Improvement In Cardiac Function Research Articles

Injectable hydrogel for co-delivery of 5-azacytidine in zein protein nanoparticles with stem cells for cardiac function restoration

Heart failure is major cause of mortality associated with mostly Myocardial infarction (MI). Transplanting mesenchymal stem cells (MSC) have exhibited potential role in myocardial regeneration. Secretion of immune-modulatory cytokines and various growth factors after transplantation plays significant role in remodelling process of MI region. However, low retention, higher shear stress during administration and rejection at host infarct environment hinders therapeutic efficacy. Myocardial regeneration demands for accurate spatio-temporal delivery of MSCs with supportive vascular network that leads to improvement of cardiac function. In this study, injectable alginate based microporous hydrogel has been used to deliver 5-Azacytidine (5-Aza) in zein protein nanoparticle with MSCs for attenuating adverse cardiac remodelling after MI. Zein nanoparticles loaded with 5-Aza were prepared by liquid–liquid dispersion, and it was found that 35% of drug was released in 7 days supported with mathematical modelling. The presence of 5-Aza and zein in developed hydrogel supported in vitro MSC proliferation, migration and angiogenesis. Significant increased expression of cardiac specific markers, GATA4, MEF2C, MLC, SERCA and NKX2.5 was observed in vitro. 5-Aza loaded protein nanoparticle with MSCs encapsulated hydrogels in rat MI model also exhibited substantial improvement of functional cardiac parameters such as cardiac output and ejection fraction. Histopathological analysis showed reduced fibrosis, attenuated infarct expansion and cardiac tissue restoration and angiogenesis. In brief, we developed nanocarrier-hydrogel system a promising strategy for co-delivering 5-Aza as cardiac differentiation cue with MSCs to achieve higher cell retention and enhanced improvement in myocardial regeneration after MI.

Pheochromocytoma Presenting With Cardiomyopathy in an Otherwise Healthy Young Patient: A Rare Case Report

Background: Pheochromocytomas are rare neuroendocrine tumors. The classic triad of symptoms includes diaphoresis, episodic headache, and tachycardia. Rarely, patients may develop cardiomyopathy associated with pheochromocytoma. It is uncommon for cardiomyopathy to be the initial presenting symptom of pheochromocytoma and can lead to a delayed diagnosis.Clinical Case: The patient is a 30-year old female with no significant medical history who presented with complaints of dyspnea, fever and malaise. The patient had no known prior history of hypertension and did not report complaints of headache, diaphoresis or palpitations. Patient was hypertensive and tachycardic on admission. Upon treatment with intravenous fluids, the patient acutely decompensated and developed respiratory failure requiring emergent intubation. CT of the chest, abdomen and pelvis was performed which showed diffuse bilateral pulmonary edema as well as a circumscribed, heterogeneously enhancing 4.4 cm mass involving the right adrenal gland. An echocardiogram was performed which showed significant left ventricular dysfunction with ejection fraction of 5%. Patient had wide fluctuations in her blood pressure during admission ranging from hypotension to extreme hypertension. She did require the use of epinephrine and milrinone when hypotensive. Due to the use of vasopressors, plasma fractionated metanephrines and 24-hour urine fractionated metanephrines and catecholamines were not recommended to be obtained as these medications may contribute to false positive testing. A dedicated CT of the abdomen with and without contrast was performed to further assess the patient’s right adrenal mass; this revealed a 3.9 x 2.4 x 4.9 cm right adrenal mass with 33% absolute washout and 17% relative washout concerning for pheochromocytoma. The patient underwent an open right adrenalectomy during admission. Surgical pathology results were consistent with a pheochromocytoma measuring 5.2 cm at greatest dimension; the tumor was confined to the adrenal gland and completely excised. Following her surgery, the patient’s clinical status improved significantly over the next several days. She was discharged home in stable condition on hospital day #18. An echocardiogram was repeated 2 months after her hospitalization with ejection fraction improved to 58%.Conclusion: Catecholamine-induced cardiomyopathy in pheochromocytoma is rare, occurring in approximately 8–11% of patients with pheochromocytoma. Cardiomyopathy as the initial presentation of pheochromocytoma is very uncommon. It is important to accurately diagnose pheochromocytoma-related cardiomyopathy as early detection and resection can lead to marked improvement in cardiac function and prevent catastrophic consequences including death.

