Cardiac Morphology Research Articles

Association between GDF-15 levels and cardiac morphology and function in cardiac magnetic resonance imaging: insights from UK Biobank data analysis

Abstract Background/Introduction Growth Differentiation Factor-15 (GDF-15) has emerged as a biomarker associated with cardiovascular disease and adverse cardiac outcomes. Cardiac morphology and function, assessed through cardiac magnetic resonance imaging (CMR), are critical indicators of cardiovascular pathology. Understanding the relationship between GDF-15 levels and LV characteristics could provide valuable insights into cardiac pathophysiology and disease progression. Purpose This study aims to investigate the association between GDF-15 levels and cardiac morphology and function, utilizing data from the UK Biobank and CMR. By analyzing various CMR-derived parameters, including LV strain, myocardial mass, LV mass-to-volume ratio, ventricular and atrial volumes, we seek to elucidate the impact of GDF-15 on cardiac structure and function. Methods Data from the UK Biobank, including 2,264 participants, were analyzed. The median age of the analyzed participants was 55 years, with a median BMI of 26.0. Among the participants, 53% were females and 47% were males. CMR-derived variables related to cardiac morphology and function, along with GDF-15 levels, were examined. Multiple linear regression models were constructed to assess the association between GDF-15 levels and cardiac parameters, adjusting for age, sex, and other relevant covariates. Confidence intervals (CI) and p-values were calculated to determine the significance of observed associations. Results Analysis of the UK Biobank data revealed significant associations between GDF-15 levels and specific cardiac parameters (table1). Notably, GDF-15 levels were negatively associated with LV myocardial mass (LVM)(coefficient = -1.146, p = 0.0071), LV end-diastolic volume LVEDV)(coefficient = -3.321, p < 0.0001), LV end-systolic volume (coefficient = -1.876, p < 0.0001), as well as right atrial maximum volume (coefficient = -3.025, p < 0.0001) and minimum volume (coefficient = -1.858, p = 0.0003). In addition, LVM/LVEDV was positively associated with GDF-15 level (p<0.03). However, no significant associations were observed between GDF-15 levels and LV strain parameters, ejection fraction, or left atrial volumes. Conclusion This study provides evidence of a significant association between GDF-15 levels and selected parameters of cardiac morphology and function, as assessed by CMR in the UK Biobank population. These findings suggest a potential role of GDF-15 in modulating specific aspects of cardiac structure, function and left ventricle concentric remodeling warranting further investigation.GDF 15

Lipin1 prevents ischemic heart disease by regulating lipid homeostasis

Abstract Background Lipid metabolism plays a crucial role in the pathophysiology of cardiovascular diseases. Lipin1 plays a pivotal role in lipid metabolism regulation. In the nucleus, Lipin1 acts as a transcriptional co-stimulatory molecule, interacting with peroxisome proliferator–activated receptor–gamma coactivator 1 alpha (PGC1α) and peroxisome proliferator–activated receptor alpha (PPARα). In the cytoplasm, Lipin1 functions as a phosphatidate phosphatase, converting phosphatidic acid to diacylglycerol to regulate lipid metabolism. Low expression of Lipin1 has been implicated in the severity of cardiac dysfunction in mice. Purpose This study aimed to investigate the role of Lipin1 in the cardiac remodeling after myocardial infarction (MI), revealing its impact on lipid metabolism and molecular pathway associated with cardiac dysfunction. Methods Two types of transgenic mice, cardiomyocyte-specific Lipin1 knockout (cKO) and overexpression (cOE) mice were used in this study. Eight to ten-week-old male mice were subjected to MI by coronary artery ligation. Cardiac lipid droplets were quantified, and triacylglycerol and free fatty acid levels were measured one week after MI surgery. Four weeks after MI, cardiac morphology and function were evaluated using echocardiography, alongside measurements of body weight (BW) and heart weight (HW). Additionally, gene expression analysis and histological evaluation were conducted to assess fatty acid metabolism, cardiac fibrosis, inflammation, and oxidative damage. Results Before MI surgery, there were no differences in HW/BW ratio, left ventricular end-diastolic diameter (LVDd) or LV fractional area change (LVFAC) among cKO/ cOE mice and their littermate controls. After MI, cKO mice exhibited significant cardiac dysfunction with larger LVDd, lower LVFAC and increased HW/BW ratio compared to littermate controls. This was accompanied by exacerbated cardiac fibrosis, increased inflammation, and augmented reactive oxygen species accumulation compared with their controls. Conversely, cOE mice displayed improved LVFAC, reduced cardiac fibrosis, inflammation, and reactive oxygen species accumulation compared to their littermate controls. Notably, the transgene of Lipin1 induced changes in the number of cardiac lipid droplets (LDs). cKO mice hearts showed a reduction in cardiac LDs with decreased levels of triacylglycerol and free fatty acids compared to the littermate controls. In contrast, cOE mice displayed increased cardiac LDs and upregulated expression of fatty acid metabolism–related genes after MI. Conclusion These results suggested that Lipin1 has a protective role against ischemic injury through controlling lipid metabolism in ischemic cardiomyocytes. Thus, Lipin1 emerges as a potential therapeutic target for myocardial infarction.

