Cardiac Organ Research Articles

Extent of iron induced organ damage in patients with hematological disorders.

Objective: To determine the extent of iron induced organ damage in patients of Haematological disorders who are transfusion dependent, presenting in the emergency department of SZH, Lahore. Study Design: Cross Sectional study. Setting: Department of Emergency, Shaikh Zayed Hospital, Lahore. Period: December 25, 2020 to June 24, 2021. Methods: A total of 100 patients aged 10-60 years, of both genders, diagnosed with haematological disorders, and receiving multiple blood transfusions were included in this study. Demographic details were noted including name, age, sex, diagnosis, duration of receiving transfusions and number of transfusions received per month. Patients were evaluated clinically for organ damage including pulmonary, hepatic, renal, and cardiac organs using Denver MOF score. Results: Mean age of patients was 35.33±14.27 years. Mean duration of receiving transfusion was 6.69±2.71 months. There were 67 (67%) males and 33 (33%) female patients. Primary diagnosis was Autoimmune Haemolytic Anemia (AIHA) in 18 (18.00%) patients, Aplastic anemia in 34 (34%) patients, Thalassemia in 37 (37%) patients and Myelodysplastic syndrome (MDS) in 11 (11%) patients. Multiple organ damage was found in 23 (23%) patients. Pulmonary damage was diagnosed in 21 (21%) patients, hepatic damage in 21 (21 %) patients, renal damage in 20 (20%) patients and cardiac damage in 15 (15%) patients. Conclusion: There is a high frequency of multi-organ damage in patients of Haematological disorders requiring chronic blood transfusions. In this study, multi-organ damage was diagnosed in 23% patients requiring chronic blood transfusion.

Early minimal residual disease eradication in light chain amyloidosis generates deeper and faster cardiac response

Minimal residual disease (MRD) is of growing interest in light chain (AL) amyloidosis and is associated with higher rates of cardiac response. A new graded cardiac response criteria has been proposed for better assessment of cardiac improvement. We evaluated MRD status in 63 patients with cardiac AL amyloidosis using next generation flow cytometry (sensitivity ≥ 1*10–5) within four cycles after treatment initiation and cardiac response kinetics. All patients were treated with first-line proteasome inhibitor (100%) and predominantly bortezomib (87.3%). The overall early MRD negative rates were 33.3%. Patients who achieved early MRD negativity were less likely to harbor t(11;14) (21.1% vs 57.5%, P = 0.009). The MRD negative rates amongst patients in hematologic complete response were 66.7% (14/21), and in very good partial response 29.2% (7/24). Early MRD negativity was associated with a higher likelihood of achieving ≥ cardiac partial response (≥ CarPR) (66.7% vs 38.1%, P = 0.032) and ≥ cardiac very good partial response (≥ CarVGPR) (38.1% vs 11.9%, P = 0.023) throughout first-line therapy. The cumulative incidence curve of achieving ≥ CarPR (P = 0.034) and ≥ CarVGPR (P = 0.026) showed significant difference between early MRD negative and positive group. After a median follow-up time of 27.2 months, the median progression free survival was longer in early MRD negative group (not reached vs 31.3 months, P = 0.033). Early MRD eradication in cardiac AL amyloidosis generated deeper and faster cardiac organ response.

Out-of-hospital cardiac arrest in patients with psoriasis

Abstract Background Psoriasis is a complex autoinflammatory disease that has been associated with atherosclerosis, higher risks of cardiovascular diseases, and electrocardiographic changes. Whether these risk factors lead to higher risks of out-of-hospital cardiac arrest (OHCA) is undetermined. Purpose To investigate whether psoriasis is associated with OHCA. Method Using the nationwide Danish Cardiac Arrest Registry, we identified adult (≥18 years) OHCA patients of presumed cardiac cause with and without psoriasis between June 1st 2001 and December 31st 2019. The association of cardiac arrest was estimated using time-varying Cox regression fitted with a nested case-control design where we matched up to five controls per case on age, sex and year of OHCA and 4 comorbidities: ischemic heart disease, congestive heart failure, cardiovascular risk factors, and major extra cardiac organ disease. In subgroup analyses, the main analysis was repeated in patients with severe psoriasis (presence of inpatient hospital contact during the previous year) as compared to mild psoriasis. Results We included 43,967 OHCA cases and matched with 219,772 controls from the general population. The median age was 72 years, 68% were male and 26% had ischemic heart disease, 21% had congestive heart failure, 57% had cardiovascular risk factors, and 33% had extra cardiac organ disease (Table 1). We identified 1,145 (2.6%) cases and 4,971 (2.3%) controls who had psoriasis. Compared with cardiac arrest cases without psoriasis, cases with psoriasis had similar age and sex distribution, prevalence of ischemic heart disease, and congestive heart failure, but a higher prevalence of cardiovascular risk factors, major extra cardiac organ disease and Charlson score distribution. Psoriasis was significantly associated with higher hazard ratios of OHCA: HR 1.16 [95% confidence interval: 1.08 - 1.23] (Figure 1). Compared to no psoriasis, having severe psoriasis was significantly associated with higher hazard of OHCA: HR 1.98 [95% confidence interval: 1.10 - 3.61], while mild psoriasis was not (Figure 1). Conclusion In this nationwide nested case-control study, psoriasis was significantly associated with increased hazard of out-of-hospital cardiac arrest. Furthermore, the association was only significant with severe psoriasis compared to those without psoriasis, while mild psoriasis was not. This study highlights the importance of examining cardiovascular risk factors and prioritizing prevention of cardiovascular disease in patients with psoriasis.Figure 1Table 1

