Myocardial Disarray Research Articles

Myocardial Disarray and Fibrosis across Hypertrophic Cardiomyopathy Stages Associate with ECG Markers of Arrhythmic Risk.

Myocardial disarray, an early feature of hypertrophic cardiomyopathy (HCM) and a substrate for ventricular arrhythmia, is poorly characterised in prehypertrophic sarcomeric variant carriers (SARC+LVH-). Using diffusion tensor cardiac magnetic resonance (DT-CMR) we assessed myocardial disarray and fibrosis in both SARC+LVH- and HCM patients and evaluated the relationship between microstructural alterations and electrocardiographic (ECG) parameters associated with arrhythmic risk. Sixty-two individuals (24 SARC+LVH-, 24 HCM and 14 matched controls) were evaluated with multiparametric CMR including stimulated echo acquisition mode (STEAM) DT-CMR, and blinded quantitative 12-lead ECG analysis. Mean diastolic fractional anisotropy (FA) was reduced in HCM compared to SARC+LVH- and controls (0.49±0.05 vs 0.52±0.04 vs 0.53±0.04, p=0.009), even after adjustment for differences in extracellular volume (ECV) (p=0.038). Both HCM and SARC+LVH- had segments with significantly reduced FA relative to controls (54% vs 25% vs 0%, p=0.002). Multiple repolarization parameters were prolonged in HCM and SARC+LVH-, with corrected JT interval (JTc) being most significant (354±42ms vs 356±26ms vs 314±26ms, p=0.002). Among SARC+LVH-, JTc duration correlated negatively with mean FA (r=-0.6, p=0.002). In HCM, the JTc interval showed a stronger association with ECV (r=0.6 p=0.019) than FA (r=-0.1 p=0.72). JTc discriminated SARC+LVH- from controls (Area-under-the-receiver-operator-curve 0.88, CI 0.76-1.00, p<0.001), and in HCM correlated with the ESC HCM sudden cardiac death risk score (r=0.5, p=0.014). Low diastolic FA, suggestive of myocardial disarray, is present in both SARC+LVH- and HCM. Low FA and raised ECV were associated with repolarization prolongation. Myocardial disarray assessment using DT-CMR and repolarization parameters such as the JTc interval demonstrate significant potential as markers of disease activity in HCM.

Genetic variants associated with cardiac hypertrophy-related sudden cardiac death and cardiovascular outcomes in a Finnish population

BackgroundHypertrophic cardiomyopathy is a common cause of non-ischaemic sudden cardiac death (SCD). Left ventricular hypertrophy (LVH) without cardiomyopathy-related myocardial disarray is a common autopsy finding and is often associated with...

Storytelling of Hypertrophic Cardiomyopathy Discovery.

The discovery of hypertrophic cardiomyopathy (HCM) dates back to 1958, when the pathologist Donald Teare of the St. George's Hospital in London performed autopsies in eight cases with asymmetric hypertrophy of the ventricular septum and bizarre disorganization (disarray) at histology, first interpreted as hamartoma. Seven had died suddenly. The cardiac specimens were cut along the long axis, similar to the 2D echo. In the same year, at the National Institute of Health U.S.A., Eugene Braunwald, a hemodynamist, and Andrew Glenn Morrow, a cardiac surgeon, clinically faced a patient with an apparently similar morbid entity, with a systolic murmur and subaortic valve gradient. "Discrete" subaortic stenosis was postulated. However, at surgery, Dr. Morrow observed only hypertrophy and performed myectomy to relieve the obstruction. This first Braunwald-Morrow patient underwent a successful cardiac transplant later at the disease end stage. The same Dr. Morrow was found to be affected by the familial HCM and died suddenly in 1992. The term "functional subaortic stenosis" was used in 1959 and "idiopathic hypertrophic subaortic stenosis" in 1960. Years before, in 1957, Lord Brock, a cardiac surgeon at the Guy's Hospital in London, during alleged aortic valve surgery in extracorporeal circulation, did not find any valvular or discrete subaortic stenoses. In 1980, John F. Goodwin of the Westminster Hospital in London, the head of an international WHO committee, put forward the first classification of heart muscle diseases, introducing the term cardiomyopathy (dilated, hypertrophic, and endomyocardial restrictive). In 1995, the WHO classification was revisited, with the addition of two new entities, namely arrhythmogenic and purely myocardial restrictive, the latter a paradox of a small heart accounting for severe congestive heart failure by ventricular diastolic impairment. A familial occurrence was noticed earlier in HCM and published by Teare and Goodwin in 1960. In 1989-1990, the same family underwent molecular genetics investigation by the Seidman team in Boston, and a missense mutation of the β-cardiac myosin heavy chain in chromosome 14 was found. Thus, 21 years elapsed from HCM gross discovery to molecular discoveries. The same original family was the source of both the gross and genetic explanations of HCM, which is now named sarcomere disease. Restrictive cardiomyopathy, characterized grossly without hypertrophy and histologically by myocardial disarray, was found to also have a sarcomeric genetic mutation, labeled "HCM without hypertrophy". Sarcomere missense mutations have also been reported in dilated cardiomyopathy (DCM) and non-compaction cardiomyopathy. Moreover, sarcomeric gene defects have been detected in some DNA non-coding regions of HCM patients. The same mutation in the family may express different phenotypes (HCM, DCM, and RCM). Large ischemic scars have been reported by pathologists and are nowadays easily detectable in vivo by cardiac magnetic resonance with gadolinium. The ischemic arrhythmic substrate enhances the risk of sudden death.