Cardiac morphology and function in patients with primary biliary cholangitis (PBC) without cirrhosis

Abstract Background Primary biliary cholangitis (PBC) is a chronic, autoimmune liver disease causing destruction of the small intralobular bile ducts in the liver. PBC patients can also develop extrahepatic manifestations. Though patients with PBC have often elevated levels of serum lipids, data concerning cardiac involvement is inconsistent and cardiovascular changes may be underdiagnosed. Purpose The purpose of the study was to assess cardiac morphology and function in patients with PBC without cirrhosis and comparison with control subjects. Methods We studied 52 females with PBC, and included in the analysis 22 females without cirrhosis, who were compared to 44 healthy female controls matched for age (53.4 ± 9.2 and 51 ± 8.3 yrs., respectively, p =0.312). Transthoracic echocardiography (TTE) was performed with the analysis of the left ventricular (LV) global longitudinal strain (GLS) and myocardial work. Additionally, impedance cardiography was conducted, with the analysis of the autonomic function using BRS (baroreceptor sensitivity), HRV (heart rate variability) and BPV (blood pressure variability). Results Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) differed between PBC and control group (128 ± 17 mmHg vs. 116 ± 11 mmHg, p=0.007 and 78± 12 mmHg vs. 75 ± 8 mmHg, p=0.024, and 73.5 ± 12 bpm vs. 71 ± 8 bpm , p=0.024, respectively). PBC group had larger diameter of the cardiac chambers when adjusted for body surface area (BSA), including left atrium (LA/BSA) and right ventricle (RV/BSA), as well as left ventricular mass (LWMI) and relative wall thickness (RWT), with no difference in the left ventricular end diastolic diameter (LVEDD/BSA). LV ejection fraction (EF) measured by bi-plane Simpson method was higher in PBC group. LV diastolic function parameters (E/A, E/e’) differed in patients with PBC when compared with controls, however, without signs of diastolic dysfunction. LV GLS indices (GLSAVG, GLSLAX, GLS4C, GLS2C) were significantly higher in PBC group, as well as global myocardial work indexes: global myocardial work (GWI) and global constructive work (GCW). Non-invasive autonomic assessment showed lower BPV in patients with PBC without cirrhosis, but no differences in baroreceptor sensitivity and HRV. Impedance cardiography did not show differences between both groups. Conclusion Our study shows that PBC patients without cirrhosis are characterized by remodeling and functional changes of the heart, when compared to age-matched controls. These changes could imply hyperkinetic circulation even before the development of cirrhosis in PBC patients.

Changes in mitral and tricuspid valve morphology after surgical repair of pectus excavatum

Abstract Background The effect of pectus excavatum (PE) on cardiac morphology and function has been reported previously. The right heart chamber size and cardiac output improved after the surgical correction of PE. However, the effect on the mitral and tricuspid valve has not been investigated. Purpose Our purpose was to investigate the morphological changes in the tricuspid and mitral valve after PE surgery. Methods We enrolled 25 patients who underwent Nuss surgery for PE repair. The inclusion criteria were 1) aged 15 years or older, 2) Haller Index of more than 5.0, and 3) transesophageal echocardiography (TEE) during PE surgery. We measured RV size and the sphericity index of tricuspid and mitral valve using 3D echocardiography before and after the elevation of the sternum. The sphericity index was calculated as the ratio of anterior-posterior (AP)/medial-lateral (ML) dimeter for the mitral valve (MV) and septal-lateral (SL) / AP dimeter for the tricuspid valve (TV). Results Mean age was 26±11 years, and 28% was female. The Haller index was 6.9 ± 2.8. All patients had normal left ventricular and right ventricular function evaluated with transthoracic echocardiography. The chamber diameter of the base and mid in RV increased after the elevation of the chest. The AP and SL dimeter were enlarged after the elevation of the chest in the TV, and the sphericity index of TV did not change. On the other hand, AP diameter increased but ML diameter was constant in the MV, and the sphericity index of MV increased after the elevation of the chest. Therefore, the annulus size was increased but the morphology was not changed in the TV. Unlike the TV, the morphology of MV annulus became close to circular from flat shape. In several patients, trivial mitral regurgitation was observed after elevation of chest, and possibly affected by the morphological change of the MV annulus. Conclusions The surgical repair for pectus excavatum effected not only right ventricular morphology but also on the tricuspid and mitral valve. The annulus change was different between the tricuspid and mitral valve.