Long-term changes in cardiac geometry and mechanics after bariatric surgery- insights from the FatWest study

Abstract Background Patients with severe obesity have a high prevalence of subclinical cardiac organ damage including impaired longitudinal and radial cardiac mechanics. Previous studies on the impact of bariatric surgery on cardiac remodeling, most of them with short patient follow-up, have yielded inconsistent results. Purpose To assess progressive changes in cardiac geometry and mechanics up to five years following bariatric surgery. Methods In the prospective Bariatric Surgery on the West Coast of Norway (FatWest) study, cardiac remodeling was assessed by 2D echocardiography preoperatively and at six months, one year and five years after Roux-en-Y gastric bypass in a cohort of 97 patients (44±10 years, 72% women, body mass index [BMI] 41.8±4.8 kg/m²). Excess weight loss (EWL) was calculated as: absolute weight loss/(initial weight-ideal weight)x100. Left ventricular (LV) size was assessed by the LV mass/ height^2.7, LV longitudinal mechanics by the peak global longitudinal strain (GLS) and radial mechanics by the midwall shortening (MWS). LV myocardial oxygen demand was estimated from the LV mass-wall stress-heart rate product. Right ventricular diameter was measured in the basal one-third of the ventricular cavity. Left atrial (LA) reservoir function was assessed by the LA emptying fraction. Results After a mean follow-up of 63±13 months, the average postoperative EWL was 66%. Overall, both right ventricular diameter, LV mass index, LV GLS, myocardial oxygen demand and LAEF (68% vs. 64%) improved significantly at the 5-year follow-up (all p<0.05), while MWS remained unchanged (Figure). Prevalence of normal LV geometry increased gradually from 56% to 80%, while that of LV hypertrophy fell from 36% to 16% (p<0.001). Analyses of temporal trends showed that improvement in BMI, LV mass and LV GLS occurred during the first postoperative year (Figure). In Cox regression analysis, a low 5-year GLS was associated with preoperative hypertension after adjustment for age, sex, preoperative diabetes mellitus, and postoperative changes in BMI, mean blood pressure and myocardial oxygen demand (p<0.01). In a similar linear model, after adjustment for the same covariates, LV mass index at the 5-year follow-up was independently related to the magnitude of the postoperative BMI reduction (R² = 0.58, p<0.001). Conclusion Ventricular size and longitudinal mechanics are significantly improved 5 years after bariatric surgery, with the reverse remodeling occurring during the first postoperative year. Residual abnormal 5-year LV geometry and mechanics are related to preoperative hypertension and suboptimal BMI reduction.Figure

DNA methylation inhibitors adverse reaction characteristic analysis: a descriptive analysis from WHO-VigiAccess.