Pathophysiological and Pedigree Analysis of Left Ventricular Noncompaction in Japanese Macaques (Macaca fuscata).

Left ventricular noncompaction (LVNC) involving genetic mutation is categorized as an unclassified cardiomyopathy, and its diagnostic criteria have not been standardized. This could be because precise animal models of LVNC have not been created in any laboratory animal species. This study aimed to analyze the pathophysiology and familial tendency of LVNC in Japanese macaques. Two Japanese macaques with LVNC, and their parents who were suspected of having cardiac disease, were examined. One macaque with LVNC was examined using chest radiography, echocardiography, cardiac biomarkers, cardiac MRI, and pathologic examination, and the other macaque was examined using chest radiography, echocardiography, and cardiac biomarkers. Their common father and the mother of one of the macaques with LVNC were tested for chest radiography and cardiac biomarkers. Echocardiography revealed a meshwork with trabeculation and deep intertrabecular recesses in all their left ventricular walls. The 2 macaques with LVNC demonstrated a layered appearance of the myocardium, consisting of noncompacted myocardium on the endocardial side and compacted myocardium on the epicardial side, with a noncompacted/compacted ratio of 6.0 and 5.8, respectively. One of the 2 macaques with LVNC (case 1) had elevated levels of troponin I, troponin T, atrial natriuretic peptide, and brain natriuretic peptide. The second macaque with LVNC (case 2) showed blood flow in the intertrabecular recesses on echocardiography. The common father (case 3) of the 2 macaques with LVNC and the mother (case 4) of one of the macaques with LVNC had elevated levels of troponin I and troponin T. In case 1, histopathologic examination revealed fibrous thickening of the endocardium, fibrosis of the myocardial interstitium, myocardial disarray, vacuolar degeneration, anisonucleosis, and necrosis of myocardial cells. This suggests that Japanese macaques could serve as a reliable animal model of human LVNC.

Heterogenous atrial conduction in patients with hypertrophic cardiomyopathy and atrial fibrillation

Abstract Background/Introduction Hypertrophic cardiomyopathy (HCM) is characterised by myocardial thickening, fibrosis, and disarray, affecting both ventricles and atria. This pathology extends to atrial tissue, potentially influencing conductivity and contributing to arrhythmias, notably atrial fibrillation (AF). Pulmonary vein isolation to treat AF in HCM patients yields less satisfactory results compared to other patient groups. Improved understanding of the pathophysiology of AF in HCM patients could improve treatment stratification and delivery. Purpose This study aims to analyse atrial conduction properties in HCM patients with AF, compared to age, body mass index and sex-matched control patients. Methods Pre-ablation electroanatomic mapping data from 10 HCM patients and a matched control group of patients with structurally normal hearts undergoing AF ablation was retrospectively analysed. All patients underwent pre-ablation electroanatomic mapping during proximal coronary sinus pacing. This data was analysed using OpenEP software to quantify voltage mapping, conduction velocity and wave collision points. Conduction velocity was calculated using both plane fitting and triangulation methods. Wave collisions were identified by calculating the percentage of points with conduction velocity field divergence values less than -1.5. Results HCM patients exhibited significantly reduced mean left atrial bipolar voltage and greater low voltage burden &amp;lt;0.5mV than matched control patients (1.43mV vs. 2.14mV, p=0.0177; and 38.28% vs. 15.68%, p&amp;lt;0.0001), (Figure 1A and B). Wave collision points were significantly more prevalent in the HCM group (5.4% vs. 1.6%, p=0.0004), indicating more heterogeneous conduction (Figure 1C). Figure 2 shows example of divergence map with local electrograms around wave collision points. Both methods of quantifying conduction velocity showed comparable results. While average conduction velocity showed no statistically significant difference (plane fitting method - 0.61m/s in HCM group vs. 0.64m/s in control group, p = 0.465; triangulation method - 0.61m/s in HCM group, 0.64m/s in control group, p=0.393), a trend toward lower velocities in HCM patients was observed (Figure 1D and 1E). Conclusion HCM patients demonstrate significantly lower bipolar voltage and significantly greater low voltage areas than matched control patients. Atrial conduction in patients with HCM is significantly more heterogenous than matched control patients. These findings highlight marked conduction abnormalities in HCM patients which are likely to contribute to AF pathogenesis.

