Increased Left Ventricular Wall Thickness Research Articles

Electrocardiogram evolution in Anderson-Fabry disease patients during follow-up

Abstract Background Anderson-Fabry disease (AFD) is a rare and progressive X-linked metabolic disorder caused by mutations in alfa galactosidase A gene, which leads to a pathologic, multiorgan, accumulation of ceramides with cytotoxic, proinflammatory and fibrotic effects. Cardiovascular involvement represents one of the main causes of death. Although ECG has proven to be useful for early AFD recognition, little evidence is available on the evolution of ECG alterations during follow-up. Purpose and Methods The aims of the study were to describe ECG changes during a long-term follow up, and to evaluate their association with the progression of cardiac involvement. The presence of interactions between ECG changes and specific AFD therapy (treatment status) were also evaluated. 219 AFD patients from a multicentre cohort underwent 12-lead ECG extensive analysis, transthoracic echocardiography, and complete clinical evaluation. Results After the exclusion of 3 patients with a permanent pacemaker, 5 with poor ECG quality, 2 with only one ECG, and 18 ≤18 years old, 181 AFD patients composed the final cohort (age 46 [IQR 35-58], 36% male, 67% classic phenotype). Treatment status (either enzyme replacement or chaperone molecules) was distributed as follows: chronic therapy for at least one year (24%), specific therapy started during the follow up (39%), no specific therapy (37%). During a median follow up of 62 months (IQR 33-83 months), several ECG parameters showed significant changes: atrial fibrillation detection (p<0.001), PQ interval (p=0.004), left atrial enlargement (p=0.001), a new right bundle branch block (RBBB, p<0.001), QRS interval (p<0.001) and QRS fragmentation (p=0.022), QTcB interval (p=0.001), and negative T waves development (p=0.001) mostly lateral and symmetric (p=0.016). Among these, PQ interval showed a significant interaction with treatment status being significantly altered only in patients in the chronic therapy and no specific therapy groups, being stable in patients who started the specific therapy during the follow up (p for interaction=0.048). In addition, PQ, QRS interval duration, a new RBBB, and a new pathologic QT interval were associated with the evolution of the echocardiographic maximal left ventricular (LV) wall thickness during the follow up on univariable analysis, with the QRS duration losing the statistical significance on multivariable analysis but still showing a trend (p=0.089) toward an association with an increased LV wall thickness. Conclusions In this multicentric cohort of AFD patients, different ECG parameters underwent significant changes during follow-up. Of these, PQ interval duration showed a significant interaction with the specific therapy status in that it did not increase in patients who started the therapy at the begin of the follow up. PQ interval, a new RBBB and pathologic QTc development were also significantly associated with the progression of LV hypertrophy on multivariable analysis.Table 1 and Table 2Figure 1

Abstract 16825: Brahma Related Gene-1 (BRG1) Protein Mediates Helpful Compensatory Response to Retard Development of Heart Failure

Background: Chromatin remodeling can modulate transcription by changing gene accessibility. Brahma Related Gene-1 (Brg1) protein, which is an adenosine triphosphate catalytic subunit that supports chromatin remodeling, has been implicated in development of hypertrophic cardiomyopathy. However, contribution of Brg1 to the development of heart failure (HF) has not been clearly elucidated. Hypothesis: We hypothesize that Brg1 mediates compensatory response to cardiac stress; therefore, loss of Brg1 function will accelerate development of HF. Methods: The myosin light chain-2 Cre/loxP system was used to produce cardiac myocyte specific deletion of Brg1(-/-) mouse model with floxed littermates as control. Results: At baseline, Brg1(-/-) hearts showed mildly reduced left ventricular ejection fraction (LVEF). Aging to 12 months caused LV dilation and further reduction of LVEF in Brg1(-/-). We used trans-aortic constriction (TAC) for pressure overload challenge and chose similarly severe TAC induced pressure gradient as indicated by similarly fast peak flow velocities across the constriction. At 2-weeks post-TAC, Brg1(-/-) hearts exhibited severely reduced LVEF, severely dilated LV, and decreased ability to thicken LV wall during systole. In contrast, control hearts did not dilate and maintained its LVEF with increased LV wall thickness. Thus, Brg1 deletion greatly diminished the heart’s ability to compensate for aging and pressure challenge, thereby accelerating development of heart failure with reduced ejection fraction (HFrEF). Separately, RNA sequence analyses of 12-months aged hearts showed Brg1 deletion caused upregulation of 810 genes including HF associated long noncoding RNA XIST and down regulation of 50 genes, while 3-months old hearts were not significantly different. Conclusion: Brg1 mediates compensatory responses that are helpful to the heart to prevent development of HF; therefore, it is a potential treatment mechanism for HF.