DNA methylation inhibitors (azacitidine, decitabine) have revolutionized the treatment dilemma of myelodysplastic syndromes (MDS), a group of malignant hematopoietic disorders. This study evaluates the adverse drug reactions (ADRs) following the use of DNA methylation inhibitors in the World Health Organization (WHO) VigiAccess database and compares the characteristics of ADRs between the two drugs to select the drug with the minimum individualized risk for patients. This study employed a retrospective descriptive analysis method. We compiled ADR reports for two marketed DNA methylation inhibitors for the treatment of MDS from WHO-VigiAccess. Data collected included demographic data such as age groups, gender, and regions of global patients covered by ADR reports, as well as data on the disease systems and symptoms caused by ADRs recorded in the annual reports and reports received by WHO. By calculating the proportion of ADRs reported for each drug, we compared the similarities and differences in ADRs between the two drugs. Overall, 23,763 adverse events (AEs) related to the two DNA methylation inhibitors were reported in VigiAccess. The results showed that the top 10 most common AEs were febrile neutropenia, bone marrow suppression, neutropenia, anemia, pancytopenia, leukopenia, thrombocytopenia, bone marrow failure, agranulocytosis, and hematotoxicity. The top five common types of DNA methylation inhibitor AEs were blood and lymphatic system disorders (11,178 cases, 47.0%), cardiac organ diseases (1,488 cases, 6.3%), various congenital familial genetic diseases (49 cases, 0.2%), ear and labyrinth diseases (100, 4.2%), and endocrine system diseases (57, 2.4%). There is no Strong correlation between DNA methylation inhibitors and ADRs. Current comparative observational studies of these inhibitors show that there are common and specific adverse reactions in the ADR reports received by WHO for these drugs. Clinicians should improve the rational use of these drugs based on the characteristics of ADRs.

Ambulatory Blood Pressure Phenotypes, Arterial Stiffness And Cardiac Remodelling.

Evidence on the association of arterial stiffness and left ventricular (LV) concentric remodelling/ LVH assessed by echocardiography, with abnormal blood pressure (BP) phenotypes, defined by office and ambulatory BP monitoring (ABPM) in the community is scanty. We investigated this issue in the participants to the Pressioni Monitorate E Loro Associazioni (PAMELA) study. The study included 491 participants who attended the second and third survey of the PAMELA study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, blood examinations, office, ABPM, echocardiographic and Cardio-Ankle Vascular Index (CAVI) measurements. In the whole study sample (age 66+10 years, 50% males), the prevalence rates of sustained normotension (NT), white coat hypertension (WCH), masked hypertension (MH), sustained hypertension (SH) and non-dipping (ND) were 31.2, 10.0, 24.2, 34.6, and 35.8% and respectively. The likelihood of having SH, the BP phenotype carrying the greatest CV risk, was four times higher (OR= 4.31, CI:2.39-7.76, p<0.0001) in participants with increased CAVI and LV remodelling/LVH compared to their counterparts without organ damage. This association showed an incremental value in discriminating SH compared to both isolated markers of organ damage (OR=1.92,p=0.03 for increased CAVI and OR= 2.02, p=0.02 for LV remodelling/LVH). The presence of isolated but also combined organ damage was unrelated to ND. Our study provides new evidence of the incremental value of looking for both vascular and cardiac organ damage to optimize the identification and clinical management of SH in the general population.

Optimized new Shengmai powder inhibits myocardial fibrosis in heart failure by regulating the rat sarcoma/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular regulated protein kinases signaling pathway.

Exploring the effect of Optimized New Shengmai powder (, ONSMP) on myocardial fibrosis in heart failure (HF) based on rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular regulated protein kinases (ERK) signaling pathway. Randomized 70 Sprague-Dawley rats into sham (n = 10) and operation (n = 60) groups, then established the HF rat by ligating the left anterior descending branch of the coronary artery. We randomly divided the operation group rats into the model, ONSMP [including low (L), medium (M), and high (H) dose], and enalapril groups. After the 4-week drug intervention, echocardiography examines the cardiac function and calculates the ratios of the whole/left heart to the rat's body weight. Finally, we observed the degree of myocardial fibrosis by pathological sections, determined myocardium collagen (COL) I and COL Ⅲ content by enzyme-linked immunosorbent assay, detected the mRNA levels of COL I, COL Ⅲ, α-smooth muscle actin (α-SMA), and c-Fos proto-oncogene (c-Fos) by universal real-time, and detected the protein expression of p-RAS, p-RAF, p-MEK1/2, p-ERK1/2, p-ETS-like-1 transcription factor (p-ELK1), p-c-Fos, α-SMA, COL I, and COL Ⅲ by Western blot. ONSMP can effectively improve HF rat's cardiac function, decrease cardiac organ coefficient, COL volume fraction, and COL I/Ⅲ content, down-regulate the mRNA of COL I/Ⅲ, α-SMA and c-Fos, and the protein of p-RAS, p-RAF, p-MEK1/ 2, p-ERK1/2, p-ELK1, c-Fos, COL Ⅰ/Ⅲ, and α-SMA. ONSMP can effectively reduce myocardial fibrosis in HF rats, and the mechanism may be related to the inhibition of the RAS/RAF/MEK/ERK signaling pathway.