She Has a Big and Weak Heart

Abstract Background: Acromegaly is a rare clinical syndrome caused by excessive production of growth hormone. The incidence rate is 3 to 4 cases per million people per year. It is a sporadic disease seen in middle-aged adults. Anterior pituitary adenoma secreting the growth hormone (GH) is the most common etiology. Other rare causes include hypothalamic and neuroendocrine tumors. Treatment modalities include surgical, radiotherapeutic and pharmacological with a goal to reduce or remove the tumor, prevent recurrences, and improve comorbidities. The persistent hypersecretion of GH and insulin-like growth factor-1 (IGF-1) leads to an overgrowth in many tissues, including connective tissue, cartilage, bone, skin, and visceral organs. Cardiovascular disease is one of the critical systemic complications resulting in about 60% of the deaths. The cardiovascular manifestations include hypertension, cardiomyopathy (CMP), congestive heart failure, and arrhythmias. Our patient presented with congestive heart failure and dilated CMP in the setting of undiagnosed Acromegaly. Clinical Case: 45 -year old Caucasian lady presented with complaints of worsening shortness of breath, chest tightness, and palpitations for one month. Past medical history includes hypertension, type 2 diabetes mellitus, obesity, and hyperlipidemia. She was diagnosed with dilated CMP in her early 30s, AICD placement seven years ago and normal cardiac catheterization three years ago. On physical exam, she was found to have an enlarged nose and bibasilar crackles. Vitals were stable and proBNP: 4,699 (1-150 pg/ml). ECHO revealed EF of 30-35%, severely dilated left ventricle. Cardiac catheterization showed severely decreased left ventricular systolic dysfunction and elevated LVEDP. Further workup - GH: 16 (<10 ng/ml) and IGF-1: 637 (62 - 205 ng/ml), A1C 13.2%. Pituitary MRI showed a 1.6 cm macroadenoma, extending to the right cavernous sinus border with a deviation of the pituitary stalk to the left. On neurosurgical evaluation, she was considered to be a poor surgical candidate due to her underlying CMP. Currently, she is in the process of getting started on oral octreotide treatment. Conclusion: Cardiovascular disease is the most captious complication and a leading cause of mortality in Acromegaly patients. The subtle clinical presentation results in a diagnostic delay for 5-10 years. A careful review of history and physical examination is vital to identify acromegalic features in non-ischemic DCM. Early diagnosis with prompt treatment has shown improvement in cardiac function and reduced mortality. This case underscores the importance of considering Acromegaly as one of the differentials in patients with dilated cardiomyopathy.

Isolated Knee Extensor Exercise Training Improves Skeletal Muscle Vasodilation, Blood Flow and Functional Capacity in HFpEF Patients

Background Patients with HFpEFexperience severe exercise intolerance due in part to impaired skeletal muscle vascular function during exercise. Whole body exercise interventions yield only modest improvements in cardiac function and functional capacity, and are often not well-tolerated due to severe dyspnea. Therefore, training interventions that isolate smaller muscle groups to improve vascular function may be effective at improving exercise capacity in HFpEF patients while minimizing shortness of breath. Hypothesis Eight weeks of isolated knee extension (KE) exercise training will improve leg blood flow and increase exercise capacity in patients with HFpEF. Methods Nine HFpEF patients (66±5 years, 6 females) performed graded KE exercise (5, 10, and 15W) and maximal aerobic exercise testing (cycle ergometer) before and after 8 weeks of isolated KE training (3x per week, 30 min per leg). Vascular function was assessed by measuring skeletal muscle blood flow (femoral artery ultrasound), mean arterial pressure (ECG-gated sphygmomanometer), and femoral vascular conductance (FVC; index of vasodilation) during graded KE exercise. Functional capacity, quantified as peak pulmonary oxygen uptake (V̇O2, Douglas bags), peak cardiac output (Qc, acetylene rebreathing) and arterial-venous oxygen difference (a-v O2 diff) were measured during a graded maximal cycle exercise to assess cardiac and peripheral adaptations to isolated KE training. Results Eight weeks of isolated KE training lowered blood pressure (Δ: pre: 22±13, post: 12±10.1 mmHg; P=0.02) and improved blood flow (Δ: pre: 950±332, post: 1263±355 ml/min; P=0.02) during 15W isolated KE exercise. The increase in blood flow was due to improved skeletal muscle vasodilation (ΔFVC: pre: 810±417, post: 1234±347 ml/min/100mmHg; P=0.01). During maximal exercise testing, KE training had a small but variable effect on peak Qc (pre: 12.5±3.7, post: 13.2±3.9 l/min; P=0.19), and peripheral oxygen extraction (a-v O2 diff: pre: 10.6±1.8, post: 11.0±1.7 ml/100ml; P=0.17), but resulted in a 13% improvement in peak V̇O2 (pre:12.5±5.5, post: 14.0±6.0; P=0.01). Conclusions Eight weeks of isolated KE training improved skeletal muscle vascular function and blood flow delivery during KE exercise, resulting in improved functional capacity in patients with HFpEF. Exercise interventions aimed at increasing skeletal muscle and vascular function may be effective therapeutic options for HFpEF patients that experience severe dyspnea during whole body exercise.

Effects of Modified Simultaneous Unipolar Saline-Irrigated Radiofrequency Ablation in Patients with Atrial Fibrillation Combined with Mitral Valve Disease.