Abstract 17679: Prognostic Implications of Left Ventricular Hypertrophy Regression Based on 4-Tiered Classification of Left Ventricular Hypertrophy

Introduction: 4-tiered classification of left ventricular (LV) hypertrophy (LVH), which accounts for increased LV wall thickness and LV volume, has been suggested to identify subgroups of patients at differential risk. This study was conducted to evaluate prognostic impact of 4-tiered classification of LVH in newly diagnosed hypertension patients with LVH. Methods: We retrospectively enrolled patients who had LVH on echocardiography at the time of diagnosis and had serial echocardiography taken within a 6-18-month interval with anti-hypertensive medication. Patients were divided into 5 groups based on 4-tiered LVH classification (eccentric LVH with dilatation or without dilatation, concentric with dilatation or without dilatation), and LVH regression group by the follow up echocardiography. The primary outcome was the composite of adverse cardiovascular (CV) outcomes, including CV death, hospitalization for heart failure, coronary revascularization, stroke, and aortic events. Results: Among the 837 patients in the five groups the concentric LVH group and dilated eccentric group demonstrated significantly higher incidence of CV outcomes. Compared with LVH regression group, those with dilated concentric (adjusted hazard ratio [adjHR]: 8.95; 95% confidence interval [CI]: 4.34 to 18.48), dilated eccentric (adjHR: 6.24; 95% CI: 2.96-13.18), non-dilated concentric (adjHR: 2.04; 95% CI: 1.26-3.32) LVH exhibited increased in CV risk according to multivariable cox-regression analysis. However, the non-dilated eccentric LVH group did not demonstrate a significant increase in CV risk (adjHR: 0.75; 95% CI: 0.24-2.35). Conclusions: In patients with hypertension, regression of LVH during anti-hypertensive treatment is associated with better CV outcomes. However, non-dilated eccentric group were not increase CV risk compared with regression group. The 4-tiered LVH classification can be helpful to stratifying CV risk in patients with hypertension.

An anisotropic electromagnetic hydrogel promotes cardiomyocyte maturation and post-infarction cardiac repair

Effective therapies for myocardial infarction (MI) are essential in lowering associated mortality rates. While hydrogel-based patch therapy has shown promise in improving post-MI cardiac function; it falls short in terms of mature stimulation and lacks the necessary combination of conductive, mechanical, and anisotropic cues for optimal efficacy. In this study, we developed an anisotropic hydrogel by incorporating polydopamine-reduced graphene oxide-ferric oxide (PDA-rGO-Fe3O4) nanohybrids into gelatin methacrylate (GelMA) hydrogels under a direct current-driven magnetic field. Cardiomyocytes (CMs) cultured on anisotropic hydrogels demonstrated oriented growth and exhibited symmetrical contraction-relaxation behaviors, surpassing the performance of cells cultured on pure GelMA and isotropic ones. Moreover, both external electrical and alternating magnetic field stimulations enhanced sarcomere functionality, gap junction protein expression, and electrophysiological activities in CMs within the anisotropic hydrogel group. In an acute MI rat model, the application of the anisotropic hydrogel patch significantly improved cardiac function, mitigated adverse left ventricular (LV) dilation and remodeling, reduced infarct size, increased LV wall thickness, promoted angiomyogenesis, and preserved the structural and connected features between CMs. Overall, our findings highlight the potential of electromagnetic, conductive, and anisotropic GelMA-based hydrogels as scaffolds for mimicking the natural functional myocardium layer and developing effective cardiac patches.

Diagnosis and management of patients with left ventricular hypertrophy: Role of multimodality cardiac imaging. A scientific statement of the Heart Failure Association of the European Society of Cardiology.

