Reduction In Systolic Function Research Articles

CARDIOGENIC SHOCK DUE TO SPONTANEOUS CORONARY ARTERY DISSECTION

Abstract Spontaneous coronary artery dissection (SCAD) is an important but rare cause of myocardial infarction (MI) in young adults, particularly women. Current guidelines recommend conservative treatment, given the low angiographic success and the high complication rate of percutaneous coronary intervention. However, in SCAD patients presenting with STEMI or cardiogenic shock the needs of urgent revascularization is critical and PCI may be life threatening. We present a case report occurs in our Hospital of a 42–year–old young woman without cardiovascular risk factors or notable comorbidities which was admitted to our emergency department for typical chest pain. At admission the patient had a cardiovascular arrest from refractory ventricular fibrillation who was rescued according to ACLS protocol. After resumption of ROSC, EKG showed anterolateral STEMI (FIGURE 1). Bedside echocardiography showed a severe reduction in systolic function (EF 30%) due to akinesia of the apex, septum and antero–lateral wall, with absence of noticeable valvulopathy, pericardial effusion or pathological findings in the right heart sections. Therefore the patient underwent to Cath–lab for emergent coronary angiography that showed ostial DA subocclusion with SCAD type 2a on middle tract (Figure 2) IVUS (intravascular ultrasound) imaging confirmed the diagnosis of SCAD, served to guided angioplasty on the LM–DA axis and to confirme optimal stent placement (FIGURE 3). Subsequently, the course was complicated by a double shock component: first SCAI C cardiogenic shock that requested or IMPELLA CP implantation and second haemorrhagic shock due to profound hepatic bleeding because of traumatic injury caused by prolonged resuscitation maneuvers. Mechanical ventricular support ensured haemodynamic stability to allow percutaneous embolisation of the hepatic arteries and patient stabilization. Once the haemorrhagic focus was treated and cardiac function recovered, the patient‘s condition gradually improved leading to a rapid weaning of haemodynamic and respiratory support. No neurological sequelae were observed after the acute phase. Conclusions 1) Urgent revascularization in patients with SCAD and high clinical instability is life threatening. IVUS imaging is crucial to confirm the diagnosis and guide the procedure. 2) The IMPELLA support in this case provided short–term haemodynamic support in a double component of shock.

MULTIDISCIPLINARY APPROACH TO A DIFFICULT CASE OF ACUTE HEART FAILURE DUE TO POSSIBILE ISOLATED CARDIAC SARCOIDOSIS

Abstract Background Cardiac sarcoidosis (CS) is a rare, infiltrative cardiomyopathy that results from granulomatous inflammation affecting the heart with high morbidity and mortality. It is usually associated with a systemic (i.e. pulmonary) involvement, but lone heart involvement has been described. Even with extensive multidisciplinary evaluation making a firm diagnosis is difficult, especially in case of isolated CS where the endomyocardial biopsy (EBM) diagnostic yield is low (20–30%). Case Description A 71–year–old patient, heavy smoker with no previously known diseases, was admitted with a 3–month history of dyspnea. On admission he showed typical features of heart failure with reduced ejection fraction (HFrEF). A coronary angiography excluded coronary artery disease, while echocardiography (TTE), cardiac magnetic resonance (CMR), and positron emission tomography (FDG–PET) showed a pattern consistent with a non–ischemic dilated cardiomyopathy with reduction in systolic function, and signs of active inflammation (highly suspected CS). Two electroanatomic mapping driven EBM were made but no clear histological signs of CS (i.e., granulomatous inflammation) were detected. The patient was treated with corticosteroids and HFrEF optimal medical therapy (sacubitril/valsartan, mineralocorticoid receptor antagonists, beta–blockers, dapagliflozin) and a temporary wearable defibrillator (LifeVest) was applied. At 2–month follow–up, despite a moderate improvement in the systolic function and HF symptoms, after a multidisciplinary discussion, considering the extensive left ventricle scar, inflammatory involvement, and the presence of multiple non–sustained ventricular tachycardia, a permanent cardioverter–defibrillator (ICD) was implanted. Conclusion This case highlights how, even with (repeated) extensive multidisciplinary evaluation (TTE, CRM, FGD–PET, EBM), a definitive diagnosis of isolated CS often remains presumptive. The presence of an experienced cardiomyopathy team (HF specialists, cardiac imager, electrophysiologists, internal medicine doctor) can help in the diagnostic–therapeutic management of these patients with inflammatory heart disease.