A New Inherited Syndrome Causing Sudden Cardiac Death with Distinct ST-Segment Depression and Ankyrin-2-Mutation.

Sudden cardiac death (SCD) is a serious threat. In individuals under the age of 35 years sudden arrhythmic death is the most frequent cause. In younger persons, genetically determined cardiac diseases (eg, cardiomyopathies and ion-channel diseases) account for an important proportion of these cases. We investigated the case of a 23-year-old male with SCD, specific ECG changes and left ventricular hypertrophy. Family history was significant for SCD in the paternal line. A precise analysis was performed by an international multidisciplinary expert panel including autopsy of the index patient's heart, molecular autopsy, whole-exome sequencing, analysis of the pedigree and examination of available family members. Three cases of SCD were reported in paternal relatives. The index patient exhibited specific ECG changes (ST-depression), which were also found in five paternal relatives and the brother of the index patient. Post-mortem analysis of the heart yielded mild idiopathic concentric hypertrophy without myocardial disarray. The genetic analysis of the index patient showed two nucleotide variations in two different genes (ANK2: c.11791G>A, MYO18B: c.3761G>A), which were also expressed in five relatives. Two family members had showed all indicators of the inherited syndrome including distinct ECG changes and genetic changes. We describe a distinct inheritable syndrome causing SCD, characterized by specific ECG changes and mutations of ANK2 and MYO18. As far as we know this is the first description of this syndrome.

Cryo-X-ray phase contrast imaging enables whole biopsy imaging prior to multi-omic analysis

Abstract Background Analysis of myocardial biopsies using conventional two-dimensional (2D) histological techniques is limited in the detection of important three-dimensional (3D) structural features, such as disarray, due to sectioning and artefacts from dehydration or chemical processing. More advanced techniques such as light-sheet microscopy, micro-computed tomography or synchrotron radiation-based X-ray phase contrast imaging can provide non-destructive, 3D histological information at high resolution for formalin-fixed and/or paraffin-embedded (FFPE) biopsies. However, formalin fixation induces crosslinking of proteins which can impact quality and their subsequent analysis, for example, fragmentation of nucleic acids. A method for imaging 3D structure of myocardial biopsies in near-native state is needed which can then be followed by downstream multi-omic applications. Purpose To develop a technique called cryogenic X-ray phase contrast imaging (Cryo-X-PCI) to image snap-frozen myocardial biopsies at controlled low temperatures, followed by multi-omic analysis starting with analysis of DNA and RNA. Methods Myocardial biopsies (n=46) were obtained from C57BL/6 mice and snap-frozen in liquid nitrogen fresh or after 4% paraformaldehyde (PFA);10% formalin fixation. Pilot human aortic stenosis biopsies were also included (n=3, fresh). X-PCI was performed at -70°C using a cryojet, 20 keV beam energy and 0.65 µm detector pixel size (Figure 1). Datasets were reconstructed using Gridrec algorithm and Paganin phase retrieval. Morphologic analysis (myocardial disarray index, fractional anisotropy, helical angle, and intrusion angle) of biopsies was performed using a structure tensor-based approach via in-house MATLAB script. After imaging, DNA and RNA were extracted from murine biopsies followed by assessment of quantity and quality. Results Increased intercellular space between aggregates of myocytes was observed in all samples. This is consistent with reported findings in skeletal muscle using cryogenic conditions. Nonetheless, morphologic analysis of the biopsies proved possible (Figure 2). Optimal recovery of DNA and RNA was obtained from fresh frozen samples as compared to 4% PFA-fixed or 10% formalin-fixed samples. Conclusions This study demonstrates Cryo-X-PCI as a potential tool for analysing myocardial biopsies of heart muscle disease including morphologic analyses. Levels of DNA and RNA were not significantly affected indicating that downstream genomics, proteomics and transcriptomics analyses should be feasible.Setup for Cryo-X-PCI of frozen biopsiesMorphologic analysis of a biopsy

Electrophysiological and Histopathological Characteristics of Ventricular Tachycardia Associated With Primary Cardiac Tumors