PROTEIN SOLUBLE SUPPRESSION OF TUMORIGENICITY 2 (sST2) SEBAGAI PENANDA KERUSAKAN KARDIOVASKULAR PADA PREEKLAMSIA

Preeclampsia as a pregnancy complication was still a direct cause of maternal death, especially in developing countries. The process of abnormal trophoblast invasion as a pathophysiology of preeclampsia would cause an ischemic environment in the placenta. This situation caused the placenta to release pro-inflammatory cytokines and anti-angiogenic factors into the maternal circulation, resulting in the vasocontriction of blood vessels, endothelial dysfunction in the vasculature of maternal organs, and the production of different clinical features depending on the organs affected. Vascular and myocardial muscle damage was a complication that causes cardiovascular disorders and could increase maternal morbidity and mortality in preeclampsia. sST2 as part of the interleukin (IL)-1 receptor, was a biomarker used to indicate myocardial muscle damage in cardiac disease. There had been a growing number of research investigating the use of sST2 as a marker of cardiac muscle damage in patients with heart failure. Some of them concluded that sST2 can be used as a predictor of acute cardiac muscle damage. Others stated that sST2 as a marker could accompany chronic cardiac defects. Preeclampsia, as a disease in pregnancy that showed damage to maternal organs, was starting to be studied using this biomarker as a marker for damages to the cardiac organ. There were studies that showed differences in sST2 levels in preeclampsia with and without complications. Preeclampsia with cardiac complications was characterized by damage to the myocardial muscle, especially to the left ventricular area. The sST2 protein was starting to be used as a marker for this damage. Further research was still being carried out to improve the use of this biomarker as a marker for other damage to the maternal cardiac organ.

Association Between Elevated Body Mass Index and Cardiac Organ Damage in Children and Adolescents: Evidence and Mechanisms.

Although a number of pathophysiological aspects of childhood obesity have been reported, few information are available on obesity-related cardiac organ damage. The present study was aimed at assessing the impact of anthropometric, blood pressure (BP) and metabolic variable on cardiac structure and function in youth. In 78 subjects aged 5-16 years attending the outpatient clinic of cardiovascular risk (Valencia, Spain) anthropometric and metabolic variables, clinic and ambulatory BP and echocardiographic parameters were assessed. Subjects were also classified according to the presence of insulin resistance. Subjects mean age (±SD) amounted to 12.03±2.4 years and males to 53.8%. Ten subjects were normoweight, 11 overweight, 39 obese, and 18 severely obese. No significant difference in office and ambulatory BP was detected among different bodyweight groups. A significant direct correlation was observed between left ventricular mass index (LVMI) and obesity markers [body mass index (BMI): r=0.38, waist circumference (WC): r=0.46, P<0.04 for both]. Left ventricular hypertrophy, relative wall thickness and left atrial diameter were significantly related to BMI and WC. In contrast, office and ambulatory BP were unrelated to other variables, and differences in LVMI among different BP phenotypes were not significant. When partitioning the population by insulin resistance, LVMI, adjusted for confounders, was significantly greater in the insulin-resistant group. In children and adolescents characterized by different body weight patterns, weight factors "per se" and the related insulin resistance state appear to represent the main determinants of LVMI and left ventricular hypertrophy, independently on BP values and BP phenotypes.

Optimized New Shengmai Powder modulation of cAMP/Rap1A signaling pathway attenuates myocardial fibrosis in heart failure

BackgroundOptimized New Shengmai Powder (ONSMP) is a traditional Chinese medicine formula with significant anti-heart failure and myocardial fibrosis effects, but the specific molecular biological mechanisms are not fully understood.MethodsIn this study, we first used network pharmacology to analyze the ONSMP's active ingredients, core signaling pathways, and core targets. Second, calculate the affinity and binding modes of the ONSMP components to the core targets using molecular docking. Finally, the heart failure rat model was established by ligating the left anterior descending branch of the coronary artery and assessing the effect of ONSMP on myocardial fibrosis in heart failure using echocardiography, cardiac organ coefficients, heart failure markers, and pathological sections after 4 weeks of drug intervention. The cAMP level in rat myocardium was determined using Elisa, the α-SMA and FSP-1 positive expression determined by immunohistochemistry, and the protein and mRNA levels of the cAMP/Rap1A signaling pathway were detected by Western Blotting and quantitative real-time PCR, respectively.ResultsThe result shows that the possible mechanism of ONSMP in reducing myocardial fibrosis also includes the use of 12 active ingredients such as baicalin, vitamin D, resveratrol, tanshinone IIA, emodin, 15,16-dihydrotanshinone-i to regulate β1-AR, AC6, EPAC1, Rap1 A, STAT3, and CCND1 on the cAMP/Rap1A signaling pathway, thereby inhibiting the proliferation of cardiac fibroblasts and reduce the excessive secretion of collagen, effectively improve cardiac function and ventricular remodeling in heart failure rats.ConclusionThis research shows that ONSMP can inhibit myocardial fibrosis and delay heart failure through the cAMP/Rap1A signaling pathway.