“A BROKEN TRANSPLANTED HEART”: A CASE OF TAKOTSUBO SYNDROME IN A HEART TRANSPLANT RECIPIENT

Abstract 75–year–old female patient went to the emergency department for oppressive chest pain radiating to the left arm and dyspnea, developed after an argument with family members. The patient underwent heart transplant in 2010 because of chronic ischemic heart disease. In history: systemic arterial hypertension, former smoking, dyslipidemia, and chronic renal failure. At blood tests: TnIHS 78.4 ng/L (<29 ng/L), CK–MB 1.9 microg/L, PROBNP–NT 43,000 pg/ml, creatinine 2 mg/dL. ECG showed inverted T waves in DI, AVL and V4 to V6 (fig 1). Transthoracic echocardiography was remarkable for a moderate reduction in systolic function (EF 38%), akinesia of apical portion, mid–segment of the IVS and mid–segment of posterior wall. Coronarography showed epicardial coronaries free of angiographically significant lesions. We decided to not perform ventriculography to avoid worsening renal function. At clinical stabilization, the patient underwent cardiac MRI with evidence of hypokinesia of the mid–ventricular segments with preserved global systolic function and hypo/akinesia of right ventricular apex with endocavitary thrombosis. Tissue characterization images were compatible with the presence of diffuse phlogistic involvement of the left ventricular myocardium (most evident at the mid–ventricular segments), in the absence of areas of myocardial necrosis. On pre–dimission echocardiogram, global left ventricular systolic function appeared markedly improved (auto EF 52%). DISCUSSION Our case is a rare case of Takotsubo syndrome (TS) in a transplanted heart. While TS accounts for 1–2% of all ACS in the general population, there is no precise data on its prevalence in heart transplant recipients. Although the pathophysiological mechanism underlying TS is still debated, there is evidence of hyperactivation of the sympathetic system with excessive catecholamine release. What is particular in our clinical case is that transplanted heart is denervated (because of resection of the post–ganglionic neural axons), although in some patients there is progressive reinnervation starting around the second year. Myocardial scintigraphy with iodine–123 meta iodobenzylguanidine can be used to study reinnervation. In our case, the presence of typical angor may be a clinical indicator of reinnervation, as many transplant patients present with CAV in the absence of chest pain.

Left ventricular remodeling in twin pregnancy, noninvasively assessed using hemodynamic forces and pressure-volume relation analysis: prospective, cohort study.

This study was designed to prospectively investigate the pattern of intraventricular hemodynamic forces (HDFs) associated with left ventricular (LV) function and remodeling in women with uncomplicated twin pregnancy. Transthoracic echocardiography was performed on 35 women (aged 35.9 ± 4.7-yr old) during gestation (T1, <14 wk; T2, 14-27 wk; T3, >28 wk) and 6-7 mo after delivery (T0). LV HDFs were computed from echocardiography long-axis data sets using a novel technique based on endocardial boundary tracking, both in apex-base (A-B) and latero-septal (L-S) directions. HDF distribution was evaluated by L-S over A-B HDF ratio (L-S:A-B HDF ratio). At T1, L-S:A-B HDF ratio was higher than in T0 (P < 0.05) indicating HDF misalignment. At T2, a slight impairment of cardiac function was then recorded with a reduction of global longitudinal strain (GLS) and left ventricular end-systolic elastance (Ees) at pressure-volume relationship analysis versus T1 (both P < 0.05). Finally, at T3, when HDF misalignment and LV contractility reduction (GLS and Ees) were all restored, a rightward shift of the end-diastolic pressure-volume relationship (EDPVR) with an increase of ventricular capacitance was documented. In twin pregnancy, HDF misalignment in the first trimester precedes the slight temporary decrease in left ventricular systolic function in the second trimester; at the third trimester, a rightward shift of the EDPVR was associated with a realignment of HDF and normalization of ventricular contractility indexes. These coordinated changes that occur in the maternal heart during twin pregnancy suggest the role of HDFs in cardiac remodeling.NEW & NOTEWORTHY These changes indicate that 1) the misalignment of hemodynamic forces (HDFs) precedes a mild reduction in systolic function in twin pregnancy and 2) the positive left ventricular (LV) response to hemodynamic stress is mainly due to an improved diastolic function with enhanced LV cavity compliance.

Predictors and prognostic implications of left ventricular ejection fraction trajectory improvement in the spectrum of heart failure with reduced and mildly reduced ejection fraction