Insights from the assessment of anatomic valve orifice area after transcatheter aortic valve implantation using transesophageal echocardiography

Abstract Background Although transthoracic echocardiography (TTE) is the gold standard for evaluating effective valve orifice area (EOA) after transcatheter aortic valve implantation (TAVI), the continuous formula is inherently different from anatomic valve orifice area because it implies a minimum jet width through the aortic valve. It has also been reported that the doppler method with TTE overestimates the mean gradient due to pressure recovery and is even less accurate after TAVI. On the other hand, recent technological developments have improved image resolution, making valve morphology possible using transesophageal echocardiography (TEE). Purpose The purpose of this study was to compare transcatheter aortic valve (TAV) area using TEE and TTE to evaluate whether there is a significant difference in each area and to explore factors that influence the difference in area. Methods Patients who underwent TEE-guided TAVI and SAPIEN3 implantation between February 2019 and March 2023 and had aortic valve evaluation with TTE before discharge were included. We retrospectively evaluated the TAV after TAVI using TTE and TEE. Aortic valve orifice area was calculated by two methods: EOA index (doppler-area: DA) calculated by the continuous doppler formula using TTE and t-AVA index (trace-area: TA) derived by the trace method using TEE. TAV tracing was performed in early systole on the short-axis image of the aortic valve. The TAV tracing was performed by physicians specializing in echocardiography, and multiple physicians were blinded to the same case to eliminate inter-rater error. The percentage change between the two groups was calculated from the difference in area by TTE and TEE, and the 75th percentile of the percentage change was defined as the cutoff value for the group with the large difference in TAV area. Results Patients whose TAV was difficult to observe by TEE were excluded, and 464 patients were finally analyzed. TA was significantly larger than DA (1.56±0.28 cm2/m2 vs 1.18±0.26 cm2, p<0.001) and similar for all TAV sizes. However, even though TA expanded as valve size increased, the largest area of DA was observed in the 26mm TAV, and the 29mm TAV was comparable to the 26mm TAV. Only a weak correlation was shown between DA and TA (correlation coefficient: 0.356). There were 43 cases of moderate prosthetic valve-patient mismatch (PPM: EOA-i<0.85cm) in DA, but only 1 case in TA. In multivariate logistic regression analysis, women (OR 2.25, 95% CI 1.17-4.34, p < 0.015) and LV mass index (OR 1.01, 95% CI 1.00-1.02, p < 0.041) were independent factors for the large difference in TAV area. Conclusion After TAVI, the TAV area with TEE was larger than the EOA-i with TTE, and PPM was rarely seen. Depending on valve size, patient background, and cardiac morphology, there are cases of overestimation of postoperative AS in TTE, which may need to be carefully evaluated in women and patients with larger LV mass index.

Adipose tissue/ heart lipid transport determines cardiac diastolic function

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and often occurring in obese individuals. Previous research has demonstrated that the modification of lipid metabolism can prevent the onset of diastolic dysfunction. In our project we have investigated how lipid transport influences the onset of diastolic dysfunction utilizing heart- and adipose tissue-specific knockdowns of the fatty acid (FA) transport protein 1 (FatP1) in Drosophila melanogaster. Methods We generated Drosophila with heart-specific (+/+; Hand4.2-GAL4/UAS-FatP1; tdtK/+) (cFatP1-KD) and adipose tissue-specific (+/+; ppl-GAL4/UAS-FatP1; tdtK/+) (atFat-P1-KD) FatP1 knockdowns using the UAS/GAL4 system. The flies' cardiomyocytes endogenously express tdTomato, facilitating fluorescence-based live imaging of the heart by high-resolution video fluorescence microscopy, as previously described. Cardiac morphology and cardiac lipid accumulation was monitored by confocal microscopy. Additionally, mitochondrial function was evaluated using the glycolytic Seahorse assay of whole hearts. Results Blocking FA-uptake into adipose tissue in atFatP1-KD flies resulted in a highly significant reduction in relaxation velocity (p=0.0009, WT vs. atFatP1-KD), indicative of diastolic dysfunction in flies, while contraction velocity and fractional shortening (systolic function) remained unchanged. Diastolic dysfunction was associated with a significant increase of cardiac lipid droplet (LD) quantity and size in flies lacking FatP1 in adipose tissue (p=0.0275 and p<0.0001, respectively, WT vs. atFatP1-KD). Cardiac mitochondrial function was significantly impaired in atFatP1-KD flies compared to WT flies. Reducing cardiac FA uptake in heart-specific FatP1 KD flies led to a decrease in end-diastolic diameter and a significant reduction in relaxation and contraction velocity (p<0.0001 and p=0.0001, respectively, WT vs. cFatP1-KD), suggesting impairment in both diastolic and systolic function. Interestingly, the number of cardiac LDs increased in cFATP1-KD, however their size decreased significantly resulting in an overall unchanged lipid content compared to WT flies (p=0.0475 and p=0.0367, respectively, WT vs. atFatP1-KD). Mitochondrial function showed no significant alterations. Conclusion This study demonstrates that reducing FA-uptake in adipose or cardiac tissue results in cardiac dysfunction in Drosophila melanogaster. Reduction of adipose tissue FA-uptake results exclusively in diastolic dysfunction likely mediated by cardiac lipid overload and subsequent mitochondrial dysfunction. In contrast, blockade of Fatp1-mediated cardiac FA-uptake induces diastolic/ systolic dysfunction which was unrelated to alterations in cardiac lipid content and mitochondrial dysfunction suggesting alternative mechanisms. These study identifies FatP1-mediated FA-uptake in adipose tissue as a potential therapeutic target for the treatment of diastolic dysfunction.

