Dilated Left Ventricle Research Articles

TRIM35-mediated degradation of nuclear PKM2 destabilizes GATA4/6 and induces P53 in cardiomyocytes to promote heart failure.

Pyruvate kinase M2 (PKM2) is a glycolytic enzyme that translocates to the nucleus to regulate transcription factors in different tissues or pathologic states. Although studied extensively in cancer, its biological role in the heart remains unresolved. PKM1 is more abundant than the PKM2 isoform in cardiomyocytes, and thus, we speculated that PKM2 is not genetically redundant to PKM1 and may be critical in regulating cardiomyocyte-specific transcription factors important for cardiac survival. Here, we showed that nuclear PKM2 (S37P-PKM2) in cardiomyocytes interacts with prosurvival and proapoptotic transcription factors, including GATA4, GATA6, and P53. Cardiomyocyte-specific PKM2-deficient mice (Pkm2 Mut Cre+) developed age-dependent dilated cardiac dysfunction and had decreased amounts of GATA4 and GATA6 (GATA4/6) but increased amounts of P53 compared to Control Cre+hearts. Nuclear PKM2 prevented caspase-1-dependent cleavage and degradation of GATA4/6 while also providing a molecular platform for MDM2-mediated reduction of P53. In a preclinical heart failure mouse model, nuclear PKM2 and GATA4/6 were decreased, whereas P53 was increased in cardiomyocytes. Loss of nuclear PKM2 was ubiquitination dependent and associated with the induction of the E3 ubiquitin ligase TRIM35. In mice, cardiomyocyte-specific TRIM35 overexpression resulted in decreased S37P-PKM2 and GATA4/6 along with increased P53 in cardiomyocytes compared to littermate controls and similar cardiac dysfunction to Pkm2 Mut Cre+mice. In patients with dilated left ventricles, increase in TRIM35 was associated with decreased S37P-PKM2 and GATA4/6 and increased P53. This study supports a previously unrecognized role for PKM2 as a molecular platform that mediates cell signaling events essential for cardiac survival.

PSAT006 Two Cases of Pheochromocytoma Associated Takotsubo Syndrome- Importance of Early Recognition and Treatment

Abstract Introduction Pheochromocytoma is a rare catecholamine producing adrenal medullary tumor that classically presents with hypertension. Takutsubo cardiomyopathy (TC) is a rare but increasingly recognized presentation of pheochromocytoma. We present two cases of TC likely caused by pheochromocytoma. Case 1 A 60 y/o male who presented with acute onset nausea, vomiting and abdominal pain. Systolic BP was 150-160 mm Hg, and diastolic BP was 100 mmHg. Troponin was elevated (4.15 ng/ml; nl = 0-0.04). An echocardiogram showed a reduced left ventricular ejection fraction (LVEF) of 15-20% (nl = 50-75%), a mildly dilated left ventricle, and apical ballooning suggestive of TC. Coronary arteries were normal on cardiac catheterization. CT scan identified a 5.3×5.6×5.7 cm adrenal mass of 50 HU pre-contrast. Further evaluation revealed markedly elevated plasma metanephrine concentration of 858 pg/ml (nl<57) and normetanpehrine concentration of 1729 pg/ml (<148). His presentation was strongly suggestive of pheochromocytoma associated TC. He was prepared for surgery with doxazosin 2 mg twice daily followed by metoprolol succinate and metyrosine up to 500 mg/d. Final pathology revealed a 5.3 cm left pheochromocytoma with negative surgical margins. Germline genetic testing was negative for pheochromocytoma/paraganglioma pathogenic gene mutations, and an MIBG scan did not reveal metastatic disease. Echocardiogram one month after adrenalectomy showed a marked improvement in LVEF to 55-60% with no regional wall motion abnormalities, and plasma metanephrine concentrations normalized. Case 2 A 61 y/o female smoker with type 2 diabetes mellitus, hypertension, Graves disease and obesity presented with sudden onset of nausea followed by chest discomfort, bilateral shoulder discomfort and shortness of breath. Troponin was 0.6 ng/ml (nl = 0-0.04), EKG showed ST elevations in leads I, 2, V5 V6 with hyperacute T waves. Coronary arteries were normal on catheterization. She required intubation, and systolic BP ranged from 110 to 200 mm Hg. On echocardiogram the LVEF was 35% to 40% (nl = 50-75), and there was diffuse hypokinesis of the mid to apical LV myocardium with hypercontractility of the LV base, suggestive of TC. The plasma metanephrine concentration was 3.31 nmol/l (nl= 0-0.49), and normetanephrine concentration was 5.02 nmol/l (nl= 0-0.89). CT imaging revealed a 2.9 cm left adrenal mass. She underwent successful left adrenalectomy after preparation with alpha, beta blockade and metyrosine. Germline genetic testing was negative for pheochromocytoma/paraganglioma pathogenic gene mutations . Echocardiogram nine months post-adrenalectomy showed normal EF of 50-55% and resolution of apical hypokinesis. Discussion We present two pheochromocytoma patients presenting with TC that reversed following appropriate pheochromocytoma management. Few case series report the association of pheochromocytoma and TC. These patients usually present acutely without prodromal stressors commonly found with classic TC. Conclusion In the setting of TC, pheochromocytoma should be considered. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