ObjectiveTo investigate the therapeutic effects of a modified simultaneous unipolar saline-irrigated radiofrequency ablation by intracardiac operation under direct vision in patients with mitral valve diseases combined with atrial fibrillation (AF).MethodsA total of 168 patients with mitral valve diseases combined with AF who underwent unipolar saline-irrigated radiofrequency ablation modified maze procedures were enrolled and divided into the mitral stenosis (MS) group (n = 87) and the mitral insufficiency (MI) group (n = 81).ResultsThose with a left atrium diameter (LAD) < 55 mm had a better cardioversion effect during the mid-term post-operation than those with a LAD ≥ 55 mm (P < 0.05). The cardioversion effect during the mid-term post-operation was better in those with a duration of AF < 2 years than those with AF ≥ 2 years (P < 0.05). The LAD reduced significantly during the early postoperative period in the MS group (P < 0.05). Compared with the early postoperative period, LAD further reduced, and the EF increased significantly during the mid-term post-operation (P<0.05). The LAD reduced significantly during the early postoperative period in the MI group (P < 0.05), together with relatively decreased EF (P < 0.05). Compared with the early postoperative period, LAD further reduced, and the EF increased significantly during the mid-term post-operation (P<0.05). The improvement of LAD in the MI group during the mid-term post-operation was better than that in the MS group (P < 0.05).ConclusionThe cardioversion effects and the improvement in cardiac function during the mid-term post-operation were good in the radiofrequency ablation by intracardiac operation under direct vision in patients with different mitral valve diseases combined with AF. The cardioversion effects during the early postoperative period and the mid-term post-operation were better in patients with MI than in those with MS.

Characterization of cardiac extracellular vesicles upon thiamet G treatment in a rat model of acute decompensated heart failure

Acute decompensated heart failure (ADHF) is characterized by dyspnea, edema and fatigue, as well as a high morbi-mortality. Recently we observed that Thiamet G (TG) exerts protective effects in a rat model of ADHF. Extracellular vesicles (EV) are known to carry key regulatory molecules from cell-to-cell in both the heart and circulation, however, an effective isolation technique specific to cardiac EVs is yet to be discovered. Our goal is to identify cardiac-specific EV markers and to investigate the role of EVs in mediating improvement of ADHF outcomes upon TG treatment. HF was induced in 10 week-old Wistar rats via coronary ligation. Three months later, acute decompensation was induced via NaCl administration in water (1.8 g/kg), followed by injection of 25 mg/kg TG 12 hours later. Rats were sacrificed 12 hours after TG treatment, and their left ventricles (4 TG-treated, 4 untreated ADHF rats) were used to produce unpurified EVs. These EVs were then captured by EVTRAP before LC-MS analysis, followed by proteomic analysis to identify cardiac-specific EV markers and their expression in EV-subtypes. LC-MS performed on left-ventricular EVs of TG-treated and untreated ADHF rats revealed a total of 2362 proteins. In order to identify a common cardiac marker, the most abundant proteins were investigated for tissue-specificity. αB-crystallin (CRYAB) was identified as a potential marker of cardiac EVs. Furthermore, western blots of cardiac tissue-derived EVs revealed the presence of CRYAB in large and small EVs isolated via differential ultracentrifugation, precipitation, and density gradient ultracentrifugation. TG treatment improves cardiac output in a salt-induced experimental model of ADHF. EVs could be an intercellular signalling pathway involved in this improvement of cardiac function, therefore specific isolation of cardiac EVs is imperative for understanding their role in TG-mediated cardiac recovery.

Cell death‐inducing DFFA‐like effector C/CIDEC gene silencing alleviates diabetic cardiomyopathy via upregulating AMPKa phosphorylation

Cell death-inducing DFFA-like effector C (CIDEC) is responsible for metabolic disturbance and insulin resistance, which are considered to be important triggers in the development of diabetic cardiomyopathy (DCM). To investigate whether CIDEC plays a critical role in DCM, DCM rat model was induced by a high-fat diet and a single injection of low-dose streptozotocin (27.5mg/kg). DCM rats showed severe metabolic disturbance, insulin resistance, myocardial hypertrophy, interstitial fibrosis, ectopic lipid deposition, inflammation and cardiac dysfunction, accompanied by CIDEC elevation. With CIDEC gene silencing, the above pathophysiological characteristics were significantly ameliorated accompanied by significant improvements in cardiac function in DCM rats. Enhanced AMP-activated protein kinase (AMPK) α activation was involved in the underlying pathophysiological molecular mechanisms. To further explore the underlying mechanisms that CIDEC facilitated collagen syntheses in vitro, insulin-resistant cardiac fibroblast (CF) model was induced by high glucose (15.5mmol/L) and high insulin (104 μU/mL). We observed that insulin-resistant stimulation dramatically raised CIDEC expression and promoted CIDEC nuclear translocation in CFs. Meanwhile, AMPKα2 was observed to distribute almost completely inside CF nucleus. The results further proved that CIDEC biochemically interacted and co-localized with AMPKα2 rather than AMPKα1 in CF nucleus, which provided a novel mechanism of CIDEC in promoting collagen syntheses. This study suggested that CIDEC gene silencing alleviates DCM via AMPKα signaling both in vivo and in vitro, implicating CIDEC may be a promising target for treatment of human DCM.