A population-based characterisation of the relationship between anatomical and electrical axes of the heart

Abstract Introduction Cardiac anatomy, including heart size, position and orientation within the torso, is known to impact ECG morphology. Understanding the relationship between cardiac anatomy and ECG morphology through their main axes has the potential to lead to more accurate and reliable ECG biomarkers. Nevertheless, there is no standardised method for the definition of the anatomical and electrical axes of the heart. Aims To evaluate definitions of anatomical and electrical axes of the heart based on a derived metric in an undiseased population in the UKBioBank. Methods The anatomical and electrical axes of 2189 healthy subjects were computed separately in five different ways (Figure 1). Cardiac bi-ventricular anatomy was automatically segmented from cardiac MRI. Anatomical axes were computed from different combinations of anatomical landmarks (valves and apex) and axis of inertia. ECGs were transformed into vectorcardiograms (VCGs) using the Kors transformation. A range of combinations of dipole magnitudes, weighted averages and loop shape were used to define the electrical axes of the QRS loop. The anatomical-electrical relationship was quantified with the cosine of the angle between each of the 25 pairs of anatomical and electrical axes definitions. Spatial consistency was assessed by the standard deviation of this cosine across the cohort, where a higher level of spatial consistency corresponds to a lower standard deviation. Results Spatial consistency between anatomical and electrical axes exhibited a large range of standard deviation values from 0.61 for the worst pair to 0.14 for the best pair of definitions. The pair with the highest spatial consistency was defined by the valvular plane centre and the apex (VPA) for the anatomical axis, and the direction of maximum QRS dipole magnitude (maxQRS) in the VCG for the electrical axis (Panel A and B in Figure 2). The anatomical-electrical relationship was not significantly correlated with BMI, age or gender despite the individual anatomical and electrical axes showing significant correlation (Frontal plane: anatomical axis was most impacted by BMI, R=0.53 & p<0.0001, and electrical axis by gender R=0.37 & p<0.0001). Conclusion In this healthy population, the most spatially consistent definition of anatomical and electrical axes is defined by VPA and maxQRS. This spatial consistency is not affected by BMI, age or gender, suggesting an intrinsic relationship between the pair of measures, and represents a potential strategy to permit correction for patient anatomic factors when interpreting ECGs.Figure 1.Axes Definition MethodsFigure 2.Results

Impaired myocardial energetics and lower cardiac reserve in response to exercise stress in adults born preterm

Abstract Background/Introduction Preterm birth (<37 weeks’ gestation) affects 10% of live births globally and associates with an increased risk of heart failure, early cardiovascular-related mortality, and altered cardiac morphology. At rest, left ventricular (LV) ejection fraction (EF) is similar between adults born preterm and term, but right ventricular (RV) EF is lower in preterm-born adults. Exercise stress uncovers LVEF impairment in preterm-born adults but RVEF response to exercise stress has not been studied. The underlying cause of the impaired LVEF reserve and lower RVEF at rest in preterm-born adults remains uncertain and whether altered myocardial energetics contribute to this cardiac dysfunction is currently unknown. Purpose To measure resting myocardial energetics and ventricular function at rest and during exercise stress to determine whether reduced cardiac reserve in preterm-born adults may be explained by impaired myocardial energetics. Methods We conducted a cross-sectional, observational, case-control study of preterm (n=64; mean gestational age =31 weeks) and term-born (n=36) adults aged 34±5 years to compare myocardial energetics and ventricular function. Following maximal cardiopulmonary exercise testing (CPET), participants underwent 31-phosphorus magnetic resonance (MR) spectroscopy (31-P MRS) and cardiovascular MR imaging (CMR) on a 3-Tesla Siemens MR scanner. 31-P MRS was used to measure myocardial phosphocreatine to adenosine triphosphate ratio (PCr/ATP) as a measure of myocardial energetics. We obtained CMR-derived LVEF and RVEF at rest and during 40% peak wattage exercise (determined from CPET) using a MR compatible cardio-step module and steady-state free precession real-time cine imaging. Outcomes were analysed using unpaired Student’s t-tests and presented as mean±standard deviation. Results Age, body mass index, and sex did not differ between groups (p>0.05). PCr/ATP was 1.8±0.4 in preterm-born adults and 2.0±0.4 in term-born adults (p=0.01, Figure 1). Preterm-born adults had a similar LVEF versus term-born adults at rest (60.3±7.6 versus 62.1±4.5; p=0.19) though resting RVEF was lower in preterm-born adults (53.4±6.7 versus 55.9±4.5; p=0.05). LVEF increased by 6.5±5.5% in preterm-born adults and 10.9±6.0% in term-born adults from rest to 40% peak exercise (p<0.001), while RVEF increased by 9.2±6.3% in preterm-born adults versus 12.0±6.3% in term-born adults (p=0.06) (Figure 2). PCr/ATP associated with resting RVEF in preterm-born adults (R²=0.27, p=0.002), but was not associated with resting LVEF or the delta change in LVEF and RVEF with exercise stress. Conclusions Resting myocardial energetics is impaired in adults born preterm relative to term-born adults, with both the LV and RV demonstrating reduced functional reserve when challenged with low to moderate exercise stress. Metabolic modulators may help prevent progression to heart failure in preterm-born adults.Figure 1Figure 2