BackgroundThe latest guidelines emphasize the significance of evaluating the left ventricular ejection fraction (LVEF) trajectory in patients with heart failure (HF). Because patients with HF with reduced ejection fraction (HFrEF) and HF with mildly reduced ejection fraction (HFmrEF) have reduction in systolic function, they might be in a trajectory of LVEF improvement after medical and device-based therapies. While previous studies have primarily focused on LVEF improvement in HFrEF, there is limited research on LVEF trajectory improvement across the spectrum of HFrEF and HFmrEF. This study aimed to assess the determinants and prognostic implications of LVEF trajectory improvement in HFrEF and HFmrEF patients. MethodsThe cohort was classified into the improved group (HFrEF-to-HF with improved ejection fraction (HFimpEF) and HFmrEF-to-HF with preserved ejection fraction (HFpEF)) and the unimproved group (lack of improved group criteria). The primary endpoints were the composite of all-cause mortality or HF hospitalization, all-cause mortality, and HF hospitalization. Predictors of LVEF trajectory improvement were also evaluated. ResultsA total 1303 patients were included in the study (improved/unimproved group: n = 497/806). Cox regression analysis showed that the improved group experienced lower risks of prespecified end points than the unimproved group. Multivariate logistic regression analysis showed that atrial flutter, use of spironolactone, and treatment with catheter ablation were associated with LVEF trajectory improvement, while myocardial infarction, prior percutaneous catheter intervention or coronary artery bypass graft, E/e′, and left ventricular end-diastolic diameter were identified as negative predictors of LVEF trajectory improvement. In the improved subgroup, the prognosis for the HFrEF-to-HFimpEF and HFmrEF-to-HFpEF was comparable. ConclusionsLVEF trajectory improvement patients had improved clinical outcomes and it was associated with important clinical, baseline cardiac structure and function, and treatment factors. Outcomes were similar in both HFrEF-to-HFimpEF and HFmrEF-to-HFpEF subgroups. These results suggest that emphasis should be placed on LVEF trajectory improvement to improve the outcomes of this population.

Anesthesia-induced Takotsubo cardiomyopathy in trigeminal neuralgia: illustrative case

Takotsubo syndrome (TS) represents a form of nonischemic cardiomyopathy characterized by sudden and temporary weakening of the myocardium. Many data suggest a primary role for sympathetic overstimulation in its pathogenesis. Nevertheless, these correlates are less easily identified during anesthesia. A 50-year-old female patient with a 4-year history of drug-resistant left trigeminal neuralgia. She was scheduled for surgical microvascular decompression. In the operating room, after induction of general anesthesia and oral intubation, the electrocardiogram revealed a significant ST segment elevation along with a sudden decrease in systolic blood pressure and heart rate. Administration of atropine caused a conversion into ventricular tachycardia. The advanced cardiac life support protocols were applied with prompt defibrillation and rapid recovery at sinus rhythm. A transthoracic echocardiogram revealed apical akinesia with ballooning of the left ventricle with a reduction of systolic function. An emergency coronary arteriography was performed, showing normal epicardial coronary vessels. After 4 days, echocardiography revealed normalization of the left ventricular function with improvement of the ejection fraction. In patients affected by trigeminal neuralgia, chronic pain can lead to a state of adrenergic hyperactivation, which can promote TS during the induction of general anesthesia, probably through the trigeminocardiac reflex.

Pharmacokinetics of a single dose of Aficamten (CK-274) on cardiac contractility in a A31P MYBPC3 hypertrophic cardiomyopathy cat model.

Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiac disease in cats and lacks efficacious preclinical pharmacologic intervention, prompting investigation of novel therapies. Genetic mutations encoding sarcomeric proteins are implicated in the development of HCM and small molecule myosin inhibitors are an emerging class of therapeutics designed to target the interaction of actin and myosin to alleviate the detrimental effects of inappropriate contractile protein interactions. The purpose of this study was to characterize the pharmacodynamic effects of a single oral dose of the novel cardiac myosin inhibitor aficamten (CK-274) on cardiac function in purpose bred cats with naturally occurring A31P MYBPC3 mutation and a clinical diagnosis of HCM with left ventricular outflow tract obstruction (LVOTO). Five purpose bred cats were treated with aficamten (2mg/kg) or vehicle and echocardiographic evaluations were performed at 0, 6, 24, and 48 h post-dosing. High dose aficamten (2mg/kg) reduced left ventricular fractional shortening (LVFS%) by increasing the LV systolic internal dimension (LVIDs) and reduced isovolumic relaxation time (IVRT) compared with baseline without significant adverse effects. The marked reduction in systolic function and reduced IVRT coupled with an increased heart rate in treated cats, suggest a lower dose may be optimal. Further studies to determine optimal dosing of aficamten are indicated.