Low-volume high-intensity interval training for cardiometabolic health.

High-intensity interval training (HIIT) is characterised by short bouts of high-intensity submaximal exercise interspersed with rest periods. Low-volume HIIT, typically involving less than 15min of high-intensity exercise per session, is being increasingly investigated in healthy and clinical populations due to its time-efficient nature and purported health benefits. The findings from recent trials suggest that low-volume HIIT can induce similar, and at times greater, improvements in cardiorespiratory fitness, glucose control, blood pressure, and cardiac function when compared to more traditional forms of aerobic exercise training including high-volume HIIT and moderate intensity continuous training, despite requiring less time commitment and lower energy expenditure. Although further studies are required to elucidate the precise mechanisms of action, metabolic improvements appear to be driven, in part, by enhanced mitochondrial function and insulin sensitivity, whereas certain cardiovascular improvements are linked to increased left ventricular function as well as greater central and peripheral arterial compliance. Beyond the purported health benefits, low-volume HIIT appears to be safe and well-tolerated in adults, with high rates of reported exercise adherence and low adverse effects.

Hyperbaric oxygen therapy effectively alleviates D-galactose-induced-age-related cardiac dysfunction via attenuating mitochondrial dysfunction in pre-diabetic rats.

Currently, the prevalence of obesity in aging populations is fast growing worldwide. Aging induced by D-galactose (D-gal) is proven to cause the worsening of cardiac dysfunction in pre-diabetic rats via deteriorating cardiac mitochondrial function. Hyperbaric oxygen therapy (HBOT) has been shown to attenuate D-gal-induced cognitive deterioration through decreased inflammation and apoptosis. We tested the hypothesis that HBOT alleviates D-gal induced cardiac dysfunction via improving mitochondrial function in pre-diabetic rats. Wistar rats (n=56) were fed normal diet or high-fat diet for 12 weeks. For subsequent 8 weeks, they were subcutaneously injected either vehicle (0.9% normal saline) or D-gal (150mg/kg/day). Rats were randomly subdivided into 7 groups at week 21: sham-treated (normal diet fed rats with vehicle (NDV), high-fat diet fed rats with vehicle (HFV), normal diet fed rats with D-gal (NDDg), high-fat diet fed rats with D-gal (HFDg)) and HBOT-treated (HFV, NDDg, HFDg). Sham rats received ambient pressure of oxygen while HBOT-treated ones received 100% oxygen given once daily for 60 minutes at 2 atmosphere absolute. HBOT reduced metabolic impairments, mitochondrial dysfunction and increased autophagy, resulting in an improvement of cardiac function in aged pre-diabetic rats.

Omecamtiv mecarbil evokes diastolic dysfunction and leads to periodic electromechanical alternans

Omecamtiv mecarbil (OM) is a promising novel drug for improving cardiac contractility. We tested the therapeutic range of OM and identified previously unrecognized side effects. The Ca2+ sensitivity of isometric force production (pCa50) and force at low Ca2+ levels increased with OM concentration in human permeabilized cardiomyocytes. OM (1 µM) slowed the kinetics of contractions and relaxations and evoked an oscillation between normal and reduced intracellular Ca2+ transients, action potential lengths and contractions in isolated canine cardiomyocytes. Echocardiographic studies and left ventricular pressure–volume analyses demonstrated concentration-dependent improvements in cardiac systolic function at OM concentrations of 600–1200 µg/kg in rats. Administration of OM at a concentration of 1200 µg/kg was associated with hypotension, while doses of 600–1200 µg/kg were associated with the following aspects of diastolic dysfunction: decreases in E/A ratio and the maximal rate of diastolic pressure decrement (dP/dtmin) and increases in isovolumic relaxation time, left atrial diameter, the isovolumic relaxation constant Tau, left ventricular end-diastolic pressure and the slope of the end-diastolic pressure–volume relationship. Moreover, OM 1200 µg/kg frequently evoked transient electromechanical alternans in the rat in vivo in which normal systoles were followed by smaller contractions (and T-wave amplitudes) without major differences on the QRS complexes. Besides improving systolic function, OM evoked diastolic dysfunction and pulsus alternans. The narrow therapeutic window for OM may necessitate the monitoring of additional clinical safety parameters in clinical application.