Acute echocardiographic assessment of patients with ST-elevation myocardial infarction in detecting clinically hidden hemodynamic deterioration

Abstract Background Transthoracic echocardiography (TTE) offers an immediate non-invasive assessment of cardiac morphology and function that can be performed bedside. Acute TTE in the catheterization laboratory (cath.lab.) may be helpful to identify markers of subsequent development of cardiogenic shock (CS) in patients with ST-elevation myocardial infarction (STEMI) in addition to the previously validated ORBI risk score. This relationship has not been investigated thoroughly previously. Purpose To investigate the association between acute TTE estimates of left ventricular (LV) function prior to primary percutaneous coronary intervention (pPCI) in STEMI patients and pro-B-type natriuretic peptide (proBNP) as a proxy associated with of CS development. Method From September 2023 all non-CS STEMI patients at one tertiary heart center underwent acute bedside TTE in the cath.lab. and ORBI risk score assessing the risk of CS development aiming for inclusion of 500 patients. The 5 minutes TTE-protocol consisted of LV ejection fraction (EF), LV outflow tract velocity time integral (LVOT VTI), mitral inflow (E and E/A), mitral deceleration time, and mitral annular early diastolic velocity é lateral. The primary endpoint was proBNP measured 24 hours (h) after pPCI (12-36h) stratified in quartiles (Q4 vs. Q1-3). The correlation between proBNP and TTE measurements and proBNP and ORBI risk score was examined using univariate linear regression models. Results Until now 153 STEMI patients (mean age 64 years, 25% female) were studied. Anterior STEMI was present in 36%, and median time from cath. lab. arrival to first wire over the culprit lesion was 28 minutes (IQR 24; 37). Patients with high proBNP level (Q4 vs. Q1-3) had significantly higher heart rate (median 84 bpm vs. 72 bpm) and Killip Class>1 (16% vs. 0%) at admission, but similar lactate levels (1.8mM vs. 1.5mM), systolic blood pressure (130 mmHg vs. 137 mmHg), and out-of-hospital cardiac arrest (11% vs. 12%). Patients with high proBNP levels (Q4 vs. Q1-3) had significantly lower LVEF (35% vs. 50%), higher E/é lateral (median 11.4 vs. 7.9), and higher ORBI risk score (median 8 vs. 4). LVEF, LVOT VTI, E/é lateral, and ORBI risk score were significantly associated with proBNP (Figure 1). Two patients developed CS after the pPCI; one with high proBNP level Q4, and one deceased prior to proBNP measurement. Conclusion Acute TTE is an easy tool for assessment of the acute hemodynamic status in STEMI patients bedside in the cath.lab., and it can be without delaying time to revascularization. LVEF, LVOT VTI, E/é lateral, and ORBI were all parameters associated with increased levels of the hemodynamic biomarker proBNP, and may together with the ORBI risk score improve the assessment and risk stratification of STEMI-patients at risk of CS-development.Figure 1.

Myocardial determinants of Functional limitation in advanced Fabry cardiomyopathy

Abstract Background Cardiac involvement in Fabry Disease (FD) manifests as left ventricular hypertrophy (LVH) often complicated by myocardial fibrosis and/or inflammation. Both LVH and advanced tissue alterations can be non-invasively detected and quantified by cardiac magnetic resonance (CMR) with Late Gadolinium Enhancement (LGE). Impairment in functional capacity has been previously reported in FD patients. However, there is limited data regarding the determinants of myocardial alterations in exercise intolerance in FD. Methods Among 190 consecutive FD patients referred for CMR, 41 simultaneously performed a cardiopulmonary exercise test (CPET) to evaluate functional capacity. All patients underwent an extensive CMR protocol to provide a detailed evaluation of cardiac morphology and function, including multiparametric tissue characterization. CPET parameters were compared between patients with advanced Fabry cardiomyopathy (Group B), characterized by hypertrophy, inflammation, and fibrosis, and FD patients without irreversible cardiac damage (Group A). Results Group B patients were older compared to Group A (57.0 years vs 33.5 years, p<0.001), had a greater LVH (LVMI: 117 g/sqm vs 76.5 g/sqm, p<0.001; LVMWT 17 vs 10 mm, p<0.001). LV ejection fraction was preserved in both groups but Group B patients had a lower peak VO2 value compared to group A (17.8 ml/kg/min vs 21.9 ml/kg/min, p=0.025), a lower (but not significant) percent-predicted peak VO2. A negative linear correlation was identified between the LGE extension (expressed as % of LV mass) and peak VO2 (r=-0.553, p=0.014). This correlation remained consistent even after excluding patients under chronic beta-blocker therapy (r=-0.678, p=0.045). No significant correlation between LV mass and peak VO2 was found. Conclusions in patients with FD, the presence of advanced tissue alterations detected by LGE is associated with reduced functional capacity (low peak VO2) despite preserved LV ejection fraction, with a significant negative correlation.