Donor Electrocardiogram Associations With Cardiac Dysfunction, Heart Transplant Use, and Survival: The Donor Heart Study

BackgroundPotential organ donors often exhibit abnormalities on electrocardiograms (ECGs) after brain death, but the physiological and prognostic significance of such abnormalities is unknown. ObjectivesThis study sought to characterize the prevalence of ECG abnormalities in a nationwide cohort of potential cardiac donors and their associations with cardiac dysfunction, use for heart transplantation (HT), and recipient outcomes. MethodsThe Donor Heart Study enrolled 4,333 potential cardiac organ donors at 8 organ procurement organizations across the United States from 2015 to 2020. A blinded expert reviewer interpreted all ECGs, which were obtained once hemodynamic stability was achieved after brain death and were repeated 24 ± 6 hours later. ECG findings were summarized, and their associations with other cardiac diagnostic findings, use for HT, and graft survival were assessed using univariable and multivariable regression. ResultsInitial ECGs were interpretable for 4,136 potential donors. Overall, 64% of ECGs were deemed clinically abnormal, most commonly as a result of a nonspecific St-T-wave abnormality (39%), T-wave inversion (19%), and/or QTc interval >500 ms (17%). Conduction abnormalities, ectopy, pathologic Q waves, and ST-segment elevations were less common (each present in ≤5% of donors) and resolved on repeat ECGs in most cases. Only pathological Q waves were significant predictors of donor heart nonuse (adjusted OR: 0.39; 95% CI: 0.29-0.53), and none were associated with graft survival at 1 year post-HT. ConclusionsECG abnormalities are common in potential heart donors but often resolve on serial testing. Pathologic Q waves are associated with a lower likelihood of use for HT, but they do not portend worse graft survival.

A miniature illumination probe in lightsheet fluorescence microscopy for real-time imaging injured adult zebrafish’s ventricular recuperation

Imaging adult zebrafish’s cardiac organ is often hampered by the limited volume of the internal cavity. This research study aims to design, manufacture and apply a miniature illumination probe amended with an aluminum-coated polydimethylsiloxane (PDMS) concave cylindrical mirrors as well as 3D-printed casings for probe assembly in a light-sheet fluorescence microscopy to explore its applicability of visualizing adult zebrafish’s ventricle. The system was calibrated and characterized. The experimental results successfully demonstrated the tracking of the ventricular regeneration in female adult zebrafish at multiple time points and can be conducive to other heart-related research in in vivo settings.

Long-Term Follow-Up of Patients With Elevated Aldosterone-to-Renin Ratio but Negative Confirmatory Test: The Progression of Primary Aldosteronism Phenotypes.

About 10% of patients with arterial hypertension have a positive screening test for primary aldosteronism (PA) and 50% to 70% of them have a negative confirmatory test: the appropriate follow-up of these patients is currently unknown. We investigated the incidence of PA in patients with previous negative confirmatory testing, after at least a 2-year follow-up. One hundred eighty-four patients with a previously elevated aldosterone-to-renin ratio followed by a negative confirmatory test were recruited in 2 hypertension centers (Torino and Munich). We repeated the screening test for PA and, if positive, the confirmatory test (seated saline infusion test or captopril challenge test). Primary end point of the study was the incidence of newly diagnosed overt PA, as defined by a positive confirmatory test. After a mean follow-up of 5 years, 20% of patients developed overt PA. When subtype diagnosis was offered systematically, one-third of patients displayed unilateral PA. Patients who developed PA showed worsening of blood pressure control and a higher rate of cardiac organ damage, despite similar implementation of antihypertensive therapy, compared with patients without PA. A mild progression of autonomous aldosterone secretion was evident even in patients without confirmed PA but with relatively stable control of blood pressure levels over time. About one-fifth of patients with a negative confirmatory test develop overt PA over time. A clinical follow-up of patients with a negative confirmatory test is advisable, along with the repetition of PA investigation, primarily in patients with worsening of blood pressure control.