BackgroundVentricular tachycardia (VT) associated with primary cardiac tumors (PCTs) originating from the ventricles is rare, but lethal, in young patients. ObjectivesThis study aimed to clarify the mechanisms underlying primary cardiac tumor-related ventricular tachycardia (PCT-VT) and establish a therapeutic strategy for this form of VT. MethodsAmong 67 patients who underwent surgery for VT at our institute between 1981 and 2020, 4 patients aged 1 to 34 years, including 3 males, showed PCT-VT (fibroma, 2; lipoma, 1; and hamartoma, 1), which was investigated using a combination of intraoperative electroanatomical mapping and histopathological studies. ResultsAll 4 patients developed electrical storms of sustained VTs refractory to multiple drugs and repetitive endocardial ablations. The VT mechanism was re-entry, and intraoperative electroanatomical mapping showed a centrifugal activation pattern originating from the border between the tumor and healthy myocardium, where fractionated potentials were detected during sinus rhythm. Histopathological studies of serial sections of specimens acquired from these areas revealed tumor infiltration into the surrounding myocardium with cell disorganization, exhibiting myocardial disarray. Several myocardia entrapped in the tumor edges contributed to the development and sustainment of re-entrant VT activation. In the 2 patients in whom complete resection was unfeasible, encircling cryoablation to entirely isolate the unresectable tumor was effective in suppressing VT occurrence. ConclusionsThe mechanism underlying PCT-VT involves re-entry localized at the tumor edges. Myocardial disarray associated with tumor infiltration is a substrate for this form of VT. Cryoablation along the border between the tumor and myocardium is a promising therapeutic option for unresectable PCT-VT.

Revisiting Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Current Practice and Novel Perspectives.

Sarcomeric hypertrophic cardiomyopathy (HCM) is a prevalent genetic disorder characterised by left ventricular hypertrophy, myocardial disarray, and an increased risk of heart failure and sudden cardiac death. Despite advances in understanding its pathophysiology, treatment options for HCM remain limited. This narrative review aims to provide a comprehensive overview of current clinical practice and explore emerging therapeutic strategies for sarcomeric HCM, with a focus on cardiac myosin inhibitors. We first discuss the conventional management of HCM, including lifestyle modifications, pharmacological therapies, and invasive interventions, emphasizing their limitations and challenges. Next, we highlight recent advances in molecular genetics and their potential applications in refining HCM diagnosis, risk stratification, and treatment. We delve into emerging therapies, such as gene editing, RNA-based therapies, targeted small molecules, and cardiac myosin modulators like mavacamten and aficamten, which hold promise in modulating the underlying molecular mechanisms of HCM. Mavacamten and aficamten, selective modulators of cardiac myosin, have demonstrated encouraging results in clinical trials by reducing left ventricular outflow tract obstruction and improving symptoms in patients with obstructive HCM. We discuss their mechanisms of action, clinical trial outcomes, and potential implications for the future of HCM management. Furthermore, we examine the role of precision medicine in HCM management, exploring how individualised treatment strategies, including exercise prescription as part of the management plan, may optimise patient outcomes. Finally, we underscore the importance of multidisciplinary care and patient-centred approaches to address the complex needs of HCM patients. This review also aims to encourage further research and collaboration in the field of HCM, promoting the development of novel and more effective therapeutic strategies, such as cardiac myosin modulators, to hopefully improve the quality of life and outcome of patients with sarcomeric HCM.

A Mouse Model of Dilated Cardiomyopathy Produced by Isoproterenol Acute Exposure Followed by 5-Fluorouracil Administration.

Appropriate dilated cardiomyopathy (DCM) animal models are highly desirable considering the pathophysiological and clinical heterogeneity of DCM. Genetically modified mice are the most widely and intensively utilized research animals for DCM. However, to translate discoveries from basic science into new and personalized medical applications, research in non-genetically based DCM models remains a key issue. Here, we characterized a mouse model of non-ischemic DCM induced by a stepwise pharmacologic regime of Isoproterenol (ISO) high dose bolus followed by a low dose systemic injection of the chemotherapy agent, 5-Fluorouracil (5-FU). C57BL/6J mice were injected with ISO and, 3 days after, were randomly assigned to saline or 5-FU. Echocardiography and a strain analysis show that ISO + 5FU in mice induces progressive left ventricular (LV) dilation and reduced systolic function, along with diastolic dysfunction and a persistent global cardiac contractility depression through 56 days. While mice treated with ISO alone recover anatomically and functionally, ISO + 5-FU causes persistent cardiomyocyte death, ensuing in cardiomyocyte hypertrophy through 56 days. ISO + 5-FU-dependent damage was accompanied by significant myocardial disarray and fibrosis along with exaggerated oxidative stress, tissue inflammation and premature cell senescence accumulation. In conclusions, a combination of ISO + 5FU produces anatomical, histological and functional cardiac alterations typical of DCM, representing a widely available, affordable, and reproducible mouse model of this cardiomyopathy.