LBSAT63 Cushing Syndrome As A Presentation Of Adrenocortical Carcinoma.Case Report

Abstract Introduction adrenocortical carcinoma is a rare endocrine malignancy (1) Case: 44 year old afro American female with no past medical history. No regular medications. Amenorrhea for 2 years. smokes cigarettes. Irrelevant family history. She presented with itchiness after cat scratch and was found to have hypertension urgency 229/123. Review of systems was positive for weight gain and easy bruises. Physical examination alert and oriented with body mass index of 31 kg/m2 heart rate 75 beats per minute normal heart sounds and clear lungs with scratch marks on left hand. bilateral lower extremities pitting edema, supraclavicular fat pad and violet abdominal striae. No facial plethora or hirsutism or lymphadenopathy or acne. Laboratory work up was remarkable for hypokalemia and metabolic alkalosis. High plasma morning cortisol level 53.6ug/dl normal between 6.2 and 29, 24hour urine cortisol and DHEAS and low ACTH FSH and LH. Estradiol 261pg/ml 17hydroxyprogesterone 49ng/dl and prolactin 31.7ng/ml. HBA1C 6.7. Normal renin aldosterone TSH and plasma and 24hour metanephrine and normetanephrine. Normal creatinine liver function and complete blood count. CT abdomen and pelvis with contrast showed large lobular heterogeneously enhancing mass in the left adrenal gland of 9. 0×10.1×10.1cm with left kidney posterior displacement and left renal vein compression. The pancreatic tail and splenic vein were draped over the mass. The right adrenal gland and other abdominal organs were unremarkable. DEXA scan showed osteopenia. CT chest showed 5mm right lower lobe nodule and compression fracture in the 7th thoracic vertebrae. Echocardiogram showed dilated left ventricle dimension with reduced ejection fraction 45%. The diagnosis was made for ACTH independent Cushing syndrome with adrenal mass. She underwent open left adrenalectomy distal pancreatectomy splenectomy and left nephrectomy in another institution. Histopathology showed 12×7.5×7 cm stage III adrenal cortical malignancy T3N0M0. Extensive necrosis and capsular invasion but negative surgical margins. Possibility of lung metastasis. Postoperative cortisol level 6. 02ug/dl. She was kept on postoperative slow tapering hydrocortisone with plan of chemotherapy and Mitotane. Conclusion adrenocortical carcinoma has a poor prognosis. It usually metastasizes to distant organs at time of diagnosis and rarely presents as Cushing syndrome. Surgical resection is the main management of localized tumors with controlling the effects of secreted hormones. Adjuvant therapies are chemotherapy radiotherapy and Mitotane according to the tumor stage and size. Mitotane is adrenal cytotoxic agent showed increase survival of advanced stages(1).

Preliminary Data on Echocardiographic Evaluation and Serum Taurine Concentration in Healthy Dogs of Two Breeds (10 Golden Retrievers and 12 German Shorthaired Pointers) with Different Predispositions to Nutritional Dilated Cardiomyopathy: A Pilot Study.

Dilated cardiomyopathy (DCM) is the most common myocardial disorder in dogs, and it is primarily considered to be an inherited or genetic disease with a higher prevalence in specific breeds such as Doberman Pinschers and Great Danes. Recently, several publications have reported concerns about cases of DCM in unusual breeds (Golden Retrievers-GRs) and associated them with specific diets (grain-free, high in pulses or potatoes, or low in taurine and amino acid precursors). Because taurine is involved in the digestion and absorption of fat and liposoluble vitamins, including vitamin D, the aims of this pilot study were: (1) to compare serum taurine and serum vitamin D (both implicated in cardiac function and absorbed from food) between healthy GRs and German Shorthaired Pointers (GSPs), breeds with different predispositions to nutritional DCM; (2) to highlight the differences between the echocardiographic variables in the two breeds; and (3) to evaluate the associations between the serum taurine and vitamin D concentrations and the echocardiographic features. Ten Golden Retrievers and twelve German Shorthaired Pointers were enrolled for complete hematobiochemical analyses, cardiac examinations, and serum taurine and vitamin D evaluations. The serum taurine concentrations were significantly lower in the GR dogs than in GSPs. All GRs were clinically healthy, but some echocardiographic variables, such as the sphericity index (related to left ventricle dilatation) as well as the end-systolic volume index and fractional shortening (both related to left ventricle systolic function), were different from the published reference ranges.