“CHRYSIN” AMELIORATES CARDIAC HYPERTROPHY IN RATS

Abstract Objective: Cardiac hypertrophy: thickening of cardiac muscle which causes decreased pumping ability of heart, results in cardiac dysfunction. Chrysin, is a naturally occurring flavone, found in bee propolis and honey and possesses anti-oxidant, anti-inflammatory, anti-diabetic, anti-estrogenic, anti-tumour and anti-apoptotic properties. Present study investigates the effect of Chrysin on isoproterenol induced cardiac hypertrophy in male albino wistar rats. Design and method: Male wistar albino rats were divided into eight groups: Group 1 (Control); Group 2 (Isoprotorenol); Group 3; 4; 5 and 6 (Chrysin 15, 30, and 60 mg/kg and 60 mg/kg per se p.o. respectively), Group 7 (Losartan 10 mg/kg; p.o.) and Group 8 (Losartan 10 mg/kg; p.o. + Chrysin 60 mg/kg; p.o.) in which respective compound was given accordingly. ISO (3 mg/ kg; s.c.) was administered daily for 28 days to all groups except normal and per se to induce Cardiac Hypertrophy. On day 29, animals were anesthetized, blood was taken from heart and serum was separated for estimation of cardiac injury parameters and inflammatory cytokines level. Thereafter, rats were sacrificed and heart was isolated and preserved for biochemical, histopathological, ultra-structural, immuno-histochemical and western blot analysis. Results: Chrysin with Losartan treatment of 28 days significantly attenuated cardiac hypertrophy via. decreased cardiac injury markers, inflammatory cytokine, oxidative stress and apoptosis. The combination of Chrysin and Losartan exhibited significant effect to that of Chrysin or Losartan separately. The histopathological, Immunhistochemical and immunoblot analysis showed that the chrysin attenuates cardiac hypertrophy via modulation in MAPK pathways and showing anti-apoptotic effect. The combination of Chrysin and Losartan showed beneficial effect among all groups. Conclusions: Chrysin and Losartan reduce Isoprotorenol- induced cardiac hypertrophy by mitigating oxidative stress, inflammation and apoptosis resulting in improvement of cardiac function, structural changes and antioxidants levels. Chrysin and Losartan in combination attenuated DNA damage or apoptosis and showed best cardio-protection against Cardiac hypertrophy.

SODIUM HYDROGEN SULFIDE IMPROVES RENOVASCULAR HYPERTENSION-INDUCED MALADAPTIVE CARDIAC REMODELING AND DIASTOLIC DYSFUNCTION BY REDUCING OXIDATIVE STRESS AND MMP ACTIVITY

Objective: To evaluate whether treatment with sodium hydrogen sulfide (NaHS) improves cardiac function and remodeling of two kidney-one clip (2K-1C) rats through inhibition of matrix metalloproteinase (MMP) activity and oxidative stress. Design and method: 2K-1C hypertension was surgically induced in male Wistar rats (200 g; ethics commitee #118/2019) by an implantation of a silver clip (0.2 mm) in the left renal artery. Control rats (2K) was submitted to laparotomy. SBP and echocardiograph were registered. The NaHS (0.24 mg/Kg/day; i.p.) treatment or vehicle (0.6% DMSO in saline; i.p.) was initiated in the second week after the surgeries and lasted for 28 days. Hearts were collected and western blotting to MMP-2, Nox2 and Nox4 were performed in the left ventricles. MMPs localization and activity were also evaluated by in situ zymography. Reactive oxygen species (ROS) were investigated by dihydroethidium (10 μM). Data are presented as mean ± S.E.M. of different experimental n. Two-way ANOVA with Bonferroni correction was used (P &lt; 0.05). Results: SBP values of 2K-1C (165.47 ± 3.98mmHg, n = 12) were increased compared to 2K rats (133.28 ± 2.48mmHg, n = 10; P &lt; 0.0001) in the first week after the surgery. NaHS treatment decreased SBP of 2K-1C NaHS (155.60 ± 5.72mmHg, n = 5) compared to 2K-1C vehicle (202.13 ± 5.57mmHg, n = 7; P = 0.0003). Isovolumetric relaxation time analysis showed increases in values from 2K-1C rats (40.31 ± 2.97ms, n = 7) and NaHS treatment (28.04 ± 1.05ms, n = 5) normalized this parameter (P = 0.0018). 2K-1C rats (2.30 ± 0.11 mm, n = 7) presented increased interventricular septum thickness and NaHS treatment (1.99 ± 0.0 mm, n = 5) reduced this parameter (P = 0.028). MMP-2, Nox2 or Nox4 expression was not different in all groups. The gelatinolytic activity of MMPs was higher in 2K-1C vehicle rats (18,029.31 ± 1,225.42U, n = 3) and NaHS (12,092.70 ± 868.22U, n = 3) reduced it (P = 0.021). In 2K-1C rats (33,868.95 ± 2,103.74U, n = 3), ROS were higher compared to control and NaHS treatment (22,019.50 ± 914.08 U, n = 3) decreased this value (P = 0.0021). Conclusions: Our results showed beneficial effects of NaHS treatment in 2K-1C rats, thus leading to SBP decrease, cardiac function improvement and reduction in both MMPs activity and oxidative stress.