Clinical findings using echocardiography and plasma cardiac troponin I and pathological findings in dogs with hypertrophic cardiomyopathy: A retrospective study.

Hypertrophic cardiomyopathy (HCM) is considered rare in dogs, and there is a lack of clinical data. Cardiac troponin I (cTnI) is a biomarker of cardiomyocyte damage and necrosis and can be used to diagnose cat and human HCM. We investigated whether the presence of cTnI in clinical data can be used in conjunction with echocardiography to diagnose canine HCM. This study comprised client-owned dogs with clinical evidence of concentric hypertrophy on echocardiographic images, serum total thyroxine levels of ≤5 µg/dl, systolic blood pressure of ≤180 mmHg, and absence of aortic stenosis. All cases were necropsied. Cardiomyocyte hypertrophy (mean diameter, 18.3 ± 1.8 µm), myocardial fiber disarray (70%), interstitial fibrosis (80%), and small vessel disease (100%) were assessed. In dogs with HCM, the left ventricles were concentric, almost symmetrical, and hypertrophied above the aortic diameter. The end-diastolic interventricular septum normalized to body weight [intraventricular septal thickness in diastole (IVSDN)] was 0.788 [interquartile range (IQR), 0.7-0.92], which exceeded the normal range (5%-95%, IQR: 0.33-0.52). In total, 70% of the dogs with HCM had syncope and dyspnea, and all dogs had high cTnI levels (median, 3.94 ng/ml), exceeding the upper limit of normal (0.11 ng/ml) and indicating cardiomyocyte damage. IVSDN and serum cTnI levels were correlated (ρ = 0.839, p = 0.01). Ventricular wall thickening and high serum cTnI levels can provide a presumptive diagnosis of HCM and prompt the initiation of treatment or additional diagnostic investigations.

Hydrogen sulfide alleviates uremic cardiomyopathy by regulating PI3K/PKB/mTOR-mediated overactive autophagy in 5/6 nephrectomy mice.

The gasotransmitter hydrogen sulfide (H2S) plays important physiological and pathological roles in the cardiovascular system. However, the involvement of H2S in recovery from uremic cardiomyopathy (UCM) remains unclear. This study aimed to determine the therapeutic efficacy and elucidate the underlying mechanisms of H2S in UCM. A UCM model was established by 5/6 nephrectomy in 10-week-old C57BL/6 mice. Mice were treated with sodium hydrosulfide (NaHS, H2S donor), L-cysteine [L-Cys, cystathionine gamma-lyase (CSE) substrate], and propargylglycine (PPG, CSE inhibitor). Treatment of H9C2 cardiomyocytes utilized different concentrations of uremic serum, NaHS, PPG, and PI3K inhibitors (LY294002). Mouse heart function was assessed by echocardiography. Pathological changes in mouse myocardial tissue were identified using hematoxylin and eosin and Masson's trichrome staining. Cell viability was assessed using the Cell Counting Kit-8. The protein expressions of CSE, p-PI3K, PI3K, p-PKB, PKB, p-mTOR, mTOR, and autophagy-related markers (Beclin-1, P62, and LC3) were detected using Western blotting. We found that NaHS and L-Cys treatment attenuated myocardial disarray, fibrosis, and left ventricular dysfunction in UCM mice. These abnormalities were further aggravated by PPG supplementation. Enhanced autophagy and decreased phosphorylation of PI3K, PKB, and mTOR protein expression by UCM were altered by NaHS and L-Cys treatment. In vitro, uremic serum increased overactive autophagy and decreased the phosphorylation levels of PI3K, PKB, and mTOR in cardiomyocytes, which was substantially exacerbated by endogenous H2S deficiency and attenuated by pre-treatment with 100µm NaHS. However, the protective effects of NaHS were completely inhibited by LY294002. These findings support a protective effect of H2S exerted against UCM by reducing overactive autophagy through activation of the PI3K/PKB/mTOR pathway.