ОПЫТ НАБЛЮДЕНИЯ ДЕТЕЙ С КАВАСАКИ-ПОДОБНЫМ (МУЛЬТИСИСТЕМНЫМ ВОСПАЛИТЕЛЬНЫМ) СИНДРОМОМ В ВОСТОЧНО-СИБИРСКОМ РЕГИОНЕ РОССИИ

The pathogenetic basis for Pediatric Multisystem Inflammatory Syndrome (PMIS) associated with SARS-CoV-2 is systemic vasculitis resulting from hyperproduction of pro-inflammatory cytokines associated with dysregulation of the immune response. Clinical manifestations of PMIS include fever with features of Kawasaki Syndrome (KS) and multi-organ dysfunction coupled with frequent unusual heart involvement, ranging from mild with minimal ECG changes or elevated troponin to fulminant myocarditis or Takotsubo syndrome (TTS). The purpose of the research was to study the characteristics of cardiovascular disorders in Kawasaki-like multisystem inflammatory syndrome associated with COVID-19 in children observed in the East Siberian area of Russia. A single-center retrospective cohort study was carried out on the basis of the Irkutsk Oblast Regional Children's Clinical Hospital (Irkutsk, Russia): 36 patients with PMIS associated with COVID-19 in Nov. 18, 2020 - Dec. 31, 2021, including 21 boys (M/F ratio 1.4:1) at the average age of 7.5 years old (1.5 months to 17 years old). The diagnostic signs of KS were observed in 34 (94%) children, including the complete set of diagnostic signs in 21 (58%). Refractory fever and a sharp increase in inflammatory biomarkers were detected in all 36 (100%) children; multiorgan dysfunction in 31 (86%); thrombocytopenia in 24 (67%); gastrointestinal syndrome in 25 (69%); cerebral dysfunction in 24 (66)%; various cardiovascular disorders in 30 (83%), including: dilatation of the left ventricle (LV) and a decrease in myocardial contractility in 3 (8%); moderate coronary dilatation in 5 (14%); thickening of the posterior LV walls in diastole in 5 (13%); thickening of the interventricular septum in diastole in 6 (16%). According to the MRI results performed in 15 children the signs of myocardial damage were found in 6 (40%). LV dilatation and decreased myocardial contractility were noted in 3 (8%) children, clinically apparent thrombotic complications in 3 (8%) children as well, and severe neurological deficit in one patient (3%). An increase in the level of D-dimer was observed in 26 (72%) patients, thrombocytopenia in 24 (67%), a statistically significant correlation between thrombocytopenia and myocardial damage was found (R=-0.506, p=0.001). The treatment measures were given as follows: inotropic support (dobutrex/dobutamine) was received by 8 (22%), artificial lung ventilation - by 8 (22%), intravenous human immunoglobulin 1.5-2.0 g/kg/course - by 28 (77%), dexamethasone - by 24 (67%), tocilizumab - by 2 (5%) patients. All 36 (100%) patients have survived. Conclusion: the Kawasaki-like multisystem inflammatory syndrome associated with COVID-19 was accompanied by the cardiovascular disorders (pericarditis, arrhythmias, abnormal ECG changes, elevated troponin and/or natriuretic peptide, LV thickening on echocardiography, coronary dilatation) in most patients, although LV dilatation and decreased myocardial contractility were observed in a few cases only. A negative correlation between thrombocytopenia and myocardial damage was found, which may indicate the involvement of thrombotic microvascular inflammation in the genesis of myocardial disorders.

Peripartum Cardiomyopathy Due to Gestational Hypertension and Tocolytic Therapy

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a rare and sometimes fatal systolic heart failure that affects women during late pregnancy or the early postpartum period. The risk factors contributing to this condition are advanced maternal age, multiparity, administration of tocolytic agents, underlying cardiac disease, iatrogenic volume overload, preeclampsia, and hypertension. In patients with gestational hypertension (GH) and other risk factors, close monitoring is mandatory during pregnancy as well as in the postpartum period. CASE REPORT: A 38-year-old patient previously treated for endometriosis, infertility, and GH was transferred from the clinic of gynecology due to diagnosed congestive heart failure. 5 days before admission, she gave birth to her first child. Before delivery, she was treated with tocolytic therapy. She received methyldopa due to GH which was abruptly discontinued after her delivery. Echocardiography on admission revealed moderately reduced left ventricular (LV) systolic function with an ejection fraction (EF) of 37% with dilated left ventricle (LV) and pulmonary artery hypertension secondary to LV failure. During hospitalization, the patient was with signs of volume overload, but with a good response on parenteral diuretic therapy. She was additionally treated with guideline-recommended heart failure therapy. The controlled echocardiography showed improvement of LV function with an EF of 42%. CONCLUSION: PPCM is a rare condition with high morbidity and mortality. An LVEF <30%, marked LV dilatation, LV end-diastolic diameter >6.0 cm, and RV involvement are associated with adverse outcomes. Although delivery of the fetus and the placenta triggers the resolution of symptoms and recovery to the nonpregnant state of various organisms, the contrary happens with blood pressure. Its peak time is 3–6 days after delivery. Hypertension medication must not be immediately terminated. Prolonged tocolytic therapy is a risk factor for PPCM due to causing decreased baroreflex sensitivity. Patients with risk factors should be closely monitored for eventual cardiac complications.