CXCR4 ANTAGONIST AMD3100 PROMOTES MILD IMPROVEMENTS OF CARDIAC FUNCTION AND PULMONARY MECHANICS IN PULMONARY HYPERTENSIVE RATS

Background Pulmonary arterial hypertension (PAH) is a lethal cardiopulmonary disease characterized by an increase in resting pulmonary pressure ≥25 mmHg. Poor survival and functional limitations of PAH patients have fueled research for new alternative therapeutic strategies. So far, pre-clinical findings suggested promising effects of stem cell-based therapies. AMD3100 is a highly selective CXCR4 antagonist that enhances autologous bone marrow-derived stem cell mobilization and is currently used in stem cell transplantation and the treatment of leukemia. So far, however, it remains unclear whether AMD3100 can provide salutary effects in the treatment of PAH. Methods PAH was induced in adult male Wistar rats (Protocol number 087/15) by an intraperitoneal injection of monocrotaline (MCT, 60 mg/kg IP), while the Control (CTL) group was treated an equivalent volume of vehicle. Two weeks after the MCT injection, MCT-administered rats were randomly treated with AMD3100 (1 mg/kg/day IP for 14 days) or vehicle, totalling 3 groups: CTL, MCT, and AMD3100. Echocardiography and pneumotachography were used to assess cardiac function and pulmonary mechanics, respectively. Right ventricular (RV) hypertrophy was assessed by the Fulton index. Data were analyzed with One-way and Two-way ANOVA (Prism®, GraphPad) and were expressed as mean ± SEM. Results MCT and AMD3100 groups exhibited an equally progressive decrease in body weight compared to the CTL group (p Conclusion Our study indicates that treatment with AMD3100 provides mild improvement of cardiac and pulmonary function in pulmonary hypertensive rats.

Diastolic Cardiac Function Improvement by Liraglutide Is Mainly Body Weight Reduction Dependent but Independently Contributes to B-Type Natriuretic Peptide Reduction in Patients with Type 2 Diabetes with Preserved Ejection Fraction.

Objectives A single-arm prospective study was conducted among Japanese patients with type 2 diabetes having preserved ejection fraction. The aim was to investigate (1) whether liraglutide therapy could improve B-type natriuretic peptide (BNP) levels and diastolic cardiac function assessed by the E-wave to E′ ratio (E/E′) using transthoracic echocardiography (TTE), and (2) whether E/E′ contributed to BNP improvement independent of bodyweight reduction (UMIN000005565). Methods Patients with type 2 diabetes and left ventricular ejection fraction (LVEF) ≥ 40% without heart failure symptoms were enrolled, and daily injection with liraglutide (0.9 mg) was introduced. Cardiac functions were assessed by TTE before and after 26 weeks of liraglutide treatment. Diastolic cardiac function was defined as septal E/E′ ≥ 13.0. Results Thirty-one patients were analyzed. BNP and E/E′ improved, with BNP levels declining from 36.8 ± 30.5 pg/mL to 26.3 ± 25.9 pg/mL (p = 0.0014) and E/E′ dropping from 12.7 ± 4.7 to 11.0 ± 3.3 (p = 0.0376). The LVEF showed no significant changes. E/E′ improved only in patients with E/E′ ≥ 13.0. Favorable changes in E/E′ were canceled when adjusted for body mass index (BMI). Multivariate linear regression analysis revealed that the left ventricular diastolic diameter and ∆E/E′/∆BMI contributed to ∆BNP/baseline BNP (p = 0.0075, R2 = 0.49264). Conclusions Liraglutide had favorable effects on BNP and E/E′ but not on LVEF. E/E′ improvement was only seen in patients with diastolic cardiac function. Body weight reduction affected the change of E/E′. The BMI-adjusted E/E′ significantly contributed to the relative change of BNP. GLP-1 analog treatment could be considered a therapeutic option against diabetic diastolic cardiac dysfunction regardless of body weight. This trial is registered with the University Hospital Medical Information Network in Japan, with clinical trial registration number: UMIN000005565.

Change in Kidney Function and 2-Year Mortality After Transcatheter Aortic Valve Replacement