Abstract 15848: Prognostic Value of Left Ventricular Diastolic Function in Patients With Hypertrophic Cardiomyopathy

Background: Diastolic dysfunction (DD) is frequently present in patients with hypertrophic cardiomyopathy (HCM) due to abnormal left ventricular (LV) relaxation, wall hypertrophy, increased LV filling pressures and myocardial disarray and fibrosis, even though ejection fraction (EF) remains preserved until late stages. Our aim was to investigate in a large cohort whether contemporary markers of DD and increased filling pressures are associated with outcomes in these patients. Methods: We screened consecutive patients with HCM who had transthoracic echocardiography and no significant valvular heart disease. The associations of septal/lateral e’ velocity, E/e’, left atrial volume index (LAVi), and tricuspid regurgitant velocity (TR) with all-cause mortality were tested. A diastolic score (DS) was also calculated (1 point for each abnormality in e’, E/e’, TR, LAVi). Results: 1,496 patients with HCM were studied (mean age 52±15 yrs; 61% men; LV EF 69±7%; Table). Diastolic abnormalities were highly prevalent in these patients ( Table ). In the subset without septal reduction therapy (SRT; n=900), at a median followup of 9 years (IQR 7-11 yrs; n=78 deaths), increased E/e’ and DS were strongly associated with mortality (log-rank P &lt;.0001 for both; Figure ). However, E/e’ did not remain significant in multivariable models after adjustment for known cardiac risk factors or other significant confounders ( Table ). In contrast, DS &gt;2 remained independently associated with ~2-fold higher mortality risk (adjusted HR 1.91 [1.14-3.20, P =.01]; n=693; Table). In patients who underwent SRT (n=596), these associations showed the same trend but attenuated. Conclusion: In HCM patients who did not require SRT, the severity of DD was associated with mortality, independent of cardiac pump function or known cardiac risk factors. The composite score was more powerful than E/e’. Further studies are needed to fully understand the impact of DD in these patients with and without SRT.

Abstract 14068: Reduced Left Atrial Conduction Velocity in Patients With Hypertrophic Cardiomyopathy and Normal Left Atrial Voltage Presenting for Paroxysmal Atrial Fibrillation Ablation

Introduction: Patients with hypertrophic cardiomyopathy (HCM) exhibit abnormal cardiac tissue arrangement characterized as myocardial disarray. The incidence of atrial fibrillation (AF) is increased 4-fold in patient with HCM and confers a 4-fold increased risk of death. Catheter ablation is less effective in HCM, with a 2-fold increased risk of AF recurrence. The mechanisms of AF perpetuation and recurrence in HCM are poorly understood. We sought to investigate the left atrial conduction characteristics in patients with HCM, paroxysmal AF and normal left atrial bipolar voltage. Methods: We analyzed 24 consecutive patients with HCM and 24 consecutive controls, all presenting for radiofrequency (RF) ablation of paroxysmal atrial fibrillation. Only patients with normal left atrial voltage (mean voltage &gt;0.8 mV) were included in the study. Intracardiac electrograms were extracted from CARTO (Biosense Webster Inc.) mapping system and analyzed using custom Matlab/Python code interfacing with Core OpenEP software. Conduction velocity was calculated using local activation time gradients. Results: There was no difference in baseline demographic characteristics or atrial size measured by echocardiography between HCM and control patients. Patients with HCM had significantly reduced atrial conduction velocity and conduction velocity dispersion compared to controls (Fig A,C) [0.62±0.03 m/s vs 0.44±0.04 m/s, p=0.002], despite no differences in bipolar voltage (Fig B,D) or voltage dispersion. Patients with HCM had significantly less freedom from AF than controls after catheter ablation [OR for recurrence 3.3 (1.02-10.90), p&lt;0.05 vs control]. Conclusion: Atrial conduction velocity and dispersion is significantly reduced in patients with HCM and paroxysmal AF, possibly contributing to arrhythmia perpetuation and persistence after catheter ablation. This finding may be useful in characterizing left atrial properties beyond bipolar voltage.

Mitral valve abnormalities in decedents of sudden cardiac death due to hypertrophic cardiomyopathy and idiopathic left ventricular hypertrophy