Cardiac resynchronization therapy in treatment of a non-ischemic cardiomyopathy patient with massive left ventricular thrombus

Rationale: Left ventricular thrombosis is a severe and potentially fatal complication of cardiomyopathies with reduced ejection fraction. The mainstay of treatment is anticoagulation, with variable response to thrombus resolution. In patients with reduced ejection fraction and left bundle branch block, cardiac electrical resynchronization is established as a very effective therapy, leading to improvement in left ventricular function. Patient concerns: We present the case of a 64-year-old male with non-ischemic cardiomyopathy with severely reduced ejection fraction and left bundle branch block, who was implanted with a dual-chamber pacemaker in 2018 for sick sinus node disease and who was admitted for progressive shortness of breath. Diagnosis: Echocardiography showed a dilated left ventricle with a severely reduced ejection fraction (15%) and a massive left intraventricular thrombus. Interventions: The patient was started on anticoagulant and heart failure therapy without any response in thrombus size, so as a last resort measure, cardiac resynchronization therapy was added. Outcomes: The 6-month echocardiography follow-up showed a significant improvement in left ventricular function and complete thrombus resolution. Lesson: Cardiac resynchronization therapy promotes reverse remodeling and improves the contraction sequence in the left ventricle, thus eliminating the triggers for thrombosis and aiding in thrombus resolution.

The impact of residual mitral regurgitation on outcomes in patients with primary mitral regurgitation undergoing mitral valve transcatheter edge-to-edge repair

Abstract Background Mitral valve transcatheter edge-to-edge repair (M-TEER) has become an established therapeutic approach for patients at high surgical risk with relevant mitral regurgitation (MR). While robust data exists on the impact on outcome of residual MR (rMR) following M-TEER for patients with secondary MR, data on the exact role of rMR in primary MR is currently scarce. This study aimed to investigate the adverse impact of relevant rMR on outcomes in a real-world population of patients undergoing M-TEER for primary MR. Methods This single-center, retrospective analysis includes data from 364 consecutive patients with relevant primary MR treated by M-TEER at a high-volume center between 11/2008–01/2020. Post-procedural rMR was defined as the MR grade determined by transthoracic echocardiography before discharge. Primary endpoint was defined as all-cause mortality; the composite secondary endpoint included all-cause mortality or rehospitalization for heart failure at 1-year follow-up. Kaplan-Meier estimates and Cox regression analysis were performed to study the impact of rMR on outcomes. Results In this high-risk population (mean age 78.6±7.4 years, 55.2% male, median logistic EuroSCORE 17.5% [interquartile range 10.4; 27.7], median STS Score 4.4% [interquartile range 2.8; 6.6]), rMR at discharge was successfully reduced to none/mild (≤1+) in 191 (52.5%) patients. Moderate rMR (=2+) was found in 129 (35.4%) patients and moderate-to-severe or severe rMR (≥3+) was present in 44 (12.1%) patients post-procedurally. Patients with rMR≥3+ presented with enlarged left atria at baseline (left atrium volume: rMR≤1+: 101.8ml [interquartile range (IQR): 77.3, 129.6]; rMR=2+: 113.7ml [IQR: 90.4, 154.3]; rMR≥3+: 123.0ml [IQR: 92.9, 147.5]; p=0.009) and dilated left ventricle (left ventricle end-diastolic diameter: rMR≤1+: 54.8±8.7mm; rMR=2+: 59.7±9.8mm; rMR≥3+: 59.1±10.0mm; p<0.001). Baseline NT-proBNP was significantly higher in patients with relevant post-precedural rMR (≥3+) compared to patients with none/mild or moderate rMR (p=0.038). Kaplan-Meier analyses demonstrate significant differences for the primary and secondary endpoints (Figure 1). Compared to patients with none/mild and moderate rMR, higher rates of all-cause mortality were reported in patients with rMR≥3+ at 1-year follow-up (rMR≤1+: 16.2%; rMR=2+: 23.9%; rMR≥3+: 40.0%; p[log-rank] = 0.007). Moreover, adjusted cox regression analysis identified rMR≥3+ as an independent predictor of adverse outcome (Hazard Ratio = 2.70 [95%-confidence interval: 1.12–6.50]; p=0.027). Conclusions Our data provides first evidence that clinical outcome in patients with primary MR undergoing M-TEER is impacted by the grade of post-procedural rMR. This analysis, therefore, emphasizes the importance of minimizing rMR to the lowest possible grade in order to achieve optimal long-term survival. Funding Acknowledgement Type of funding sources: None.