Left ventricular (LV) hypertrophy consists in an increased LV wall thickness. LV hypertrophy can be either secondary, in response to pressure or volume overload, or primary, i.e. not explained solely by abnormal loading conditions. Primary LV hypertrophy may be due to gene mutations or to the deposition or storage of abnormal substances in the extracellular spaces or within the cardiomyocytes (more appropriately defined as pseudohypertrophy). LV hypertrophy is often a precursor to subsequent development of heart failure. Cardiovascular imaging plays a key role in the assessment of LV hypertrophy. Echocardiography, the first-line imaging technique, allows a comprehensive assessment of LV systolic and diastolic function. Cardiovascular magnetic resonance provides added value as it measures accurately LV and right ventricular volumes and mass and characterizes myocardial tissue properties, which may provide important clues to the final diagnosis. Additionally, scintigraphy with bone tracers is included in the diagnostic algorithm of cardiac amyloidosis. Once the diagnosis is established, imaging findings may help predict future disease evolution and inform therapy and follow-up. This consensus document by the Heart Failure Association of the European Society of Cardiology provides an overview of the role of different cardiac imaging techniques for the differential diagnosis and management of patients with LV hypertrophy.

Abstract GS.11: Exercise Therapy During Doxorubicin Treatment Provides Sex-specific Cardioprotection

Moderate-intensity exercise is routinely prescribed to patients with cardiovascular diseases to improve cardiac function. It has also been recommended in patients undergoing anti-cancer chemotherapy to attenuate cardiotoxic effects. We recently identified that moderate endurance exercise in healthy mice causes the remodeling of cardiac physiology in a sex-specific manner. Therefore, we hypothesized that exercise therapy applied during doxorubicin chemotherapy would produce sex-specific cardioprotection. Male and female mice were divided into three groups, 1) sedentary control, 2) DOX - doxorubicin treated at 5 mg/kg/week for 6 weeks, and 3) EXDOX - 2 weeks of forced treadmill running for 2 weeks before DOX + exercise for an additional 6 weeks. Mouse health was tracked daily. Total body weight, echocardiography, and electrocardiography were assessed every 2 weeks. At the end of the protocol, triple parametric optical mapping was performed to determine the remodeling of cardiac metabolism-excitation-contraction coupling (MECC). DOX treatment increased morbidity and reduced total body weight in both males and females. DOX-induced action potential duration (APD) prolongation in both sexes and, additionally, in males alone, increased anisotropic ratio of conduction (index for arrhythmogenicity) and rise time of calcium transients (CaRT). In EXDOX mice, the onset of morbidity was delayed in both males and females compared to DOX mice. Total body weight in male EXDOX mice, but not females, was further reduced compared to DOX treatment alone. Echocardiography revealed increased LV wall thickness in male and female EXDOX mice vs DOX, while stroke volume was reduced in females alone. Next, DOX-induced APD prolongation was prevented in EXDOX females but not males. Furthermore, DOX-induced increase in CaRT was further increased in EXDOX males, in addition to increased calcium transient duration and reduced calcium decay constant. Taken together, these data suggest significant sex dimorphism in cardiac adaptation to DOX treatment and exercise therapy during DOX treatment. Female mice undergoing exercise therapy during DOX treatment demonstrated greater cardioprotection and attenuation of MECC remodeling.

Myocardial Fibrosis and Cardiomyopathy Risk: A Genetic Link in the MESA.

Common genetic variants are associated with risk for hypertrophic cardiomyopathy and dilated cardiomyopathy and with left ventricular (LV) traits. Whether these variants are associated with myocardial fibrosis, an important pathophysiological mediator of cardiomyopathy, is unknown. Multi-Ethnic Study of Atherosclerosis participants with T1-mapping cardiac magnetic resonance imaging in-whom extracellular volume was assessed, and genotyping information was available were included (N=1255). Log extracellular volume (%) was regressed on 50 candidate single nucleotide polymorphisms (previously identified to be associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and LV traits) adjusting for age, sex, diabetes, blood pressure, and principal components of ancestry. Ancestry-specific results were pooled by fixed-effect meta-analyses. Gene knockdown experiments were performed in human cardiac fibroblasts. The SMARCB1 rs2186370 intronic variant (minor allele frequency: 0.18 in White and 0.50 in Black participants), previously identified as a risk variant for dilated cardiomyopathy and hypertrophic cardiomyopathy, was significantly associated with increased extracellular volume (P=0.0002) after adjusting for confounding clinical variables. The SMARCB1 rs2070458 locus previously associated with increased LV wall thickness and mass was similarly significantly associated with increased extracellular volume (P=0.0002). The direction of effect was similar in all 4 ancestry groups, but the effect was strongest in Black participants. The variants are strong expression quantitative loci in human LV tissue and associated with genotype-dependent decreased expression of SMARCB1 (P=7.3×10-22). SMARCB1 knockdown in human cardiac fibroblasts resulted in increased TGF (transforming growth factor)-β1-mediated α-smooth muscle actin and collagen expression. Common genetic variation in SMARCB1 previously associated with risk for cardiomyopathies and increased LV wall thickness is associated with increased cardiac magnetic resonance imaging-based myocardial fibrosis and increased TGF-β1 mediated myocardial fibrosis in vitro. Whether these findings suggest a pathophysiologic link between myocardial fibrosis and cardiomyopathy risk remains to be proven.