Abstract Background The sole identification of left ventricular hypertrophy (LVH) in a young individual that died suddenly may often lead to an erroneous diagnosis of hypertrophic cardiomyopathy (HCM). Emerging data suggests that idiopathic LVH (ILVH) and HCM may be separate entities. Aim We aimed to report on the prevalence and nature of mitral valve (MV) abnormalities, in a cohort of sudden cardiac death (SCD) victims with a post-mortem examination consistent with HCM and ILVH. Methods We reviewed 6860 consecutive cases of SCD referred to our specialist cardiac pathology centre between 1994 and 2020. SCD was defined as death from a cardiovascular cause within 12 hours of apparent well-being. HCM was defined by the presence of LVH, in the absence of abnormal loading conditions and characterised by myocyte disarray at histology. ILVH was defined as unexplained LVH (heart weight &amp;gt;500 g in males and &amp;gt;400 g in females) and left ventricular (LV) wall thickness &amp;gt;15mm, in the absence of myocardial disarray or secondary causes of LVH. The MV was examined for patency, circumference, thickening, nodularity, ballooning, bulging between cords, perforation, and the presence of impact lesions in the LV outflow tract (LVOT) and aortic outlet. Results Of the total cases of SCD, 264 (4%) were due to HCM (mean age 41±18 years, 78% males, LV maximal wall thickness 19±6 mm) (Figure 1). Ante-mortem symptoms were reported in 44 (17%) cases and for the majority (n=217, 82%) HCM was established at post-mortem. Death was attributed to ILVH in 253 (3%) cases (mean age 43±16 years, 80% males, LV maximal wall thickness 18±4 mm). MV abnormalities were found in 58 (22%) decedents with HCM (mean age 38±17 years; 72% males) and in 13 (5%) decedents with ILVH (mean age 55±15 years; 77% male), p&amp;lt;0.001. Amongst the 58 (22%) cases with HCM and MV abnormalities, 15 (6%) cases had multiple MV abnormalities. These included impact lesions associated with thickening of the anterior leaflet of the MV (n=39) and degenerative changes (n=34) such as bulging and ballooning; and thickening and nodularity. Decedents with HCM exhibiting MV abnormalities were younger than decedents with a normal MV (38±17 versus 45±19 years; p=0.08). Among the 253 decedents with ILVH, 13 (5%) cases exhibited MV abnormalities, which largely included degenerative changes (n=12). Among decedents with HCM and ILVH exhibiting MV abnormalities, the former was significantly younger (38±17 versus 55±15; p=0.001). Myocardial fibrosis was observed in 162 (61%) cases of HCM and 99 (39%) cases of ILVH, p&amp;lt;0.001. Conclusions MV abnormalities are over four-fold more common in individuals with HCM than those with ILVH and may be considered as additional macroscopic features to differentiate between these two entities. Furthermore, the inherent descriptive terminologies used when assessing the MV, support a greater emphasis on the standardisation and quantification of MV abnormalities as part of the autopsy in victims of SCD. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Acknowledgements: We thank the charitable organisation, Cardiac Risk in the Young (CRY) who fund and support the CRY Cardiovascular Pathology Unit and CRY database.

Mitral valve abnormalities in decedents of sudden cardiac death due to hypertrophic cardiomyopathy and idiopathic left ventricular hypertrophy.

Mitral valve abnormalities in decedents of sudden cardiac death due to hypertrophic cardiomyopathy and idiopathic left ventricular hypertrophy.

Sexual dimorphism in testosterone programming of cardiomyocyte development in sheep.

Perturbed in utero hormone milieu leads to intrauterine growth retardation (IUGR), a known risk factor for left ventricular (LV) dysfunction later in life. Gestational testosterone (T) excess predisposes offspring to IUGR and leads to LV myocardial disarray and hypertension in adult females. However, the early impact of T excess on LV programming and if it is female specific is unknown. LV tissues were obtained at day 90 gestation from days 30-90 T-treated or control fetuses (n = 6/group/sex) and morphometric and molecular analyses were conducted. Gestational T treatment increased cardiomyocyte number only in female fetuses. T excess upregulated receptor expression of insulin and insulin-like growth factor. Furthermore, in a sex-specific manner, T increased expression of phosphatidylinositol 3-kinase (PI3K) while downregulating phosphorylated mammalian target of rapamycin (pmTOR)-to-mTOR ratio suggestive of compensatory response. T excess 1) upregulated atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), markers of stress and cardiac hypertrophy and 2) upregulated estrogen receptors1 (ESR1) and 2 (ESR2), but not in androgen receptor (AR). Thus, gestational T excess upregulated markers of cardiac stress and hypertrophy in both sexes while inducing cardiomyocyte hyperplasia only in females, likely mediated via insulin and estrogenic programming.NEW & NOTEWORTHY The present study demonstrates sex-specific effects of gestational T excess between days 30 and 90 of gestation on the cardiac phenotype. Furthermore, the sex-specific programming is likely secondary to perturbation in both estrogen and insulin signaling pathways collectively. These findings are supportive of the role of androgen excess to serve as early biomarkers of CVD and could be critical in identifying therapeutic targets for LV hypertrophy and predict long-term CVD.