P325 CARDIAC SARCOIDOSIS…TYPICAL CLINICAL PRESENTATION

Abstract We report the case of a 50–year–old man without previous medical hystory who was admitted to our department for recurrent syncopes for several months. Throughout the 24 hours ECG Holter it has been underlined several advanced atrioventricular block episodes, hence the patient underwent to definitive pacemaker implant. After 3 months, due to sustained ventricular tachycardia, the patient incurred a out–of–hospital cardiac arrest; the patient was subjeced to cardio pulmonary resuscitation with the restoration of the sinus rithm following defibrillation. Unfortunatly, due to the resuscitation maneuvers, sternal fracture resulted. During the hospitalization in the Cardiology department, he underwent coronary angiography wich showed non significant lesions. Cardiac Magnetic Resonance was also performed among the tests. The examination was found to be particularly hard to understand due to the presence of the sternal injury that deformed the pectus and affected dynamics of the right ventricle, causing systolic bulging of the subtricuspid region of the right ventricular wall. During the dynamic sequences, there was a mild bi–ventricular reduction in systolic function. In post contrast imaging, extended transmural LGE of the basal interventricular septum and right ventricular wall, as well as multifocal involvement of the left ventricle were found. Examination was not of univolcal interpretation: the patient was tranferred to another Center to perform MR PET wich was found to be strongy suggestive of sarcoidosis, later confirmed by extra cardiac biopsy. For this reason an ICD upgrade was performed along side the immunosoppressive therapy. Sarcoidosis is an inflammatory disease characterized by the presence of noncaseous granulomas in one or more organs or tissues; at the cardiac level it can “mimic” different cardiomyopathies as an insidious diagnosis. The presence of a post–traumatic pectus excavatum leads to dyskinesia of the rignt venticular wall, reduction of the bi–ventricular systolic funcion combine with an extensive late enhancement could suggest arrhytmogenic dysplasia with bi–ventricular involvement. However, by focusing on the clinical presentation (in particular the onset charaterized by unexplained advanced AV block in a young and healthy subjet and subsequent ventricular arrhytmias), through a multimodal and multidisciplinary imaging approach it was posible to diagnose sarcoidosis with cardiac involvement and refer the patient to adequate therapy.

309 Upgrading from a dual-chamber pacemaker to a cardiac resynchronization therapy defibrillator in situs inversus totalis with dextrocardia following mitral valve replacement and tricuspid annuloplasty using a left-sided approach

Abstract A 71-year-old female patient was referred to our centre to upgrade a dual-chamber pacemaker to a cardiac resynchronization therapy defibrillator (CRT-D) following the detection of worsened systolic function (ejection fraction: 25–30%) via transthoracic echocardiography. The patient had situs inversus totalis with dextrocardia. She had undergone mitral valve replacement and tricuspid annuloplasty in July 2019, with a concomitant left upper pulmonary lobectomy for neoplasm, detected at cardiac tomography incidentally. In January 2020, we performed an upgrade of the preexisting device to a CRT-D system because the patient developed heart failure, reduction in systolic function, and numerous nonsustained ventricular tachycardias. The right ventricular lead that had been previously implanted was extracted. To facilitate the intervention, we decided to flip the fluoroscopic image, obtained with a right-anterior oblique view, by 180 °C (right–left), creating the optical impression of a levocardial position.

ACUTE RIGHT VENTRICULAR DYSFUNCTION FIXED IN A HEARTBEAT

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Acute right ventricular (RV) dilation is often associated with acute pulmonary embolism (PE) or right-sided myocardial ischemia. Acute RV dilation can lead to RV failure, in which the RV doesn't maintain sufficient blood flow through the pulmonary circulation. Common causes of RV failure include pulmonary arterial hypertension (PAH), COPD, and massive PE. In the ICU, pulmonary vascular disease complicated by insufficient myocardial contractility as well as derangements in excessive preload or afterload can result in changes in cardiopulmonary physiology. Determining the cause of RV decompensation and reversing it is integral in the initial management of RV failure. CASE PRESENTATION: 82-year-old female with no known medical history was admitted to medical service for sepsis secondary to cholecystitis requiring percutaneous cholecystectomy tube placement. She received IV fluids and appropriate antibiotics. On day two of hospitalization, a rapid response was called due to hypoxemia and increased work of breathing. Vital signs were afebrile, BP 88/56, HR 110, RR 26. She was placed on BIPAP and transferred to the ICU. Physical examination findings were significant for decreased breath sounds and 2+ edema in both lower extremities. Laboratory values were significant for elevated troponin 0.242 and BNP 1,000. No evidence of ischemia on EKG. CT angiography (CTA) showed bilateral pleural effusions but did not show evidence of PE. Bedside transthoracic echocardiogram (TTE) showed septal bounce and mild left atrial dilation and hypokinesis. Repeat TTE two days later showed a newly developed severely dilated RV with a severe reduction in systolic function, severely dilated right atrium and dyssynergic ventricular septal motion. Right heart cardiac catheterization confirmed elevated pulmonary artery pressures to 60-65 mmHg. Fluids were stopped, Lasix was given and sepsis was treated. TTE two days later showed marked improvement and near normalization of the RV systolic function. DISCUSSION: The patient's first TTE showed septal bounce consistent with pre-existing RV pressure overload. Acute severe RV dilation combined with hypotension likely represented an acute pulmonary hypertension crisis. The lack of a large PE on CTA ruled out thromboembolic disease for the cause of the acute dilation. RV infarct was unlikely as this would not cause elevated pulmonary artery pressures and elevated pulmonary vascular resistance. RV systolic function was restored once her sepsis was treated and fluids were stopped. It is likely that she had pre-existing primary pathology, such as chronic PAH, which was tipped over by her sepsis. CONCLUSIONS: Our patient manifested with acute RV failure in the setting of her septic physiology. Most cases of RV failure have gradual recovery; however, our case demonstrates an instance of varying RV function with significant rapid improvement in cardiac function. REFERENCE #1: Ventetuolo CE, Klinger JR. Management of acute right ventricular failure in the intensive care unit. Ann Am Thorac Soc. 2014;11(5):811-822. doi:10.1513/AnnalsATS.201312-446FR REFERENCE #2: Acute decompensated pulmonary hypertensionLaurent Savale, Jason Weatherald, Xavier Jaïs, Constance Vuillard, Athénaïs Boucly, Mitja Jevnikar, David Montani, Olaf Mercier, Gerald Simonneau, Elie Fadel, Olivier Sitbon, Marc HumbertEuropean Respiratory Review Dec 2017, 26 (146) 170092; DOI: 10.1183/16000617.0092-2017 REFERENCE #3: Matthews JC, McLaughlin V. Acute right ventricular failure in the setting of acute pulmonary embolism or chronic pulmonary hypertension: a detailed review of the pathophysiology, diagnosis, and management. Curr Cardiol Rev. 2008;4(1):49-59. doi:10.2174/157340308783565384 DISCLOSURES: No relevant relationships by Joseph Bahgat, source=Web Response No relevant relationships by Frantz Hastrup, source=Web Response