Cardiac magnetic resonance patterns of left ventricular hypertrophy in aortic stenosis patients

Abstract Background Left ventricular (LV) hypertrophy is a known compensatory mechanism to pressure overload in aortic stenosis (AS) patients. However, by cardiac magnetic resonance (CMR) different patterns of LV adaptation are seen in this group of patients. Aim To describe the patterns of LV adaptation (by CMR) and to analyze its structure and function indexes in AS patients referred for surgical aortic valve replacement (AVR). Methods We prospectively studied 134 consecutive patients (age: 73y [IQR 68–77y], 49% men) with severe symptomatic AS - mean transaortic pressure gradient (AVmean): 61±1.5 mmHg; mean aortic valve area: AVA): 0.7±0.1 cm2, referred for surgical AVR with no previous history of ischemic cardiomyopathy or other. All patients underwent electrocardiogram, 2D transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR) before surgery for LV assessment and tissue characterization. Five patterns of LV structure were considered: normal ventricular structure (normal LV mass/volume ratio [M/V], normal LVMi and normal indexed LV end-diastolic volume (LVEDVi); concentric remodeling: increased M/V, normal LVMi; concentric hypertrophy: increased M/V and LVMi; eccentric hypertrophy: increased LVMi and LVEDVi, normal M/V and ejection fraction; and adverse remodeling: dilated left ventricle, increased LVMi and normal M/V in the context of an impaired ejection fraction. Echocardiogram and CMR structural and functional indexes were compared between these groups. Results At baseline study, at CMR: mean LV indexed mass [LVMi]: 80.3±26.5 g/m2; mean end-diastolic LV indexed volume [LVEDVi]: 84.4±24.5 mL/m2 and median geometric remodeling ratio [M/V]: 0.95 g/mL [IQR 0. 81–1.08 g/mL]. Overall, 22% patients had normal LV structure, 30% concentric remodeling ventricular geometry, and two patients had an adverse remodeling pattern. LV hypertrophy was the most prevalent pattern and occurred in 48% of subjects (concentric 43%; eccentric 4%). In our cohort, the severity of AS (AVmean (p<0.001), LV function (LV ejection fraction [p<0.001] and Global longitudinal strain [p<0.001]), LV loading conditions (indexed left atrial volume [p<0.001] and E/e' ratio [p<0.001]) and NT-proBNP (p<0.001) were related to the pattern of LV structure (Table 1). Conclusions In our cohort, AS patients presented several distinct patterns of LV remodeling. Disease severity, functional repercussion and loading conditions are distinct between them. Funding Acknowledgement Type of funding sources: None.

Pressure overload and volume overload-induced chronic heart failure are associated with characteristic left ventricular myocardial proteomic alterations

Abstract Introduction Hemodynamic overload induces pathological remodeling of the left ventricle (LV) and eventually heart failure (HF). The two types of chronic hemodynamic stress, namely pressure overload (PO) and volume overload (VO) evoke characteristically different functional and structural alterations in the myocardium. Nevertheless, whether PO- and VO-induced HF are also associated with distinct LV proteomic alterations has not been investigated yet. Aim Hence, we thought to perform a proteomic analysis on LV myocardial samples from rat models of PO- and VO-induced HF. Methods PO–induced HF was evoked by transverse aortic constriction (TAC). VO–induced HF was established by creating an aortocaval fistula (ACF). Age-matched sham-operated animals served as controls for TAC (ShamT) and ACF (ShamA), respectively. Pressure-volume (P-V) analysis, echocardiography, histology and quantitative real-time PCR were carried out to provide a detailed characterization of the two HF models. Peptides obtained via the digestion of myocardial proteins with trypsin and LysC were labeled with isobaric tags (TMT16) and measured with LC-MS/MS in a bottom-up explorative proteomic approach. Differential expression and gene ontology enrichment analysis (GO:BP) was carried out on summarized protein reporter ion intensities. Results In both the TAC and ACF groups, presence of typical signs and symptoms of HF (dyspnea at rest, fatigue, ascites) increased lung-to-tibial length ratio and elevated LV natriuretic peptide mRNA expression levels confirmed the development of advanced HF. Furthermore, the TAC model was associated with massive wall thickening, concentric LV hypertrophy (LVH), marked interstitial fibrosis and substantially impaired active relaxation and passive filling (slope of end-diastolic P-V relationship: 0.103±0.015 vs. 0.023±0.003mmHg/μl, TAC vs. ShamT, P<0.001). In contrast, the ACF model was predominantly characterized by LV dilatation, eccentric LVH, moderate fibrosis and severely reduced LV contractility (slope of end-systolic P-V relationship: 0.5±0.1 vs. 2.3±0.3mmHg/μl, ACF vs. ShamA, P<0.001). Proteomic analysis revealed that out of the 4691 identified and quantified proteins, 1404 and 913 have shown upregulation, while 1359 and 886 downregulation in the TAC and ACF groups respectively compared to their corresponding sham groups. GO:BP analysis has indicated that the downregulation of mitochondrion organization, ATP metabolic processes and oxidative phosphorylation and the upregulation of actin cytoskeleton organization were the most profound alterations in the TAC model. In contrast, the ACF model was associated with robust downregulation of fatty acid oxidation and upregulation of endocytosis, defense and immune response on the proteomic level. Conclusions PO and VO-induced advanced HF are not only associated with characteristically different functional and structural remodeling but also with distinct LV proteomic alterations. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Office (NKFIH) of Hungary