The CHD severity classification system: development of a tool to assist with disease stratification for CHD research.

Complexity stratification for CHD is an integral part of clinical research due to its heterogenous clinical presentation and outcomes. To support our ongoing research efforts into CHD requiring disease severity stratifications, a simplified CHD severity classification system was developed and verified, with potential utility for clinical researchers without specialist CHD knowledge or access to clinical/medical records. A two-tiered analysis approach was undertaken. First-tier analysis included the audit of a comprehensive system based on: i) timing of intervention, ii) cardiac morphology, and iii) cardiovascular physiology using real patient data (n = 30), across 10 common CHD lesions. Second-tier analysis allowed for a simplified version of the classification system using morphology as a stand-alone predictor. Twelve clinicians of varying specialities involved in CHD care ranked 10 common lesions from least to most severe based on typical presentation and clinical course. First-tier analysis identified that cardiac morphology was the principal driver of complexity. Second-tier analysis largely confirmed the ranking and classification of the lesions into the broad CHD severity groups, although some variation was noted, specifically among non-cardiac specialists. This simplified version of the classicisation system, with morphology as a stand-alone predictor of severity, allowed for effective stratification for the purposes of analysis. The findings presented here support this comprehensive and simple CHD severity classification system with broad utility in CHD research, particularly among clinicians and researchers with limited knowledge of CHD. The model may be applied to produce locally relevant research tools.

Cryodehydration applied to bovine fetal hearts: A model for studying cardiac organogenesis.

The study aimed to standardize the cryodehydration technique for bovine fetal hearts, focusing on optimizing protocols for each developmental stage to preserve morphological characteristics. We analyzed 29 bovine fetal hearts categorized into early, middle, and late developmental stages. These hearts underwent cryodehydration until a 60%-70% reduction in original fluid volume was achieved. Biometric data were recorded and statistically analyzed using Pearson correlation tests for age versus weight and age versus number of cryodehydration sessions. Morphometric comparisons before and after cryodehydration were performed using paired t-tests. In Group I, hearts exhibited well-defined structures, including the atrium cordis, ventriculus cordis, auricula atrii, aorta, truncus pulmonalis, and ramus coronaries arteria, which were preserved in Groups II and III. Additionally, in Group I the heart had a conical or flat apex cordis, whereas those in Groups II and III had a more pronounced apex. The average number of cryodehydration sessions required was 9.38 (±1.2) days for Group I, 12.37 (±1.4) days for Group II, and 15 days for Group III. A positive correlation was found between age and sample weight, indicating that more developed hearts were heavier. Similarly, there was a positive correlation between gestational age and the number of cryodehydration sessions, suggesting that more advanced stages required more cryodehydration sessions. Paired t-tests demonstrated high statistical significance in the morphometric parameters before and after cryodehydration, indicating a loss of mass during dehydration. However, there was no alteration in the macroscopic structure of the hearts, which remained morphologically preserved. In conclusion, cryodehydration shows promise for preserving and analyzing the external morphological characteristics of bovine fetal cardiac development. It also provides lightweight, odorless, and easy-to-handle specimens ideal for detailed morphological studies and offers a unique perspective for investigating cardiac morphology in biological research contexts.

TRAITER: Transformer-guided diagnosis and prognosis of heart failure using cell nuclear morphology and DNA damage marker.

Heart failure (HF), a major cause of morbidity and mortality, necessitates precise diagnostic and prognostic methods. This study presents a novel deep learning approach, Transformer-based Analysis of Images of Tissue for Effective Remedy (TRAITER), for HF diagnosis and prognosis. Employing image segmentation techniques and a Vision Transformer, TRAITER predicts HF likelihood from cardiac tissue cell nuclear morphology images and the potential for left ventricular reverse remodeling (LVRR) from dual-stained images with cell nuclei and DNA damage markers. In HF prediction using 31,158 images from 9 patients, TRAITER achieved 83.1% accuracy. For LVRR prediction with 231,840 images from 46 patients, TRAITER attained 84.2% accuracy for individual images and 92.9% for individual patients. TRAITER outperformed other neural network models in terms of receiver operating characteristics, and precision-recall curves. Our method promises to advance personalized HF medicine decision-making. The source code and data are available at the following link: Https://github.com/HamanoLaboratory/predict-of-HF-and-LVRR. Supplementary data are available at Bioinformatics online.