Chronic kidney disease (CKD) is prevalent in the population of patients undergoing transcatheter aortic valve replacement (TAVR). Data on the association of TAVR with kidney function are scarce, as are data on the relationship between changes in kidney function after TAVR and mortality. To describe the changes in kidney function (both periprocedural and at steady state) after TAVR and to explore the association of TAVR with midterm mortality. This single-center, retrospective cohort study was conducted at a public, tertiary academic medical center, which serves as a regional referral center for valvular heart interventions. Consecutive cases of patients undergoing TAVR from November 5, 2008, to December 31, 2019, were included in the study, with available baseline and post-TAVR data on kidney function. Steady state (1 month) change in kidney function after TAVR. Significant improvement or deterioration in renal function was defined as a greater than or equal to 10% change in estimated glomerular filtration rate (eGFR). Overall mortality at 2-year follow-up. A total of 894 patients (mean [SD] age, 82.2 [7.1] years; 452 women ([51.2%]) were evaluated. A total of 362 patients (40.5%) were treated from 2017 to 2019, 348 patients (38.9%) were treated from 2013 to 2016, and 184 patients (20.5%) were treated from 2008 and 2012. Patients had a mean (SD) Society of Thoracic Surgeons (STS) score of 5.2% (4.0%) and a mean (SD) eGFR of 65.1 (23.1) mL/min/1.73 m2. Acute kidney injury occurred in 115 (11.1%) patients by 48 hours, of whom 73 (63.5%) resolved by discharge. One month after TAVR, eGFR improved by at least 10% in 329 patients (36.8%) and deteriorated by at least 10% in 233 patients (26.1%). Overall, CKD stage remained stable or improved in 720 patients (80.6%), and only 5 patients (0.97%) progressed to stage 5 CKD 1 month after TAVR. A deterioration of 10% or greater in eGFR 1 month after TAVR was associated with a hazard ratio of 2.16 (95% CI, 1.24-5.24; P = .04) at 2-year mortality. Patients who showed CKD status resolution (eGFR improvement to >60 mL/min/1.73 m2 after TAVR) had a similar 2-year mortality to those with baseline eGFR greater than 60 mL/min/1.73 m2 and vice versa. Factors associated with steady state CKD status resolution after TAVR included lower STS score, higher left ventricular ejection fraction, higher baseline eGFR, no acute kidney injury at discharge from the TAVR admission, and lower contrast-eGFR ratio. In this cohort study, kidney outcomes after TAVR were reassuring; greater than 80% of patients showed stable or improved kidney function 1 month after the procedure. Improvement in kidney function was associated with a lower 2-year mortality, whereas deterioration in kidney function was associated with increased mortality. Our data suggest that cardiorenal syndrome was a possible cause of CKD in patients in need of TAVR and that there was potential for improvement in both renal and cardiac function after this procedure.

Puerarin pretreatment inhibits myocardial apoptosis and improves cardiac function in rats after acute myocardial infarction through the PI3K/Akt signaling pathway.

Puerarin demonstrates a protective effect in many cardiovascular diseases. However, the role of puerarin in acute myocardial infarction (AMI)-induced injury and the exact molecular mechanisms are not fully understood. To investigate whether puerarin pretreatment improves cardiac function and to study the mechanism of action of puerarin. Thirty rats were grouped into sham group, AMI group and AMI+puerarin (PUE) group at random (n = 10 per group). Except for the sham group, a model of AMI was established via left anterior descending artery ligation. The PUE group received puerarin 120 mg/(kg × day) for 7 days before the operation. Echocardiography was used for evaluation of cardiac function in rats and TUNEL staining for measuring myocardial apoptosis. The expression levels of p-PI3K, t-Akt, p-Akt, Bax, Bcl-2, and cleaved caspase-3 proteins were measured with western blot. Compared to the sham group, the AMI group demonstrated poor cardiac function and decreased p-PI3K, p-Akt and Bcl-2 proteins levels, while Bax, cleaved caspase-3, and myocardial apoptosis levels increased. Compared with the AMI group, the PUE group showed significant improvement in cardiac function and increased protein expression of p-PI3K, p-Akt and Bcl-2, while Bax and cleaved caspase-3 levels decreased and myocardial apoptosis was attenuated. Puerarin pretreatment in AMI can effectively improve cardiac function by inhibiting myocardial apoptosis. The molecular mechanism of this protective effect may be mediated by activating the PI3K/Akt pathway in cardiomyocytes.

Pyridostigmine improves cardiac function and rhythmicity through RyR2 stabilization and inhibition of STIM1-mediated calcium entry in heart failure.

Heart failure (HF) is characterized by asymmetrical autonomic balance. Treatments to restore parasympathetic activity in human heart failure trials have shown beneficial effects. However, mechanisms of parasympathetic‐mediated improvement in cardiac function remain unclear. The present study examined the effects and underpinning mechanisms of chronic treatment with the cholinesterase inhibitor, pyridostigmine (PYR), in pressure overload HF induced by transverse aortic constriction (TAC) in mice. TAC mice exhibited characteristic adverse structural (left ventricular hypertrophy) and functional remodelling (reduced ejection fraction, altered myocyte calcium (Ca) handling, increased arrhythmogenesis) with enhanced predisposition to arrhythmogenic aberrant sarcoplasmic reticulum (SR) Ca release, cardiac ryanodine receptor (RyR2) hyper‐phosphorylation and up‐regulated store‐operated Ca entry (SOCE). PYR treatment resulted in improved cardiac contractile performance and rhythmic activity relative to untreated TAC mice. Chronic PYR treatment inhibited altered intracellular Ca handling by alleviating aberrant Ca release and diminishing pathologically enhanced SOCE in TAC myocytes. At the molecular level, these PYR‐induced changes in Ca handling were associated with reductions of pathologically enhanced phosphorylation of RyR2 serine‐2814 and STIM1 expression in HF myocytes. These results suggest that chronic cholinergic augmentation alleviates HF via normalization of both canonical RyR2‐mediated SR Ca release and non‐canonical hypertrophic Ca signaling via STIM1‐dependent SOCE.

Transplantation of Neonatal Mouse Cardiac Macrophages into Adult Mice.