The Effects of Propofol on Left Ventricular Global Longitudinal Strain.

To determine if hemodynamic changes secondary to propofol administration are a result of direct myocardial depression as measured by global longitudinal strain (GLS). The authors hypothesized that propofol would cause a significant worsening in GLS, indicating direct myocardial depression. Prospective, observational. Endoscopy suite at a single academic medical center. Patients undergoing outpatient, elective endoscopic procedures at an outpatient clinic of a single tertiary care academic medical center. None. Limited transthoracic echocardiograms were performed before and after patients received propofol for endoscopic procedures. Post-processing measurements included GLS, 2D (dimensional) ejection fraction (2D EF), and 3D EF. Using paired sample Student's t test, no statistically significant change in GLS, 2D EF, or 3D EF was found despite statistically significant hypotension. In fact, there was a trend toward more negative GLS (improved myocardial function) in patients after receiving propofol. We found propofol did not cause a reduction in systolic function as measured by GLS, a sensitive measure of myocardial contractility. Therefore, decreases in blood pressure after a propofol bolus in spontaneously breathing patients are likely due to decreased vascular tone and not impaired left ventricular systolic function. These results should be considered in the management of propofol-induced hypotension for spontaneously breathing patients.

Upgrading from a Dual-chamber Pacemaker to a Cardiac Resynchronization Therapy Defibrillator in Situs Inversus Totalis with Dextrocardia Following Mitral Valve Replacement and Tricuspid Annuloplasty Using a Left-sided Approach

A 71-year-old female patient was referred to our center to upgrade a dual-chamber pacemaker to a cardiac resynchronization therapy defibrillator (CRT-D) following the detection of worsened systolic function (ejection fraction:25%–30%) via transthoracic echocardiography. The patient had situs inversus totalis with dextrocardia. She had undergone mitral valve replacement and tricuspid annuloplasty in July 2019, with a concomitant left upper pulmonary lobectomy for neoplasm, detected at cardiac tomography incidentally. In January 2020, we performed an upgrade of the preexisting device to a CRT-D system because the patient developed heart failure, reduction in systolic function, and numerous nonsustained ventricular tachycardias. The right ventricular lead that had been previously implanted was extracted. To facilitate the intervention, we decided to flip the fluoroscopic image, obtained with a right-anterior oblique view, by 180° (right–left), creating the optical impression of a levocardial position.

Clinical manifestations and gene mutation analysis of children with noncompaction of the ventricular myocardium: an analysis of 6 cases

This article summarizes and analyzes the clinical features and gene mutation characteristics of children with noncompaction of the ventricular myocardium (NVM). For the 6 children with NVM (4 boys and 2 girls), the age of onset ranged from 3 months to 12 years. Of the 6 children, 5 had arrhythmia, 3 had cardiac insufficiency, 1 had poor mental state, and 1 had chest distress and sighing. NVM-related gene mutations were detected in 4 children, among whom 2 had MYH7 gene mutation, 1 had PRDM16 gene mutation, and 1 had mutations in the ACTN2 and TNNT2 genes. Four children had improvement in cardiac function. The two children with no significant improvement in cardiac function had a younger age of onset, a greater reduction in systolic function on echocardiography, and greater increases in myocardial enzyme and N-terminal pro-brain natriuretic peptide. It is concluded that for children with the initial symptoms of chest distress, sighing, arrhythmia, enlarged heart shadow, and increased myocardial enzyme, echocardiography and cardiac magnetic resonance are recommended for the diagnosis of NVM. NVM can have various genetic mutations.

The cardiac impact of cisplatin-based chemotherapy in survivors of testicular cancer: a 30-year follow-up.