Mitochondrial Creatine Kinase 2 (Ckmt2) as a Plasma-Based Biomarker for Evaluating Reperfusion Injury in Acute Myocardial Infarction.

Acute myocardial infarction (AMI), characterized by irreversible heart muscle damage and impaired cardiac function caused by myocardial ischemia, is a leading cause of global mortality. The damage associated with reperfusion, particularly mitochondrial dysfunction and reactive oxygen species (ROS) formation, has emerged as a crucial factor in the pathogenesis of cardiac diseases, leading to the recognition of mitochondrial proteins as potential markers for myocardial damage. This study aimed to identify differentially expressed proteins based on the type of cardiac injury, in particular those with and without reperfusion. Male C57Bl/6J mice were either left untreated, sham-operated, received non-reperfused AMI, or reperfused AMI. Twenty-four hours after the procedures, left ventricular (LV) function and morphological changes including infarct size were determined using echocardiography and triphenyl tetrazolium chloride (TTC) staining, respectively. In addition, plasma was isolated and subjected to untargeted mass spectrometry and, further on, the ELISA-based validation of candidate proteins. We identified mitochondrial creatine kinase 2 (Ckmt2) as a differentially regulated protein in plasma of mice with reperfused but not non-reperfused AMI. Elevated levels of Ckmt2 were significantly associated with infarct size and impaired LV function following reperfused AMI, suggesting a specific involvement in reperfusion damage. Our study highlights the potential of plasma Ckmt2 as a biomarker for assessing reperfusion injury and its impact on cardiac function and morphology in the acute phase of MI.

Importance of environmental signals for cardiac morphological development in Atlantic salmon.

The hearts of salmonids display remarkable plasticity, adapting to various environmental factors that influence cardiac function and demand. For instance, in response to cold temperature, the salmonid heart undergoes growth and remodeling to counterbalance the reduced contractile function associated with dropping temperatures. Alongside heart size, the distinct pyramidal shape of the wild salmonid heart is essential for optimal cardiac performance, yet the environmental drivers behind this optimal cardiac morphology remain to be fully understood. Intriguingly, farmed salmonids often have rounded, asymmetrical ventricles and misaligned bulbi from an early age. These deformities are noteworthy given that farmed salmon are often not exposed to natural cues, such as a gradual temperature increase and changing day lengths, during critical developmental stages. In this study, we investigated whether natural environmental conditions during early life stages are pivotal for proper cardiac morphology. Atlantic salmon were raised under simulated natural conditions (low temperature with a natural photoperiod; SimNat) and compared with those reared under simulated farming conditions (SimFarm). Our findings reveal that the ventricle shape and bulbus alignment in SimNat fish closely resemble those of wild salmon, while functional analyses indicate significant differences between SimNat and SimFarm hearts, suggesting diastolic dysfunction and higher cardiac workload in SimFarm hearts. These findings highlight the profound influence of environmental factors such as water temperature and photoperiod on the structural development of the salmonid heart, underscoring the importance of early environmental conditions for cardiac health.

Effects of hemodynamic load on cardiac remodeling in fish and mammals: the value of comparative models.

The ability of the vertebrate heart to remodel enables the cardiac phenotype to be responsive to changes in physiological conditions and aerobic demand. Examples include exercise-induced cardiac hypertrophy, and the significant remodeling of the trout heart during thermal acclimation. Such changes are thought to occur in response to a change in hemodynamic load (i.e. the forces that the heart must work against to circulate blood). Variations in hemodynamic load are caused by either a volume overload (high volume of blood returning to the heart, impairing contraction) or a pressure overload (elevated afterload pressure that the heart must contract against). The changes observed in the heart during remodeling are regulated by multiple cellular signaling pathways. The cardiac response to these regulatory mechanisms occurs across levels of biological organization, affecting cardiac morphology, tissue composition and contractile function. Importantly, prolonged exposure to pressure overload can cause a physiological response - that improves function - to transition to a pathological response that causes loss of function. This Review explores the role of changes in hemodynamic load in regulating the remodeling response, and considers the cellular signals responsible for regulating remodeling, incorporating knowledge gained from studying biomedical models and comparative animal models. We specifically focus on the renin-angiotensin system, and the role of nitric oxide, oxygen free radicals and transforming growth factor beta. Through this approach, we highlight the strong conservation of the regulatory pathways of cardiac remodeling, and the specific conditions within endotherms that may be conducive to the development of pathological phenotypes.

Cardiac sarcoidosis: diagnosis and management.