EFFECT OF POST MORTEM INTERVAL TOWARD Β-TRYPTASE AND CHYMASE EXPRESSION OF ANAPHYLACTIC HEART MAST CELLS

Background: The effects of post mortem interval on tryptase levels are unclear and have been challenging to quantify due to limited and at times contradictory research. Purpose: Analyze the effects of Post Mortem Interval (PMI) due to anaphylactic shock on the expression of β-tryptase and mast cell chymase in the heart organ. Method: This type of research was an experimental study with a randomized block design (RBD) with the same subjects and a time series for 24 hours, using 5 (five) rabbits. The measurement of β-tryptase and chymase expression was based on immunohistochemical IRS (immunoreactive score) in the heart organs of rabbits experiencing anaphylactic shock sensitization and induction of anaphylactic shock using ovalbumin. Result: Based on the results of statistical tests using univariate analysis, there was a relationship between the length of death (post mortem interval) and the expression of mast cells β-Tryptase and cardiac chymase (p-value = 0.006) and chymase (p-value = 0.002) with (p-value &lt;0.05). The effective test time with β-tryptase markers using cardiac organs was prone to long death time of 0 - 15 hours. The effective check-up time with chymase markers using the heart organ was at a long time of death of 9 hours. Conclusion: The results of the study showed that tryptase and chymase could be used as markers of anaphylactic shock.

Autopsy findings and cardiac arrest rhythms in young obese patients with sudden cardiac death of uncertain etiology

Abstract Background Obesity is associated with an increased risk of sudden cardiac death (SCD) which can be particularly devastating in young adults. In a significant proportion of SCD cases in the young, a specific cause cannot be identified. Purpose The aim of this retrospective analysis was to describe the demographics, pathological changes and cardiac arrest rhythm in young obese individuals with SCD of otherwise unknown etiology. Methods Between July 2000 and December 2018, the National Coronial Information System (NCIS) identified cases of young obese (body mass index ≥ 30) individuals with SCD between 17-35 years of age (SCD-obesity). Autopsy reports of individuals with SCD where known causes had been excluded were compared to 2 matched control cohorts of death due to motor vehicle accidents (MVA) (first group matched for age, sex, height and weight (MVA-BMI-matched) and second group matched for age and sex (MVA-age-matched)). Additionally, electrocardiographic rhythms at cardiac arrest were obtained through state-wide ambulance services for SCD-obesity individuals. Results We identified 409 cases of SCD in young obese individuals, of which 94 cases met the inclusion criteria (figure 1). Mean age was 28.44±5.6 years (range 17-35). SCD-obesity individuals were commonly males (71%). SCD-obesity individuals had significantly higher cardiac masses (521g vs 417g, p&amp;lt;0.001) compared to the MVA-BMI-matched cohort. SCD-obesity individuals also had significantly increased left ventricular wall thickness (15.6mm vs 13.5mm, p&amp;lt;0.001) and increased rates of left ventricular fibrosis (73% vs 52%, p=0.045) compared to the MVA-BMI-matched cohort. ECG rhythm strips were available for 71 (72%) SCD-obesity cases, of which 16 (23%) were unwitnessed. Asystole was noted on 7 (46.67%) of witnessed cases, and 6 (40%) had a ventricular tachycardia or fibrillation (figure 2). Conclusions SCD-obesity individuals had increased cardiac organ masses, left ventricular wall thickness and cardiac fibrosis. The cardiac arrest rhythm recorded in witnessed cases were predominantly asystole and ventricular arrythmia. Future studies are needed to determine the pathological mechanisms explaining these abnormalities in young obese sufferers of SCD.Figure 1:Case identificationFigure 2:Results

Reduced Early Mortality with Daratumumab-Based Frontline Therapy in Systemic AL Amyloidosis- Experience from the Columbia Amyloidosis Multidisciplinary Program