AimsCisplatin-based chemotherapy (CBCT) is essential in the treatment of metastatic testicular cancer (TC) but has been associated with long-term risk of cardiovascular morbidity and mortality. Furthermore, cisplatin can be detected in the body decades after treatment. We aimed to evaluate the long-term impact of CBCT on cardiac function and morphology in TC survivors 30 years after treatment.Methods and resultsTC survivors treated with CBCT (1980–94) were recruited from the longitudinal Norwegian Cancer Study in Testicular Cancer Survivors and compared with a control group matched for sex, age, smoking status, and heredity for coronary artery disease. All participants underwent laboratory tests, blood pressure measurement, and 2D and 3D echocardiography including 2D speckle-tracking strain analyses. Ninety-four TC survivors, on average 60 ± 9 years old, received a median cumulative cisplatin dose of 780 mg (IQR 600–800). Compared with controls, TC survivors more frequently used anti-hypertensive (55% vs. 24%, P < 0.001) and lipid-lowering medication (44% vs. 18%, P < 0.001). TC survivors had worse diastolic function parameters with higher E/e′-ratio (9.8 ± 3.2 vs. 7.7 ± 2.5, P < 0.001), longer mitral deceleration time (221 ± 69 vs. 196 ± 57ms, P < 0.01), and higher maximal tricuspid regurgitation velocity (25 ± 7 vs. 21 ± 4 m/s, P = 0.001). The groups did not differ in left or right ventricular systolic function, prevalence of arrhythmias, or valvular heart disease. Cumulative cisplatin dose did not correlate with cardiac parameters.ConclusionNo signs of overt or subclinical reduction in systolic function were identified. Long-term cardiovascular adverse effects three decades after CBCT may be limited to metabolic dysfunction and worse diastolic function in TC survivors.

Abstract 404: Acute Knock-down of Cardiac Peroxisome Proliferator Activated Receptor α Does Not Impair Cardiac Function

Alterations in glucose and fatty acid metabolism are believed to contribute to the development of heart failure. Peroxisome Proliferator Activated Receptor α (PPARα) is a transcription factor that regulates fatty acid metabolism and is frequently reported to be reduced in heart failure. However, it is controversial whether this decline in PPARα mediates the development of cardiac hypertrophy and heart failure. To improve our understanding of the role of cardiac PPARα we generated a tamoxifen inducible cardiac-specific PPARα knockout mouse (cPPAR -/- ). Control (Mer-Cre-Mer and Flox -/- ) mice and cPPAR -/- (Mer-Cre-Mer and Flox +/+ ) mice were treated with tamoxifen at ~2.5 months and were studied 5 weeks after treatment. We verified loss of cardiac PPARα using western blot. cPPAR -/- mice appear healthy with normal body weight gain and survival. To examine the impact of cardiac deletion of PPARα on cardiac function we performed echocardiography on control and cPPAR -/- . There was no reduction in systolic function between control and cPPAR -/- mice. Ejection fraction (Control, 56.3±0.9; cPPAR -/- , 59.7±0.1) and fractional shortening (Control, 29.1±0.5; cPPAR -/- , 31.5±0.1) were similar in cPPAR -/- compared to control hearts. Interestingly however, baseline heart rate was significantly lower in cPPAR -/- versus control mice (Control, 531.3±18.3; cPPAR -/- , 459.8±2.9 bpm). In addition to having normal cardiac function, heart weights were similar between control and cPPAR -/- mice. Overall, these data indicate that an acute reduction in myocardial PPARα per se does not cause cardiac dysfunction. However these data do not exclude the possibility that loss of PPARα could drive cardiac pathology in the context of other signals.

Echocardiographic Findings in Canine Model of Chagas Disease Immunized with DNA Trypanosoma cruzi Genes.

Simple SummaryChagas disease (ChD) has become one of the biggest public-health problems in Latin America due to its incapacitating effects and mortality rates. Therefore, it is important to detect cardiac involvement as early as possible in order to estimate the risk and prognosis before the patient becomes symptomatic. Development of anti-Trypanosoma cruzi vaccines could significantly contribute to the control of ChD. The aim of this study was to examine the usefulness of echocardiography in determining the prophylactic effect of the DNA vaccines on heart damage using T. cruzi genes cloned into an expression vector, which was intramuscularly injected to beagle dogs. Structural and functional changes in the chagasic heart were monitored easily by echocardiography, and it was determined that plasmid DNA vaccination with T. cruzi genes induced moderate protection in immunized dogs avoiding enlargement of cardiac chambers, poor contractibility, and heart failure, especially with pBCSP plasmid (the construct with TcSP gene of T. cruzi, encoding trans-sialidase protein), as was reported previously.Chagas disease (ChD) is considered an emerging disease in the USA and Europe. Trypanosoma cruzi genes encoding a trans-sialidase protein and an amastigote-specific glycoprotein were tested as vaccines in canine model. The aim for this study was determining the prophylactic effect of these genes in experimentally infected dogs by echocardiography evaluation to compare with our findings obtained by other techniques published previously. Low fractional-shortening values of non-vaccinated dogs suggested an impairment in general cardiac function. Low left ventricular ejection fraction values found in infected dogs suggested myocardial injury regardless of whether they were vaccinated. Low left ventricular diastolic/systolic diameters suggested that progressive heart damage or heart dilation could be prevented by DNA vaccination. Systolic peak time was higher in non-vaccinated groups, increasing vulnerability to malignant arrhythmias and sudden death. High left ventricular volume suggested a decrease in wall thickness that might lead to increased size of the heart cavity, except in the pBCSP plasmid-vaccinated dogs. There was an echocardiographic evidence of left ventricular dilation and reduction in systolic function in experimental chagasic dogs. Echocardiography allowed a more complete follow-up of the pathological process in the living patient than with other techniques like electrocardiography, anatomopathology, and histopathology, being the method of choice for characterizing the clinical stages of ChD.

