin, simvastatin or pravastatin and controls. METHODS: Cardiac tissue and skeletal muscle tissue were harvested during open heart surgery after patients provided written informed consent. Patients included were undergoing cardiac surgery and either taking statins (atorvastatin, rosuvastatin, simvastatin or pravastatin) or without statin therapy (controls). Contractile behaviour of cardiac auricles was tested in an ex vivo set-up and cellular respiration of both cardiac and skeletal muscle tissue samples was measured using an Oxygraph-2k. Finally, statin acid and lactone concentrations were quantified in cardiac and skeletal homogenates by LC-MS/MS. RESULTS: Fatty acid oxidation and mitochondrial complex I and II activity were reduced in cardiac muscle, while contractile function remained unaffected. Inhibition of mitochondrial complex III by statins, as previously described, was confirmed in skeletal muscle when compared to control samples, but not observed in cardiac tissue. Statin concentrations determined in skeletal muscle tissue and cardiac muscle tissue were comparable. CONCLUSIONS: Statins reduce skeletal and cardiac muscle cell respiration without significantly affecting cardiac contractility.

Effects of allopurinol and febuxostat on uric acid transport and transporter expression in human umbilical vein endothelial cells.

Uric acid induces radical oxygen species formation, endothelial inflammation, and endothelial dysfunction which contributes to the progression of atherosclerosis. Febuxostat inhibits BCRP- and allopurinol stimulates MRP4-mediated uric acid efflux in human embryonic kidney cells. We hypothesized that endothelial cells express uric acid transporters that regulate intracellular uric acid concentration and that modulation of these transporters by febuxostat and allopurinol contributes to their different impact on cardiovascular mortality. The aim of this study was to explore a potential difference between the effect of febuxostat and allopurinol on uric acid uptake by human umbilical vein endothelial cells. Febuxostat increased intracellular uric acid concentrations compared with control. In contrast, allopurinol did not affect intracellular uric acid concentration. In line with this observation, febuxostat increased mRNA expression of GLUT9 and reduced MRP4 expression, while allopurinol did not affect mRNA expression of these uric acid transporters. These findings provide a possible pathophysiological pathway which could explain the higher cardiovascular mortality for febuxostat compared to allopurinol but should be explored further.

Statins and Cardiomyocyte Metabolism, Friend or Foe?

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, and are the cornerstone of lipid-lowering treatment. They significantly reduce cardiovascular morbidity and mortality. However, musculoskeletal symptoms are observed in 7 to 29 percent of all users. The mechanism underlying these complaints has become increasingly clear, but less is known about the effect on cardiac muscle function. Here we discuss both adverse and beneficial effects of statins on the heart. Statins exert pleiotropic protective effects in the diseased heart that are independent of their cholesterol-lowering activity, including reduction in hypertrophy, fibrosis and infarct size. Adverse effects of statins seem to be associated with altered cardiomyocyte metabolism. In this review we explore the differences in the mechanism of action and potential side effects of statins in cardiac and skeletal muscle and how they present clinically. These insights may contribute to a more personalized treatment strategy.

Hemostatic Complications During Neonatal Extracorporeal Membrane Oxygenation: Roller Pump and Centrifugal Pump Driven Circuits.

Recently three different neonatal extracorporeal membrane oxygenation (ECMO) circuits have been employed in our clinic. These circuits were compared for clotting and bleeding complications. Initially, we used an ECMO circuit containing a roller pump and venous bladder without severe complications. Manufacturing of circuit components was discontinued, necessitating the replacement of this circuit by a circuit with a centrifugal pump with 3/8 inch inlet and outlet. Acute increase of oxygenator resistance requiring emergency changeout became unexpectedly a regularly occurring complication. The increase in resistance was suspected to be caused by oxygenator clotting, although oxygenator function was preserved. To prevent this complication, we changed to a levitating centrifugal pump with 1/4 inch inlet and outlet, after which no oxygenator malfunction has been observed. Macroscopic and electron microscopic analysis demonstrates that small clots are formed within the circuit, presumably in or near the centrifugal pump, which are transported to the oxygenator and clog up the hollow fiber layer at the inlet side, barely penetrating the oxygenator beyond this first layer. Our results suggest that low blood velocities accompanied with recirculation of blood within or near the centrifugal pump and/or heat generation within the pump could contribute to the formation of these clots.

Mitochondrial complex III activity: from invasive muscle biopsies to patient-friendly buccal swab analysis.