The preferential accumulation of cadmium ions among various tissues in mice

Cadmium (Cd) is hazardous to human health because of its toxicity and long half-life of clearance. Many studies have explored the relationship between chronic Cd exposure and different human diseases. However, most of the studies limited the study targets of Cd toxicity to two or three organ systems. The goal of this study was to establish a mouse model of Cd accumulation in most organ systems and to particularly investigate the potential toxic effects of Cd to the cardiovascular system. Mice were divided into three groups: the control group, Cd-100 group, and Cd-200 group. In the control group, Cd was detected in the kidney, lung, liver, heart and urine but was undetectable in the aorta, intestine, thigh bone, spinal bone and serum. Upon chronic exposure in the Cd-100 and Cd-200 groups, Cd accumulated in all tissues, with a dramatic increase in concentration. We confirmed that Cd could accumulate significantly in the heart and aorta upon chronic exposure. This finding might help to explain the potential toxic effects of Cd on these organs. In addition, the calcium concentration in the bones and kidney declined when the exposure to Cd increased. This finding aligned with the negative effects of Cd on bony mineralization and the potential direct toxic effects of Cd on bones. The impacts of Cd on the cardiovascular system were explored. Histologically, chronic Cd exposure led to myocytes hypertrophy and myocardial architecture disarray in the Cd-100 group compared to those in the control group. Our research confirms that Cd can accumulate in all of the organs studied upon chronic exposure, and suggests that the toxicity of Cd accumulation may play important roles in mediating the pathophysiologic effects in these target organs, especially the bone and heart.

A Novel miRNA Screen Identifies miRNA-4454 as a Candidate Biomarker for Ventricular Fibrosis in Patients with Hypertrophic Cardiomyopathy.

(1) Background: Left ventricular hypertrophy, myocardial disarray and interstitial fibrosis are the hallmarks of hypertrophic cardiomyopathy (HCM). Access to the myocardium for diagnostic purposes is limited. Circulating biomolecules reflecting the myocardial disease processes could improve the early detection of HCM. Circulating miRNAs have been found to reflect disease processes in several cardiovascular diseases. (2) Methods: We quantified circulating miRNA molecules in the plasma of 24 HCM and 11 healthy controls using the Human v3 miRNA Expression Assay Kit Code set (Nanostring Tech., Seattle, WA, USA) and validated differentially expressed miRNAs using RT-PCR. (3) Results: In comparison to healthy controls, the levels of six miRNAs (miR-1, miR-3144, miR-4454, miR-495-3p, miR-499a-5p and miR-627-3p) were higher in the plasma of HCM patients than healthy individuals (p < 0.05). Of these, higher levels of miR-1, miR-495 and miR-4454 could be validated by real-time PCR. In addition, elevated miR-4454 levels were significantly correlated with cardiac fibrosis, detected by magnetic resonance imaging in HCM patients. (4) Conclusions: Circulating miR-1, miR-495-3p and miR-4454 levels are elevated in the plasma of HCM patients. To the best of our knowledge, this is the first report showing a correlation between miR-4454 levels and cardiac fibrosis in HCM. This suggests miR-4454 as a potential biomarker for fibrosis in these patients.

Routine histopathology of septal myectomy for hypertrophic obstructive cardiomyopathy in a greek cohort.

Hypertrophic cardiomyopathy (HCM) is a diverse inherited disease affecting 1 in 500 individuals irrespective of gender and ethnicity. A fraction of HCM patients will eventually develop drug refractory dynamic obstruction of the left ventricular outflow tract. For such patients, septal myectomy is the procedure of choice to alleviate their symptoms and improve their quality of life. The current histopathological study, the first from the Greek region, aims to examine the hallmark histopathological characteristics of Hypertrophic Obstructive Cardiomyopathy in a population of patients undergoing septal myectomy at a single center over a ten year period. Medical records and histopathology specimens of thirty nine (n=39) patients were evaluated. The sample comprised 22 males (56.4%) and 17 females (43.6%). Mean patient age at myectomy was 53.9±16.7 years, ranging from 12 to 79 years. Maximal IVS thickness on echocardiography was available for 35 patients with a median value of 2.08cm. Peak resting LVOT Pressure Gradient was available for 33 patients with a mean value of 104.88±44.20 mmHg. Central tendency of each histopathological attribute expressed as the median value was: moderate for myocyte hypertrophy, mild for cytoplasmic vacuolization, moderate for subendocardial fibrosis, moderate for interstitial fibrosis, mild for replacement fibrosis, moderate for myofibrillar disarray and mild for capillary stenosis. Myocyte hypertrophy, present in all specimens, was positively correlated with maximal IVS thickness (tau-b=0.43, p=0.002). Replacement fibrosis was positively correlated with the grade of microvascular stenosis (tau-b=0.45, p=0.004). LVEF was negatively correlated with the grade of interstitial fibrosis (tau-b=-0.43, p=0.035) and with the extent of myocardial fiber disarray (tau-b=-0.42, p=0.034). Histopathological attributes were not correlated with patient gender or age thus proving that HCM has a histological phenotype unique to each patient, mainly depending on each specific sarcomeric mutation.