Therapeutic Nrf2 Activation improves LV function in the cardiomyocyte‐specific GPER knockdown mouse

BackgroundThe G protein‐coupled estrogen receptor (GPER) plays an important role in the maintenance of cardiac health partly via its link to anti‐oxidant and anti‐inflammatory pathways. The NLRP3 inflammasome is upregulated in hearts of mice with cardiomyocyte GPER gene deletion, and NLRP3 inhibition limits left ventricle (LV) dysfunction from cardiac GPER deficiency. Studies from others show that GPER mediates the inductive effect of estrogen on the transcription factor nuclear factor erythroid 2‐related factor 2 (Nrf2), the master regulator of detoxification and antioxidant systems. This in vivo animal study was designed to further confirm that lack of GPER signaling (from gene deletion or menopause) impedes Nrf2 activation, and in so doing contributes to ROS accumulation and inflammation in the cardiomyocyte. We hypothesize that chronic Nrf2 activation counteracts the adverse effects of cardiac GPER knockdown on LV function, irrespective of estrogen.MethodsMale GPER KO and WT littermates (7 months of age) were randomized to receive, via drinking water, either 8 weeks of oral treatment with the Nrf2 activator, dimethyl fumarate (KO‐DMF: n=5; WT‐DMF: n=5) at 30mg/kg/day, or its vehicle 0.08% methyl cellulose (KO‐VEH: n=5; WT‐VEH: n=5). At 9 months of age, echocardiographic indices of LV function (isoflurane anesthesia) were obtained prior to sacrifice. Data were analyzed by two‐way ANOVA for gene (GPER), treatment (DMF) and gene x treatment. P&lt;0.05 was considered significant.ResultsSomatic characteristics (e.g. body weight, hair coat appearance) were not overtly affected by GPER knockdown nor DMF treatment. As reported previously, GPER gene deletion led to significant reductions in systolic function (% fractional shortening (FS)), myocardial relaxation (e′) and increases in filling pressure (E/e′) (gene effect: P&lt;0.05). Chronic treatment with the Nrf2 activator significantly attenuated LV systolic dysfunction (treatment effect: P&lt;0.05) and nearly normalized filling pressures (E/e′) in GPER KO without modifying the normal functioning heart of the WT (gene x treatment: P&lt;0.05) (Figure ).ConclusionsThese data suggest that targeting the transcription factor Nrf2 may be a promising strategy to limit LV dysfunction as a result of cardiac oxidative stress and low‐grade inflammation from GPER deactivation (e.g., estrogen loss from ovarian extirpation or menopause).Support or Funding InformationHL051952 (CMF, LG) and AG033727 (LG)Figure 1

P4465Acute Cardio-Selective Functional Modulation via a Small-Molecule Direct Myosin-Attenuator (MYK-581) Preserves Diaphragmatic Function in vivo: Comparison versus Disopyramide