Non-caseating granulomatous infiltration of the myocardium is the hallmark of cardiac sarcoidosis (CS). CS manifests clinically as conduction disturbance, ventricular arrhythmia, sudden cardiac death and/or heart failure with reduced ejection fraction. Other than confirmation through endomyocardial biopsy, a diagnosis of probable CS can be established by histological evidence of systemic sarcoidosis in addition to characteristic clinical or advanced imaging findings. Cardiac Magnetic Resonance imaging (CMR) and 18F-flurodeoxyglycose positron emission tomography (FDG-PET) are imaging modalities indispensable in the diagnosis and monitoring of CS. FDG-PET is the method of choice for identifying the active inflammatory phase of CS and in the monitoring and modifying of immunosuppressive treatment. CMR is better suited for assessing cardiac morphology and function. Both modalities are more effective in detecting CS when used in combination than either is alone. Management of CS is primarily based upon observational data of low quality due to a paucity of randomized controlled trials. Corticosteroid therapy and/or tiered-immunosuppression are the mainstays of treatment in reducing myocardial inflammation. Steroid-sparing agents aim to limit the unfavorable side-effects of a significant steroid burden. Antiarrhythmics and guideline-directed medical therapies are utilized for control of ventricular arrhythmia and left ventricular dysfunction respectively. CS necessitates multidisciplinary care in specialized centers to most effectively diagnose and manage the disease. Additional randomized trials are warranted to further our understanding of medical optimization in CS.

Changes in Cardiac Morphology and Visceral Fat After the Use of Testosterone Associated with Aerobic Exercise in Wistar Rats Induced Diabetes

Changes in Cardiac Morphology and Visceral Fat After the Use of Testosterone Associated with Aerobic Exercise in Wistar Rats Induced Diabetes

Effects of Mitral Calcification in Severe Aortic Stenosis with Severe Mitral Regurgitation on Left Heart Remodeling, Surgical Strategy, and Outcomes

To localize and quantify mitral calcification associated with severe aortic stenosis and severe mitral regurgitation and determine its association with cardiac remodeling, operative management, and long-term survival. From July 1998 to July 2010, 158 patients with severe aortic stenosis, severe mitral regurgitation, and mitral calcification underwent surgical aortic valve replacement (SAVR, n=49) or SAVR plus mitral valve repair (SAVR+MVr, n=67) or replacement (SAVR+MVR, n=42). Mitral calcium was localized and quantified on preoperative computed tomography. Random forest methodology was used to correlate calcium volume with cardiac morphology and function. Median follow-up for survival was 4.1 years; 25% were followed ≥14 years. Larger calcium volume was associated with degenerative mitral disease, higher ejection fraction, smaller left ventricular end-systolic volume, and SAVR+MVR (median calcium volume 3.4 cm3) versus SAVR (median calcium volume 1.0 cm3) or SAVR+MVr (median calcium volume 0.41 cm3). Ten-year mortality was higher in patients with more mitral calcification (terciles: 7.1% vs 16% vs 25%), subvalvular involvement (8.1% vs 18%), and SAVR+MVR (5.4% vs SAVR=13% vs SAVR+MVr=26%). Multivariable analysis demonstrated early postoperative mortality was strongly associated with subvalvular mitral calcification, but late mortality was not associated with calcium volume or location. Larger mitral calcium volume is a marker of late-stage cardiac remodeling associated with more extensive mitral valve intervention, but it is not associated with long-term mortality. Quantitative analysis of mitral calcification with computed tomography can aid in patient selection and surgical management decisions in this complex patient population.

Aspirin reduces Ponatinib-induced cardiovascular toxic phenotypes and death in zebrafish

BackgroundPonatinib (Iclusig) is an oral tyrosine kinase BCR-ABL inhibitor for treating patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML) who are resistant to the therapies with other tyrosine kinase inhibitors. However, adverse cardiovascular events caused by Ponatinib are a serious issue that affects patients' survival rates. Thus, it is necessary to search for candidate drugs to reduce the cardiovascular toxicity of Ponatinib. PurposeTo investigate the effects of Aspirin on Ponatinib-induced cardiovascular toxicity in zebrafish. MethodsAB strain of wild type zebrafish (Danio rerio), Tg (cmlc2: GFP) transgenic zebrafish, and Tg (gata1: dsRed) transgenic zebrafish were used as in vivo models to assess survival, blood flow, cardiac morphology, and function. Thrombus formation was detected using O-dianisidine staining. The transcriptome of zebrafish larvae treated with Ponatinib was assessed using RNA sequencing. ResultsPonatinib not only reduced survival rate but also caused cardiovascular toxic events such as pericardial edema, abnormal heart structure, low heart rate, and thrombosis. In addition, whole-body transcriptome analysis showed that Ponatinib up-regulated the expression of cyclooxygenase-1 (COX-1). Compared with other antithrombotic drugs, a COX-1 inhibitor Aspirin more effectively reduced ponatinib-induced cardiovascular toxicity events and improved the survival rate of zebrafish larvae. ConclusionOur findings suggest that Aspirin exhibits the potential to reduce Ponatinib-induced cardiovascular toxicity.