Introduction: Despite advances in treatmentof systemic light chain (AL) amyloidosis, early mortality (EM) has been substantial up until recently, with a 6-month EM rate of approximately 25% in the era preceding daratumumab (Muchtar et al. Blood. 2017).Daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) is the first FDA-approved therapy for systemic AL amyloidosis based on the ANDROMEDA trial with an unprecedented hematologic complete response (Heme-CR) rate ≈ 50%. However, data on hematologic and cardiac organ response rate and estimated early mortality (EM) in different stages since routine introduction of daratumumab-based frontline therapy are lacking. Methods: We performed a retrospective cohort study of all consecutive patients treated with daratumumab-based combination therapy at Columbia Amyloidosis Multidisciplinary Program (CAMP). Hematologic and cardiac organ response rates are reported on an intention-to-treat (ITT) basis, with patients who died prior to response evaluation or those with missing data classified as non-responders. Time-to-event analyses were performed by the Kaplan-Meier method. Results: Eighty-three consecutive patients treated with daratumumab-based frontline therapy were included in the analysis. The baseline characteristics of our cohort in comparison with Dara-VCD arm of ANDROMEDA is shown in Table 1. The median age at diagnosis was 68 years (range, 40-91), with 65% being males and 13 patients (16%) of Black/African-American race. The median dFLC (involved - uninvolved) was 21.9 mg/dl, with 61% of patients having baseline dFLC&amp;gt;18 mg/dl. Mayo 2004 stage IIIa/IIIb comprised 65% of our cohort compared to 37% of ANDROMEDA trial. Thirty-three patients (44%) had NYHA Class III/IV symptoms. The daratumumab-based frontline regimens used were Dara-VCD (n=78), Dara-VD (n=2), Dara-D (n=2), and Dara-Ixazomib-D (n=1). High-dose melphalan followed by autologous hematopoietic cell transplantation (HDM-AHCT) as a part of frontline therapy was performed in 11 patients (13.4%), with melphalan dose being 140 mg/m 2 in 8, 200 mg/m2 in 2, and 100 mg/m 2 in 1 patient. Hematologic response was evaluable in 78 patients (i.e. dFLC&amp;gt;2 mg/dl at diagnosis). On an ITT basis, Heme-CR was achieved by 39 patients (50%), and very good partial response or better (Heme ≥VGPR) by 57 patients (73.1%). The median time to Heme-CR from treatment initiation was 2.7 months (range, 0.42-13.97). Among patients evaluable for cardiac organ response (i.e. NT-proBNP≥650 pg/ml; n=64), 35 (58.3%) achieved an organ response. The median time to initial cardiac response (&amp;gt;30% reduction in NT pro-BNP with absolute reduction of &amp;gt;300 pg/ml) was 2.95 months (range, 0.43-10.43). Figure 1 demonstrates comparable hematologic and numerically higher cardiac organ response rate in our cohort vs Dara-VCD arm of ANDROMEDA trial. Next, we estimated the EM rate. The estimated EM at 6 months in our cohort was 7.6% (95% CI, 3.4-15.9). 6-month EM in patients with Mayo 2004 stage IIIb was 22.2% (95% CI, 9.5-43.6) vs 1.96% (95% CI, 0.27-12.65) in those with stage I-IIIa ( p&amp;lt;0.001) [Figure 2]. By Mayo 2012 staging, the estimated 6-month EM rate in patients with stage I, II, III, and IV disease was 0% (95% CI, 0-0), 0% (95% CI, 0-0), 9.6% (95% CI, 2.4-31.3), and 12.9% (95% CI, 4.9-29.8) respectively ( p=0.0425). Among patients who underwent upfront HDM-AHCT (n=11), there was no transplant-related mortality at 100 days. On evaluating the prognostic impact of individual factors in Mayo 2012 staging (NT-proBNP, Troponin, and dFLC) on OS, dFLC&amp;gt;18 mg/dl was no longer a significant adverse prognostic factor for survival in both univariate and multivariate analysis. Updated data will be presented at the meeting. Conclusion: Despite a sicker population with more advanced cardiac involvement compared to ANDROMEDA trial, daratumumab-based frontline induction therapy led to similar Heme-CR rate and favorable cardiac organ response rate in our cohort. Additionally, estimated 6-month EM has decreased by approximately 3-fold compared to historical data, with dramatic reduction in Mayo 2004 stage I-IIIa and continued substantial EM in stage IIIb disease. Finally, as clone-directed therapy has significantly improved, light chain burden at baseline may not be a relevant prognostic factor in contemporary era and should be scrutinized in larger datasets to re-design the staging system.

HiPSCs and organoids: prediction of arrhythmogenic risks for optimized traditional Chinese medicine