Drug-induced mitochondrial dysfunction is a common adverse effect, particularly in case of statins-the most prescribed drugs worldwide. These drugs have been shown to inhibit complex III (CIII) of the mitochondrial oxidative phosphorylation process, which is related to muscle pain. As muscle pain is the most common complaint of statin users, it is crucial to distinguish it from other causes of myalgia to prevent unnecessary cessation of drug therapy. However, diagnosing CIII inhibition currently requires muscle biopsies, which are invasive and not practical for routine testing. Less invasive alternatives for measurement of mitochondrial complex activities are only available yet for complex I and IV. Here, we describe a non-invasive spectrophotometric method to determine CIII catalytic activities using buccal swabs, which we validated in a cohort of statin and non-statin users. Our data indicate that CIII can be reliably measured in buccal swabs, as evidenced by reproducible results above the detection limit. Further validation on a large-scale clinical setting is recommended.

Perigraft hygroma mimicking recurrent angiosarcoma of the right atrium.

Primary cardiac angiosarcoma is extremely rare, has a poor prognosis and has no specific clinical manifestation. A 31-year-old pregnant woman presented to the emergency department with signs of pericardial tamponade. Transesophageal echocardiography (TEE) showed a mass within her right atrium. Extensive surgical resection was performed with subsequent pericardial patch reconstruction of the right atrium. Histological examination showed the presence of an angiosarcoma. A reoperation was performed 18 months after the initial operation, because of concerns of radicality. Three years later she was re-admitted with a superior caval vein syndrome. A stent was placed to relieve symptoms. Because of the suspicion of a recurrent tumor, a second reoperation followed. During this operation, a perigraft hygroma was found pressing against the previously reconstructed superior caval vein. Histological examination after both reoperations showed no signs of a recurrent angiosarcoma. Until today, 8 years after her first surgery, the patient is still alive without any signs of recurrent tumor.

A novel intra-ventricular assist device enhances cardiac performance in normal and acutely failing isolated porcine hearts.

BACKGROUND: We recently demonstrated that a novel intra-ventricular membrane pump (IVMP) was able to increase the pump function of isolated beating porcine hearts. In follow-up, we now investigated the impact of the IVMP on myocardial oxygen consumption and total mechanical efficiency (TME) and assessed the effect of IVMP-support in acutely failing hearts. METHODS: In 10 ex vivo beating porcine hearts, we studied hemodynamic parameters, as well as arterial and coronary venous oxygen content. We assessed cardiac power (CP), myocardial oxygen consumption (MVO2), and TME (CP divided by MVO2) under baseline conditions and during IVMP-support. Additionally, five isolated hearts were subjected to global hypoxia to investigate the effects of IVMP-support on CP under conditions of acute heart failure. RESULTS: Under physiological conditions, baseline CP was 0.36 ± 0.10 W, which increased to 0.65 ± 0.16 W during IVMP-support (increase of 85% ± 24, p < 0.001). This was accompanied by an increase in MVO2 from 18.6 ± 6.2 ml/min at baseline, to 22.3 ± 5.0 ml/min during IVMP-support (+26 ± 31%, p = 0.005). As a result, TME (%) increased from 5.9 ± 1.2 to 8.8 ± 1.8 (50 ± 22% increase, p < 0.001). Acute hypoxia-induced cardiac pump failure reduced CP by 35 ± 6%, which was fully restored to baseline levels during IVMP-support in all hearts. CONCLUSION: IVMP-support improved mechanical efficiency under physiological conditions, as the marked increase in cardiac performance only resulted in a modest increase in oxygen consumption. Moreover, the IVMP rapidly restored cardiac performance under conditions of acute pump failure. These observations warrant further study, to evaluate the effects of IVMP-support in in vivo animal models of acute cardiac pump failure.

Decision Making during the Learning Curve of Minimally Invasive Mitral Valve Surgery: A Focused Review for the Starting Minimally Invasive Surgeon.

Minimally invasive mitral valve surgery is evolving rapidly since the early 1990's and is now increasingly adopted as the standard approach for mitral valve surgery. It has a long and challenging learning curve and there are many considerations regarding technique, planning and patient selection when starting a minimally invasive program. In the current review, we provide an overview of all considerations and the decision-making process during the learning curve.

Necessity of life-long follow-up after surgery for coarctation of the aorta: a case series of very late false aneurysm formation.

BACKGROUND: Coarctation of the aorta accounts for 5-7% of congenital defects of the heart and great vessels. It requires treatment in the form of open surgical or percutaneous repair. Common long-term complications include re-stenosis and aneurysm formation. The formation of a false aneurysm is a complication with a significant morbidity and mortality. CASE SUMMARY: We reviewed six cases of late false aneurysm after repair of a coarctation of the aorta. Our six cases developed a false aneurysm after an open surgical repair of a coarctation more than 30 years after initial surgical repair. All aneurysms were located at the aortic repair site. DISCUSSION: The symptoms or risk factors in the described cases are not uniform and are difficult to include in a general follow-up protocol. Guidelines recommend frequent evaluation, but do not specify duration or intervals of imaging follow-up. Our cases support the necessity of life-long follow-up in patients with open aortic repairs irrespective of symptomatology.