Influence of long-term sodium-glucose cotransporter 2 inhibition on cardiac remodeling in rats with type 1 diabetes mellitus

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. However, as most clinical trials were performed in type 2 DM, the effects of SGLT2 inhibitors in patients with type 1 DM still need further clarification. In this study, we evaluated the effects of long-term treatment with the SGLT2 inhibitor dapagliflozin on cardiac remodeling, myocardial function, and energy metabolism in rats with type 1 DM. Methods Male Wistar rats were divided into three groups: control (C, n=15); DM (n=15); and DM treated with dapagliflozin (DM+DAPA, n=15) for 30 weeks. DM was induced by streptozotocin; DAPA was added to the rat chow (5 mg/kg/day). Cardiac performance was evaluated by echocardiogram and myocardial function in isolated left ventricular (LV) papillary muscle preparations. Myocardial energy metabolism enzyme activities were evaluated by spectrophotometry. Statistical analyzes: ANOVA and Tukey or Kruskal-Wallis and Dunn. Results DM+DAPA had lower glycemia than DM [C 112 (108–116); DM 531 (522–535)*; DM+DAPA 267 (179–339) mg/dL; p<0.05 vs C and DM+DAPA]. Echocardiogram showed that DM and DM+DAPA had left atrium and left ventricle dilatation with systolic and diastolic dysfunction; in DM+DAPA, the changes were attenuated in relation to DM. Developed tension and +dT/dt were higher in DM+DAPA than DM in basal condition. After inotropic stimulation with post-pause contraction, extracellular calcium concentration elevation, and isoproterenol addition to the nutrient solution, +dT/dt and –dT/dt were higher in DM+DAPA than DM. Hexokinase, phosphofructokinase, and pyruvate kinase activity was lower in DM than the C. Phosphofructokinase and pyruvate kinase activity was higher in DM+DAPA than DM. Conclusion Long-term dapagliflozin treatment attenuates cardiac remodeling and myocardial dysfunction and preserves hexokinase, phosphofructokinase and pyruvate kinase activity in rats with type 1 diabetes mellitus. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): CNPq - National Council for Scientific and Technological Developmentdoctor

Effects of resistance exercise in the cardiac remodeling of myocardial infarction rats

Abstract Introduction Exercise is an important therapeutic strategy for heart failure (HF). However, the myocardial effects of resistance exercise during HF are not completely understood. In this study, we investigated the influence of resistance exercise on cardiac remodeling and molecular myocardial changes of rats with myocardial infarction (MI)-induced HF. Methods Three months after MI induction or simulated surgery, Wistar rats were divided into three groups: Sham (n=14); MI (n=9); and MI subjected to resistance exercise (MI-R, n=13). Exercised rats trained 3 times a week during 12 weeks performing four climbs in a ladder with progressive loads. Cardiac structure and left ventricular function were assessed by echocardiogram. Myocyte diameters were measured in histological sections. Energy metabolism, lipid hydroperoxide, antioxidant enzymes activity, malondialdehyde, and protein carbonylation were evaluated by spectrophotometry. NADPH oxidase subunits (Nox2, Nox4, p22phox and p47phox) gene expression was assessed by RT-PCR. Statistical analysis: ANOVA and Tukey test or Dunn's test. Results Mortality did not differ between MI-R and MI groups. MI-R and MI presented dilated left atrium and left ventricle with systolic and diastolic dysfunction. Exercise improved maximum carrying load with no changes in cardiac structure or left ventricle function. Myocyte diameter was lower in MI than Sham and MI-R. Lactate dehydrogenase and creatine kinase activities were lower in MI than Sham. Activity of citrate synthase and catalase was lower in MI and MI-R than Sham. Lipid hydroperoxide concentration was lower in MI-R than MI. Nox2 and p22phox gene expression was higher in MI-R than Sham. Gene expression of Nox4 was higher in both infarcted groups and gene expression of p47phox was lower in MI than Sham. Conclusion Resistance exercise is safe and well tolerated by infarcted rats. Exercise increases maximum carrying load and reduces myocardial oxidative stress with no changes in cardiac structure or left ventricle function of infarcted rats. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): CNPq - National Council for Scientific and Technological Development

The impact of elite endurance activity on cardiac remodelling in asians: an echocardiographic case control study