Accurate assessment of the risks associated with traditional Chinese medicine(TCM), such as the potential to induce serious cardiovascular adverse reactions including cardiac arrhythmias, is crucial. This article introduced the pharmacological evaluation strategies for cardiac safety and the progress in cardiac organ research, with a focus on discussing the application prospects of human induced pluripotent stem cells(hiPSCs) and organoids in assessing the risks of TCM-induced cardiac arrhythmias. Compared with traditional animal models, hiPSCs and organoid models provide better reference and predictive capabilities, allowing for more accurate simulation of human cardiac responses. Researchers have successfully generated various cardiac tissue models that mimic the structure and function of the heart to evaluate the effects of TCM on the heart. The hiPSCs model, by reprogramming adult cells into pluripotent stem cells and differentiating them into cardiac cells, enables the generation of personalized cardiac tissue, which better reflects individual differences and drug responses. This provides guidance for the assessment of TCM cardiac toxicity risks. By combining organoid model with cardiac safety pharmacology strategies such as electrocardiogram monitoring and ion channel function assessment, the impact of TCM on the heart can be comprehensively evaluated. In addition, the application of the Comprehensive in Vitro Proarrhythmia Assay(CiPA) approach improves the accuracy of evaluation. Applying the CiPA approach to TCM research reveals potential risks and provides a scientific basis for the clinical application and industrial development of TCM. In conclusion, organoid model and cardiac safety pharmacology evaluation strategies provide important tools for assessing the cardiac toxicity risks of TCM. The combination of hiPSCs model, comprehensive assessment methods, and the CiPA strategy enables an accurate assessment of the risks of TCM-induced cardiac arrhythmias, thus providing a scientific basis for the safe use and international recognition of TCM in clinical practice. This contributes to ensuring the safety and efficacy of TCM and promoting its clinical application and global acceptance.

Conserved chamber-specific polyploidy maintains heart function in Drosophila.

Developmentally programmed polyploidy (whole-genome duplication) of cardiomyocytes is common across evolution. Functions of such polyploidy are essentially unknown. Here, in both Drosophila larvae and human organ donors, we reveal distinct polyploidy levels in cardiac organ chambers. In Drosophila, differential growth and cell cycle signal sensitivity leads the heart chamber to reach a higher ploidy/cell size relative to the aorta chamber. Cardiac ploidy-reduced animals exhibit reduced heart chamber size, stroke volume and cardiac output, and acceleration of circulating hemocytes. These Drosophila phenotypes mimic human cardiomyopathies. Our results identify productive and likely conserved roles for polyploidy in cardiac chambers and suggest that precise ploidy levels sculpt many developing tissues. These findings of productive cardiomyocyte polyploidy impact efforts to block developmental polyploidy to improve heart injury recovery.

Abstract P2003: Cardiomyocyte Polyploidy: Friend Or Foe?

Developmental polyploidization (whole genome duplication) of cardiomyocytes is well conserved across mammals, birds and Drosophila . However, it is unclear whether precise control of cardiomyocyte polyploidy is essential. We found that there is a chamber-specific asymmetry to cardiomyocyte polyploidy in the Drosophila cardiac organ which is regulated by differential sensitivity of Insulin signaling. Higher ploidy cardiomyocytes correspond to the heart chamber, while lower ploidy cardiomyocytes correspond to the aorta chamber. Using immunofluorescence staining (IF), optical coherence tomography (OCT) and live imaging, we found that reducing chamber-specific ploidy affects cardiac function and reduces the velocity of circulating hemocytes, which indicates systemic heart failure. Intriguingly using human donor heart samples, we found that chamber specific asymmetry in cardiomyocyte ploidy and insulin sensitivity is similar to Drosophila . Our findings suggest that precise control of ploidy levels for cardiac organ sculpting is conserved across species. Polyploidization may have negative effects on cardiomyocyte regeneration, but our results suggest that region-specific control of ploidy levels is important for organ development and functionally.

Endurance training and L-arginine intake: Their effect on antioxidant indices in the heart muscles of rats.

Background: One of the side effects of doing sports activities is the increase of free radicals and oxidative stress. Aim: The present study aimed to investigate the effect of 8 weeks of increasing endurance training with L-arginine supplementation on oxidative indices in the cardiac organ of male Wistar rats. Methods: 32 male Wistar rats were divided into four groups control, L-arginine, endurance training, and L-arginine plus endurance training. Animals in the endurance training groups completed increasing endurance training on a motorized treadmill (60-min/session, 5 times/week) for 8 weeks. Animals in the L-arginine groups consumed an L-arginine solution daily (4 mg/kg/body weight). In the supplement group, L-arginine was given to the mice as a solution in water and as a gavage. Forty- eight hours after the last endurance training session, a heart tissue sample was taken and placed in an RNAlater liquid. Spectrophotometry and an ELISA kit were used to calculate the concentrations of glutathione peroxidase (GPX), malondialdehyde (MDA), and superoxide dismutase (SOD). Results: The present study showed that endurance training and L-arginine consumption did not affect SOD activity. L-arginine intake increased GPX. Endurance training caused a significant increase in MDA compared to the supplemented group (p = 0.01). Also, the consumption of L-arginine significantly increased the total antioxidant capacity TAC in the supplement group compared to the control group (p = 0.001). Conclusion: It seems that taking an L-arginine supplement can increase antioxidant enzymes.