In an injured neonatal myocardium, macrophages facilitate cardiomyocyte proliferation and angiogenesis and promote heart regeneration. The present study reveals that transplantation of neonatal cardiac macrophages recruited by injury promotes adult heart regeneration after myocardial infarction with improvement of cardiac function and cardiomyocyte proliferation. The results indicate that neonatal cardiac macrophage transplantation could be a promising strategy for cardiac injury treatment. Here, we provide the technical details, including the isolation of neonatal cardiac macrophages from apical resection-injured neonatal mouse hearts, the transplantation of macrophages into myocardial-infarcted adult mice, and the estimation of heart regeneration after a macrophage graft.

Sheehan Syndrome Leading to Acute Systolic and Diastolic Heart Failure: A Case Report

Introduction Endocrinopathies involving the pituitary gland, thyroid gland, parathyroid glands, or adrenal glands cause reversible cardiomyopathies. Sheehan's syndrome, a rare post-partum cause of multiple simultaneous endocrinopathies, leading to cardiomyopathy is rare. We present a young woman with newly diagnosed Sheehan Syndrome, untreated for 6 years, leading to profound combined systolic and diastolic heart failure. Case Report A 28-year-old woman presented with history of hypothyroidism presented with weakness, cold intolerance, nausea, and vomiting. She was found to have hypotension, hypoglycemia, and hypothermia. Her AM cortisol and ACTH were low, concerning for a non-primary adrenal insufficiency. She noted that after her last pregnancy 6 years prior, she had amenorrhea, hair loss, fatigue, and facial swelling. She denied a history of post-partum hemorrhage or severe blood loss. But, an MRI of her brain showed she had flattening of her anterior pituitary, consistent with a partially empty sella. Records showed that she was first diagnosed combined systolic and diastolic heart failure (with an ejection fraction of 25%) of unknown origin 2 years prior. Another transthoracic echocardiogram was ordered, and revealed severe combined systolic and diastolic cardiomyopathy with an ejection fraction of 10%. Her heart failure was attributed to her panhypopituitarism. She was treated with hydrocortisone and levothyroxine for hormone replacement. She was treated with diuretics, digoxin, and an ACE inhibitor for her heart failure. Summary Panhypopituitarism leading to heart failure is rare. In panhypopituitarism, cardiac abnormalities have been attributed to growth hormone deficiency, hypothyroidism, and corticosteroid deficiency. In hypocortisolism, the pathophysiology is not completely understood and LV dysfunction rarely occurs. Hypothyroidism, most notably from the deficiency in T3, results in bradycardia, decreased myocardial contractility, and increased systemic peripheral resistance. Improvement of cardiac function has been noted with treatment of these deficiencies. Increased awareness that Sheehan's syndrome may lead to dilated cardiomyopathy can lead to increased diagnosis and treatment of this reversible cardiomyopathy.

Deferoxamine as a Treatment for Cardiac Siderosis Induced Cardiomyopathy Post Liver Transplantation

Introduction Iron overload cardiomyopathy (CM) occurring after liver transplantation in the absence of preexisting myocardial dysfunction or severe hepatic iron overload (ie hemochromatosis) has been described post-mortem. Cardiac siderosis without primary iron overload syndromes was found to be positively correlated to both higher pretransplant transferrin saturation (TSAT) and transfusion of red blood cells. We report an unusual case of a patient with alcohol-induced cirrhosis and heterozygous C282Y mutation who developed a dilated CM post-liver transplant with confirmed cardiac siderosis treated with IV deferoxamine leading to improvement in cardiac function. Case Report A 47-year-old woman with alcohol-induced cirrhosis underwent liver transplantation with a normal pre-operative cardiac evaluation including a transthoracic echocardiogram (TTE) with left ventricular ejection fraction (LVEF) 55-60%. Pre-operative iron studies showed an iron saturation of 91% with ferritin of 156. Her post-op course was uncomplicated, receiving minimal blood products (4 units of packed red blood cells). Two months later she was hospitalized for dyspnea and large pleural effusions. TTE showed depressed LVEF 17%. A cardiac MRI demonstrated a severely dilated LV indexed to BSA (1.5) with severe myocardial siderosis indicated by decreased T2* of 9-14 ms as well as significant mid-wall myocardial fibrosis. Right heart catheterization demonstrated a normal right atrial pressure, wedge pressure 18 mmHg, mean pulmonary pressure 26 mmHg and Fick cardiac index of 2.02 L/min/m2 for which milrinone was initiated. Endomyocardial biopsy confirmed intramyocardial iron deposition and native liver biopsy had grade 2-3 iron deposition. Etiology of her CM post-transplant was attributed to HFE gene heterozygosity in the setting of cirrhosis with post-transplant iron sensitivity (hepcidin depletion). She was initiated on IV chelation therapy with deferoxamine with follow up CMRI showing improved cardiac siderosis indicated by T2* of 13-17 ms with RV function 41% from 20% and LV function 25% from 17%. She was weaned off milrinone and continued on weekly deferoxamine chelation sessions. Summary This case highlights an unusual cause of cardiac siderosis related cardiomyopathy post-liver transplantation treated with IV iron chelation therapy leading to partial LV/RV recovery.