Abstract Background Prolonged endurance training results in physiological changes to elite athletes' hearts. These changes include thickened left ventricular (LV) walls and dilated left and right ventricles that may overlap with those from pathological conditions such as hypertrophic cardiomyopathy, dilated cardiomyopathy and arrhythmogenic cardiomyopathy. While reference ranges for elite black and white athletes have been published to facilitate differentiation of physiology from pathology, data on Asian athletes remains scarce. With increasing Asian representation in international sport, it is important to ascertain the extent of physiological cardiac remodelling in Asian athletes. Purpose This study aimed to compare echocardiographic parameters of elite endurance athletes (EAs) and non-endurance controls and describe reference ranges in this population of Asian athletes. Methods Consecutive elite athletes engaging in endurance sport were identified from the Singapore Sports Cardiology Registry from January to October 2018. Controls were obtained from 3 sources: (a) skill-based athletes from the Singapore Sports Cardiology Registry, (b) healthy non-athletic volunteers from a national atrial fibrillation registry, and (c) healthy non-athletic volunteers from a national heart failure registry. All participants underwent resting two-dimensional, M-mode and Doppler transthoracic echocardiography and findings from EA were compared with controls. Results 165 participants (55 EAs, 110 controls) were analysed (median age 29 years, male gender n=95; 58%, Chinese ethnicity n=55 for EAs; 100%) Baseline characteristics between both groups were comparable (Table 1). EAs had larger LV wall thickness (9.2 vs. 8.1 mm, p<0.001), LV cavity size (50.7 vs. 48.2 mm, p<0.001), LV mass index (98.4 vs. 73.8 g/m2, p<0.001), aortic root diameter at sinus of Valsalva (30.6 vs. 28.9 mm, p<0.01), right ventricular dimensions and biatrial volumes compared to controls (Table 2). Similar results were noted after indexing to body surface area. These associations also persisted after adjusting for age. Conclusion(s) Endurance activity in elite Singaporean Chinese athletes was associated with significant structural and functional cardiac remodeling compared to controls. Reference ranges for echocardiographic parameters in this population were described, allowing for more accuracy when differentiating physiology from pathology in Asian athletes. Funding Acknowledgement Type of funding sources: None.

OCCULT NONCOMPACTION CARDIOMYOPATHY LEADING TO CARDIOGENIC SHOCK: AN INFREQUENT YET DEADLY DIAGNOSIS

OCCULT NONCOMPACTION CARDIOMYOPATHY LEADING TO CARDIOGENIC SHOCK: AN INFREQUENT YET DEADLY DIAGNOSIS

NO2 exposure contributes to cardiac hypertrophy in male mice through apoptosis signaling pathways

Nitrogen dioxide (NO2) is one of the most common indoor and outdoor air pollutants. Inhalation of NO2 is associated with an increased risk of health problems, especially cardiovascular diseases. However, the underlying pathogenic mechanisms still remain unclear. In this study, we exposed C57BL/6J mice to NO2 (2.5 ppm, 5 h/d) for 28 days and found that NO2 inhalation induced cardiac dysfunction in male mice, but not in female mice, including left ventricular dilation and cardiac systolic dysfunction. Pathological staining showed that NO2 inhalation induced eccentric hypertrophy with enlarged individual cardiomyocytes, dilated left ventricle, and thinning of the left ventricular wall in male mice. The transcriptional analysis suggested that NO2 exposure could disrupt Ca2+ homeostasis, actin cytoskeletal reorganization, myocardial contractility, and vascular dilation in male mice. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that differentially expressed genes (DEGs) were closely associated with the apoptotic signaling pathways. These findings suggested that NO2 exposure caused cardiac eccentric hypertrophy and cardiac dysfunction through apoptotic signaling pathways, and contributed to cardiotoxicity.

Assessment of clinical, paraclinical characteristics of patients receiving concomitant mitral and aortic valve replacement with On-X mechanical prosthesis at Bach Mai Hospital

Objectives: To investigate clinical and paraclinical characteristics of patients undergoing concomitant mitral and aortic valve replacement with On-X mechanical valve at Bach Mai Hospital. Subjects and methods: This was a non-controlled, prospective, descriptive study on 100 patients with severe aortic and mitral diseases undergoing concomitant aortic and mitral valve replacement with On-X valve. Clinical and paraclinical parameters were selected based on Vietnam National Heart Association and ACC/AHA guidelines. Results: Clinical manifestations included history of rheumatic heart disease (70.0%), NYHA class II (36.0%), NYHA class III (64.0%), atrial fibrillation (67.0%). Echocardiography showed dilated left ventricle (LVEDd 55.2 ± 8.9 mm, LVEDs 37.3 ± 8.1 mm), preserved left ventricular ejection fraction (63.9 ± 9.5%), moderately pulmonary arterial hypertension (47.2 ± 13.8 mmHg), and dilated left atrium (53.8 ± 10.5 mm). Conclusion: Most patients undergoing concomitant On-X aortic and mitral prosthetic valve replacement presented with moderate and severe heart failure, dilated left ventricle and left atrium, and increased pulmonary arterial pressure.
 * Keywords: Mitral and aortic valve replacement; On-X valve.