How Often Does Apical Sparing of Longitudinal Strain Indicate the Presence of Cardiac Amyloidosis?

Echocardiographic diagnosis of cardiac amyloidosis (CA) is frequently suggested by the presence of a left ventricular (LV) apical sparing pattern (ASP) on longitudinal strain (LS) assessment, the so-called "cherry on top" pattern, defined by strain magnitude preserved exclusively at the apex. However, it is unclear how frequently this strain pattern truly represents CA. This study aimed to evaluate the predictive value of ASP in the diagnosis of CA. We retrospectively identified consecutive adult patients who had the following studies performed within an 18-month period: (1) transthoracic echocardiogram and (2) either (a) cardiac magnetic resonance imaging, (b) Technetium-Pyrophosphate (PYP) imaging, or (c) endomyocardial biopsy. LS was retrospectively measured in the apical 4-, 3-, and 2-chamber views in patients who had adequate noncontrast images (n=466). An apical sparing ratio (ASR) was calculated as (average apical strain)/[(average basal strain)+(average midventricular strain)]. Patients with ASR ≥1 were evaluated for the presence/absence of CA, using established criteria. Basic LV parameters were also measured. A total of 33 patients (7.1%) had ASP. Nine of these patients (27%) had "confirmed" CA, 2 (6.1%) "highly probable" CA, 1 (3.0%) "possible" CA, and 21 (64%) no evidence of CA. When comparing patients with and without confirmed CA, there were no significant differences in ASR, average global LS, ejection fraction, or LV mass. Patients with confirmed CA were older (76 ± 9 vs 59 ± 18years, p=0.01) and had thicker posterior wall (15 ± 3 vs 11 ± 3mm, p=0.004) with a trend toward thicker septal wall (15 ± 2 vs 12 ± 4mm, p=0.05). In conclusion, the presence of ASP on LS represents confirmed or highly probable CA in only 1/3 of patients and is more likely to indicate true CA in older patients with increased LV wall thickness. Although a larger, prospective study is needed to confirm these findings, 1/3 should be considered as a large diagnostic yield that justifies further testing, given the poor outcomes associated with CA diagnosis.

Developing an Echocardiography-Based, Automatic Deep Learning Framework for the Differentiation of Increased Left Ventricular Wall Thickness Etiologies

Increased left ventricular (LV) wall thickness is frequently encountered in transthoracic echocardiography (TTE). While accurate and early diagnosis is clinically important, given the differences in available therapeutic options and prognosis, an extensive workup is often required to establish the diagnosis. We propose the first echo-based, automated deep learning model with a fusion architecture to facilitate the evaluation and diagnosis of increased left ventricular (LV) wall thickness. Patients with an established diagnosis of increased LV wall thickness (hypertrophic cardiomyopathy (HCM), cardiac amyloidosis (CA), and hypertensive heart disease (HTN)/others) between 1/2015 and 11/2019 at Mayo Clinic Arizona were identified. The cohort was divided into 80%/10%/10% for training, validation, and testing sets, respectively. Six baseline TTE views were used to optimize a pre-trained InceptionResnetV2 model. Each model output was used to train a meta-learner under a fusion architecture. Model performance was assessed by multiclass area under the receiver operating characteristic curve (AUROC). A total of 586 patients were used for the final analysis (194 HCM, 201 CA, and 191 HTN/others). The mean age was 55.0 years, and 57.8% were male. Among the individual view-dependent models, the apical 4-chamber model had the best performance (AUROC: HCM: 0.94, CA: 0.73, and HTN/other: 0.87). The final fusion model outperformed all the view-dependent models (AUROC: HCM: 0.93, CA: 0.90, and HTN/other: 0.92). The echo-based InceptionResnetV2 fusion model can accurately classify the main etiologies of increased LV wall thickness and can facilitate the process of diagnosis and workup.