Emergency surgery for ruptured sinus of Valsalva aneurysms.

OBJECTIVES: A ruptured sinus of Valsalva aneurysm is a very rare cardiac anomaly. Successful repair of these aneurysms was first described in the late 1950s. Several approaches for repair, through the aortic root or the chamber into which the aneurysm ruptures or a combination of both, have been described. We present our experience with emergency surgical repair of ruptured sinus of Valsalva aneurysms and our current surgical policy. DESIGN: A review of the St. Antonius Hospital database from January 1972 to December 2010 identified a total of 16 patients. A retrospective review of their medical records and telephonic follow-up was performed. RESULTS: Fifteen patients (13 male, three female) aged 46 ? 13 years were operated. The ruptured aneurysm arose from the right coronary (63%) and non-coronary sinus (37%) and ruptured into the right ventricle (67%) and into right atrium (33%). Primary suture closure was done in six patients and patch closure was performed in the remaining 10 patients. No intra-operative death occurred. Long-term follow-up identified one recurrent fistula from right coronary sinus to right atrium 28 years after primary suture closure. CONCLUSIONS: We performed prompt surgical repair of the ruptured sinus of Valsalva aneurysm preferably with a patch.

Case-control study on the interplay between immunoparalysis and delirium after cardiac surgery.

BACKGROUND: Delirium occurs frequently following cardiothoracic surgery, and infectious disease is an important risk factor for delirium. Surgery and cardiopulmonary bypass induce suppression of the immune response known as immunoparalysis. We aimed to investigate whether delirious patients had more pronounced immunoparalysis following cardiothoracic surgery than patients without delirium, to explain this delirium-infection association. METHODS: A prospective matched case-control study was performed in two university hospitals. Cytokine production (tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8 and IL-10) of ex vivo lipopolysaccharide (LPS)-stimulated whole blood was analyzed in on-pump cardiothoracic surgery patients preoperatively, and at 5 timepoints up to 3 days after cardiothoracic surgery. Delirium was assessed by trained staff using two validated delirium scales and chart review. RESULTS: A total of 89 patients were screened of whom 14 delirious and 52 non-delirious patients were included. Ex vivo-stimulated production of TNF-α, IL-6, IL-8, and IL-10 was severely suppressed following cardiothoracic surgery compared to pre-surgery. Postoperative release of cytokines in non-delirious patients was attenuated by 84% [IQR: 13-93] for TNF-α, 95% [IQR: 78-98] for IL-6, and 69% [IQR: 55-81] for IL-10. The attenuation in ex vivo-stimulated production of these cytokines was not significantly different in patients with delirium compared to non-delirious patients (p > 0.10 for all cytokines). CONCLUSIONS: The post-operative attenuation of ex vivo-stimulated production of pro- and anti-inflammatory cytokines was comparable between patients that developed delirium and those who remained delirium-free after on-pump cardiothoracic surgery. This finding suggests that immunoparalysis is not more common in cardiothoracic surgery patients with delirium compared to those without.

Geriatric assessment in the prediction of delirium and long-term survival after transcatheter aortic valve implantation.

OBJECTIVES: Transcatheter aortic valve implantation (TAVI) has emerged as the preferred management strategy for elderly patients with severe symptomatic aortic valve stenosis. These patients are often at high risk of postoperative delirium (POD), which is associated with morbidity and mortality. Since POD may be prevented in a considerable part of these patients, identification of patients at risk is essential. The aim of current study was to identify geriatric assessment tools associated with delirium after TAVI, and long-term mortality. METHODS: Consecutive patients were preoperatively assessed by a geriatrician between 2012 and 2017. Geriatric assessment tools consisted of cognitive, functional, mobility, and nutritional tests. POD was prospectively assessed during hospitalization after TAVI. Mortality tracking was performed by consulting municipal registries. RESULTS: A total of 511 patients were included. Median age was 80 [76-84] years, 44.8% (n = 229) were male, and 14.1% (n = 72) had a history of POD. Delirium was observed in 66 (12.9%) patients. Impaired mobility was the strongest geriatric assessment tool associated with POD (adjusted odds ratio, 2.1 [1.1-4.2], P = .028) and 2-year mortality (adjusted hazard ratio, 2.5 [1.4-4.5], P = .003). Two-year survival was reduced with more than 10% in patients with impaired mobility before TAVI (79.4% vs 91.4%, P = .013). CONCLUSIONS: This study shows that impaired mobility is currently the best single predictor for POD and 2-year mortality in high-risk patients undergoing TAVI. Prospective multicenter studies are needed to optimize and to further explore the facilitation of routine use of POD predictors in TAVI pathways of care, and subsequent preventive interventions.