Abstract Background Hypertrophic cardiomyopathy (HCM) is a heritable cardiac disease characterized by hyper-contractility, hindered relaxation, and impaired exercise capacity. Conventional negative inotropes can alleviate enhanced inotropy in HCM, but do not improve ventricular filling and have the potential to further decrease exercise capacity due to their off/on-target systemic effects. Recently, a novel small molecule cardiac-myosin attenuator, Mavacamten, has been shown to normalize hyper-contractility in the setting of HCM. This study evaluated and compared the in vivo functional selectivity of MYK-581, a mavacamten analog, with those of disopyramide (DISO), a commonly-used negative inotrope. Methods In vivo, the acute cardiac (left ventricular pressures) and neuro-muscular (force of diaphragmatic and skeletal muscle contractions) responses to MYK-581 (up to 0.5 mg/kg IV) and DISO (up to 10 mg/kg IV) were simultaneously evaluated using anesthetized and mechanically-ventilated Sprague-Dawley rats; diaphragmatic (both intrinsic and phrenic nerve stimulated) and skeletal contractions (stimulated quadriceps) were measured via strain gauges. Results MYK-581 decreased indices of systolic function (dP/dtmax: −32±2% and vmax: −14±2%, P&lt;0.05 vs. pre-dose) and increased LV EDV (+9±2%, P&lt;0.05), while preserving EDP (6±1 to 6±1 mmHg), suggesting improved ventricular distensibility. Despite these marked cardiac effects, MYK-581 preserved both diaphragmatic (23.7±2.0 to 23.3±2.2 g) and skeletal in situ function (14.9±1.4 to 13.9±0.8 g). In contrast, DISO at matched levels of negative inotropy (dP/dtmax: −25±2% and vmax: −19±2%, P&lt;0.05 vs. pre-dose) depressed diaphragmatic force (−16±3%, 23.8±1.9 to 19.8±1.2 g, P&lt;0.05). Finally, the cardiac selectivity of MYK-581 was confirmed in kinetic experiments evaluating the Ca2+-activated ATPase activity of both cardiac and diaphragmatic myofibrils. Conclusions Direct myosin modulation with MYK-581, a mavacamten analog, is characterized in vivo by reductions in systolic function with preserved filling pressures and improved LV compliance. Moreover, this cardiovascular profile was devoid in vivo of diaphragmatic/skeletal off-target effects that could further hinder exercise capacity in patients with HCM.

Left ventricular remodeling and dysfunction in obstructive sleep apnea : Systematic review and meta-analysis.

BackgroundObstructive sleep apnea syndrome (OSAS) is associated with cardiovascular mortality and morbidity. Several studies have reported that it affects the left ventricle; however, large randomized controlled trials are lacking. The current study aimed to summarize the association between OSAS and left ventricular (LV) structure and function.MethodsElectronic databases (PubMed, Embase, and Cochrane) and references were searched for articles published until March 2018. A systematic review and meta-analysis were performed to assess LV structure and function in OSAS patients based on echocardiography.ResultsIn total, 17 studies with 747 OSAS patients and 426 control participants were included. Patients with OSAS showed an increase in LV diastolic diameter (weighted mean difference [WMD], 95% CI: 1.24 [0.68, 1.80]; p < 0.001), LV systolic diameter (WMD, 95% CI: 1.14 [0.47, 1.81]; p = 0.001), and LV mass (WMD, 95% CI: 35.34 [20.67, 50.00]; p < 0.001). In addition, left ventricular ejection fraction (LVEF) significantly decreased in the OSAS group compared with the controls (WMD, 95% CIs: −1.82 [−2.76, −0.87]; p < 0.001), and the reduction in LVEF was consistent with the severity of OSAS. The OSAS group also showed an increase in left atrial diameter (WMD, 95% CI: 2.13 [1.48, 2.77]; p < 0.001) and left atrial diameter volume index (WMD, 95% CIs: 3.96 [3.32, 4.61]; p < 0.001).ConclusionObstructive sleep apnea syndrome leads to atrial dilatation, left ventricular hypertrophy, enlargement, mass increase and reduction of systolic function. Treatments for OSAS might be beneficial for the preservation of left cardiac structure and function.Electronic supplementary materialThe online version of this article (10.1007/s00059-019-04850-w) contains supplementary material, which is available to authorized users.

FIMASARTAN, AN ANGIOTENSIN II RECEPTOR ANTAGONIST, AMELIORATES AN IN VIVO ZEBRAFISH MODEL OF HEART FAILURE

Objective: Angiotensin II in the failing heart initially helps to maintain cardiac output and blood pressure, but ultimately accelerates its deterioration. In this study, we established an arrhythmia-induced heart failure (HF) model in zebrafish and investigated the role of renin-angiotensin-aldosterone system (RAAS) modulation using an angiotensin II type 1 receptor blocker, fimasartan, by assessing cellular and physiologic responses as well as morbidity and mortality. Design and method: HF was induced by exposure to 20 μM terfenadine in zebrafish larvae. Morphologic, physiologic, and functional parameters were assessed with or without fimasartan pretreatment. Results: Zebrafish exposed to terfenadine showed marked dilation of the ventricle and reduction in systolic function. Treatment with terfenadine was associated with a ten-fold higher expression of atrial natriuretic peptide (p < 0.01 vs. vehicle), increased p53 mRNA expression and chromatin fragmentation by TUNEL assay, all of which were significantly reduced with fimasartan treatment. Moreover, fimasartan improved fractional shortening (FS) (terfenadine + fimasartan 21.7 ± 2.1 % vs. terfenadine + vehicle 8.4 ± 0.7 % vs. vehicle 37.3 ± 2.1 %, p < 0.01). Finally, treatment with fimasartan remarkably reduced mortality (terfenadine + fimasartan 36.0% vs. terfenadine 96.0%, p < 0.01). Conclusions: Fimasartan effectively prevented HF and improved survival in zebrafish. Reduction of apoptotic cell death and improved hemodynamics might be the mechanisms behind these effects. Further human studies are warranted to evaluate the possible role of fimasartan in heart failure treatment.