The leaflet-annulus index in canine myxomatous mitral valve disease

Myxomatous mitral valve disease (MMVD) is the most common chronic heart valve disease, leading to the eccentric hypertrophy. Recently, the leaflet-annulus index (LAI), which focuses on the mitral valve apparatus, has been considered a prognostic factor for human mitral regurgitation (MR); however, it has not been reported in veterinary medicine. In the present study, we retrospectively evaluated the LAI in dogs with MMVD. Eight-three dogs with MMVD diagnosed using echocardiography were included in this study. The anteroposterior length, anterior and posterior cusp coaptation lengths, LAI, left ventricular end-diastolic internal diameter normalized to body weight (LVIDDN), and left atrium to aorta ratio (LA/Ao) were measured. A significant correlation between the LAI, LVIDDN, and LA/Ao of MR grading, and left ventricle dilation was observed. In conclusion, LAI could help determine annular widening, suggesting the decision of an appropriate for SVR in clinical settings.

Echocardiography in the Diagnosis of Cardiomyopathies: Current Status and Future Directions.

Cardiomyopathies are a challenging pathology and echocardiography is essential for diagnosis and prognosis. The most frequent cardiomyopathies are the dilated cardiomyopathy (DCM) and the hypertrophic cardiomyopathy (HCM), followed by the less frequent restrictive (RCM) and arrhythmogenic right ventricle cardiomyopathies (ARVC). Echocardiography can identify diagnostic features, and guide further testing for a definitive diagnosis. Echographic parameters are involved in risk score computing and prognosis assessment. While the most prevalent hallmark of HCM is the asymmetric left ventricular hypertrophy and systolic anterior motion of the mitral valve with the obstructive phenotype, DCM shows dilated left ventricle with different degrees of systolic dysfunction, and RCM is usually characterized by undilated ventricles associated with atrial enlargement. The aim of this review is to display and compare the most frequent cardiomyopathies encountered in clinical practice and highlight their most characteristic features in a useful way for the practicing clinician.

Doxycycline Attenuates Doxorubicin-Induced Cardiotoxicity by Improving Myocardial Energy Metabolism in Rats.

Aim: Evaluate the influence of doxycycline, an anti-inflammatory and matrix metalloproteinase (MMP) inhibitor, on the attenuation of chronic doxorubicin-induced cardiotoxicity in rats. Methods: We allocated male Wistar rats into four groups: control (C), doxorubicin (D), doxycycline (inhibitor of MMP, IM), and Dox + doxycycline (DIM). Groups IM and DIM received doxycycline (5 mg/kg, IP) once a week for 4 weeks. In addition, 48 h after every doxycycline injection, groups D and DIM received Dox (5 mg/kg, IP). We performed echocardiogram and evaluated TIMP-4 and collagen I protein expression, MMP-2 activity, and oxidative stress and myocardial metabolism. Results: Doxorubicin promotes left atrium (LA) and left ventricle (LV) dilatation and decreases in LV fractional shortening, which was improved by doxycycline. Moreover, doxycycline attenuated the LV cardiomyocyte hypertrophy and collagen type I expression. Doxorubicin increased phosphofructokinase and decreased beta-hydroxyacyl Co-A dehydrogenase, pyruvate dehydrogenase, citrate synthase, and ATP synthase activity, which was partially attenuated by doxycycline. Lastly, doxycycline improved antioxidant enzyme activity in the DIM group. Conclusion: Doxorubicin increases oxidative stress and promotes changes in myocardial energy metabolism, accompanied by structural and functional changes. Doxycycline attenuated the doxorubicin-induced cardiotoxicity, at least in part, through changes in myocardial energy metabolism.

Sodium nitroprusside in acute heart failure: A multicenter historic cohort study

AimsDespite evidence of hemodynamic benefit of sodium nitroprusside (SNP) treatment for acute heart failure (AHF), there are limited data about its efficacy and safety. This study aimed to assess the effectiveness and safety of SNP treatment, to explore the impact of N-terminal pro-B natriuretic peptide (NT-proBNP) reduction on clinical endpoints and to identify possible predictors of clinical response. Methods and resultsMulticenter retrospective cohort study of 200 patients consecutively admitted for AHF in 2 Italian Centers. Primary endpoint was the reduction of NT-proBNP levels ≥25% from baseline values within 48 h from the onset of SNP infusion. Secondary and safety endpoints included all-cause mortality, rehospitalization for HF at 1, 3 and 6 months, length of hospital stay (LOS) and severe hypotension. 131 (66%) patients experienced a NT-proBNP reduction ≥25% within 48 h from treatment onset, irrespective of initial systolic blood pressure (SBP). Left ventricular end diastolic diameter (LVEDD) was the only independent predictor of treatment efficacy. Patients who achieved the primary endpoint (i.e., ‘responders’) had lower LOS (median 15 [IQR:10–27] vs 19 [IQR:12–35] days, p-value = 0.033) and a lower incidence of all-cause mortality and rehospitalization for HF at 1 and 3 months compared to “non responders” (p-value <0.050). Severe hypotension was observed in 10 (5%) patients, without any adverse clinical consequence. ConclusionSNP is a safe and effective treatment of AHF, particularly in patients with dilated left ventricle. Reduced NT-proBNP levels in response to SNP is associated to shorter LOS and lower risk of 1- and 3-month re-hospitalizations for HF.Clinical trial registration.http://www.clinicaltrials.gov. Unique identifier: NCT05027360