557 RAREFACTION OF MYOCARDIAL LYMPHATIC VESSELS IN PATIENTS WITH CARDIAC AMYLOIDOSIS

Abstract Introduction In cardiac amyloidosis (CA), amyloid fibers accumulate in the extracellular spaces of the heart. It is reasonable to speculate that this accumulation could lead to a compression and obliteration of lymphatic vessels, and possibly to their eventual disappearance. As lympathic drainage removes proteins from the interstitial spaces, including amyloid precursors, an impairment of lympathic vessels could exacerbate amyloid accumulation, thus triggering a vicious circle. Methods We evaluated consecutive endomyocardial biopsies (EMB) performed as part of the standard diagnostic workup for CA or for unexplained left ventricular (LV) hypertrophy, with no specific suspicion of CA. All EMBs were performed in the septal region of the LV. Three samples were analyzed through Congo red staining and immunohistochemistry, with final confirmation of the amyloid subtype through a proteomic approach. Lymphatic vessels were visualized through antibodies targeting the specific marker podoplanin. Echocardiographic variables measured at the time of the EMB were collected. Results We examined 15 patients with CA (ATTR-CA, n=10; AL-CA, n=5; 50% men, median age 75 years [interquartile range 71-78]), and 13 patients with CA excluded (55% men, median age 68 years [59-71]). The median density of lymphatic vessels in patients with CA was 0.52 vessels/mm2 (0-3.32), and 10.90 vessels/mm2 (3.10-26.25) in patients without CA (p=0.001). No significant differences were found in LV mass index (p=0.170), interventricular septal thickness (p=0.262), relative wall thickness (p=0.078), or LV ejection fraction (p=0.262), while posterior wall thickness was higher in patients with CA (p=0.042). Three patients with ATTR-CA and 2 patients with AL-CA had no lymphatic vessels on their tissue samples. Patients with ATTR- or AL-CA did not display significant differences in the density of lymphatic vessels, or any metric of increased LV wall thickness or systolic function. Conclusions We report for the first time that patients with CA have significantly less myocardial lymphatic vessels than patients without CA, despite no significant differences in the degree of LV wall thickening or LV ejection fraction. These results support the hypothesis that the lymphatic drainage is deranged in patients with CA, possibly promoting further amyloid deposition.

Abstract 11869: Myocardial Fibrosis and Cardiomyopathy Risk: A Genetic Link in the Multi-Ethnic Study of Atherosclerosis

Introduction: Genome-wide association studies have identified common genetic variants associated with hypertrophic (HCM) and dilated cardiomyopathy (DCM) and left ventricular (LV) characteristics. However, the association of these variants with myocardial fibrosis (MF), an important pathophysiological mediator of cardiomyopathy, is unknown. Hypothesis: We used the Multi-Ethnic Study of Atherosclerosis (MESA), to evaluate the association of these loci with interstitial MF measured by cardiac MRI (CMR). Methods: Unrelated MESA participants with T1-mapping CMR and no history of MI or heart failure were included (n=1,235). We used the extracellular volume (ECV) fraction as a well-established surrogate of interstitial MF. Genotyping was performed by Affymetrix Human SNP array 6.0, and imputation was performed using the TOPMED reference panel. Log ECV(%) was regressed on 50 candidate SNPs, in each ethnicity/race group, adjusting for age, sex, and population stratification principal component. The race-specific results were pooled by fixed-effect meta-analyses using METASOFT. Results: The SMARCB1 rs2186370 intronic variant, previously identified as a risk variant for DCM and HCM, was associated with ECV (p=0.0004). The rs2186370 A allele (frequency: 0.18 in Whites, and 0.50 in African Americans) was associated with a 1.6% increase in ECV. The rs2070458 A allele (another SMARCB1 intronic variant), in complete linkage disequilibrium with rs2186370, was known previously to be associated with increased LV wall thickness, mass, and concentricity. The direction of effect was similar in all four ancestry groups, but the effect was strongest in African Americans. These variants are strong expression quantitative loci (eQTLs) in human LV tissue and are associated with genotype-dependent expression of SMARCB1 ( p =7.3х10 -22 ) and MMP11 ( p =2.5х10 -24 ). Conclusions: In conclusion, variants in two linked SMARCB1 loci previously associated with HCM, DCM and LV traits, are associated with CMR-based interstitial MF. These loci are eQTL not only for SMARCB1 but also for MMP11 an important mediator of MF . These findings underscore the important link between MF and CM, and potentially provide novel mechanistic targets in understanding the development of CM.

Abstract 12042: A Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac LDLR Expression

Background: HFpEF prevalence has surpassed that of HFrEF. Elevated accumulation of myocardial lipids is a prominent feature of HFpEF patients and the gene for lipoprotein lipase (LPL) in cardiac biopsies is decreased compared with HFrEF or healthy controls. Poloxamer-407 (p407) induces hyperlipidemia by blocking LPL and increasing plasma triglycerides (TG) and LDL cholesterol. We hypothesized that hyperlipidemia driven by p407 and overexpression (OE) of cardiac LDLR in mice mimics a subset of human HFpEF. Methods: WT-129 mice were subject to 4 wks of biweekly i.p. p407-injections with or without a single i.v. injection of AAV9-cTnT-LDLR (n=31); AAV9-cTnT-Luciferase control (n=11), or single i.v. injection with AAV9-cTnT-LDLR alone (n=10). Treatment groups were compared to an untreated group (n=26). Echo, blood pressure (BP), whole-body plethysmography (WBP), ECG telemetry, activity wheel monitoring (AWM), biochemical tests, and histological changes were assessed at 4-8 wks. Results: At 4 wks, p407 and LDLR OE led to diastolic dysfunction (DD) (prolonged IVRT, decreased E/A (p<0.05 and p<0.001 respectively)), preserved EF and increased LV wall thickness (LVID and LVAW, p<0.0001). BP and WBP were normal at 4 wks but respiration (breaths per minute) decreased at 8 wks (p<0.01). ECG and AWM respectively indicated heart block and decreased exercise activity (p<0.001). With the double treatment, total cholesterol increased in heart, skeletal muscle and liver (p<0.05), while TG was decreased only in hearts (p<0.001) and liver (p<0.05). Double treatment also promoted elevated myocardial lipids, fibrosis, increased Wet/Dry lung (p<0.001) and HW/BW (p<0.05). Xanthelasma, ascites, and cardiac ischemia were noted in the double and single, p407 + luciferase groups. Sudden death (SD) occurred between 6-12 wks in double and p407+Luciferase treatment groups. Conclusion: We present a unique model of early onset, rapidly evolving HFpEF where double treatment mice acquire DD, arrhythmia, cardiac hypertrophy, fibrosis, pulmonary congestion, exercise intolerance, and preserved EF in the absence of obesity, HTN, CKD or DM. The model may represent a subset of HFpEF wherein hyperlipidemia drives a severe phenotype with SD as a prominent endpoint.

Utility of advanced echocardiographic deformation measures to delineate cause of pathological left ventricular hypertrophy: value of a multiparametric approach

Abstract Background Early diagnosis of cardiac amyloidosis (CA) is warranted to initiate specific treatment and improve outcomes. Conventional echocardiography is unable to reliably differentiate CA from other causes of increased left ventricular (LV) wall thickness. Purpose To demonstrate the value of a multiparametric approach utilising both standard and advanced echocardiographic measures to distinguish CA from other pathological causes of increased LV wall thickness. Results Patients with HCM had the highest septal thickness, maximum LV wall thickness, septum/posterior wall (Sep/PW) thickness ratio and left ventricular outflow tract (LVOT) gradient and lowest PW thickness (p<0.0001) among all groups. Patients with CA had the lowest global longitudinal strain (GLS), tissue Doppler-derived myocardial systolic and diastolic velocities and LV ejection fraction (EF) (p<0.0001). EF strain ratio (EFSR=LVEF/GLS) and LV longitudinal strain (apex/base) ratio were highest (largest number) in CA patients (p<0.0001). Multivariate linear regression identified 5 independent predictors (PW thickness, Sep/PW thickness ratio, LVOT gradient, LV longitudinal strain (apex/base) ratio and GLS) that discriminated CA from other causes of increased LV wall thickness. A regression equation (using multivariate linear regression) {CA prediction value = (0.230*LS apex/base) − (0.002*LVOT gradient) − [0.068*(Sep/PW ratio)] + (0.007*PW thickness) + (0.022*GLS) + 0.189; r=0.667)} was derived which allowed reliable distinction of CA with a sensitivity of 92.3% and specificity of 91.2% at the optimal cut-off. Conclusion PW thickness, Sep/PW thickness ratio, LVOT gradient, LV longitudinal strain (apex/base) ratio and GLS are independent predictors of CA. We developed a multiparametric regression equation which allowed discrimination of CA from other causes of increased LV wall thickness. Future studies involving larger cohorts are required to validate these findings. Funding Acknowledgement Type of funding sources: None.

Cardiac Amyloidosis with Normal Wall Thickness: Prevalence, Clinical Characteristics and Outcome in a Retrospective Analysis.

Background: Cardiac amyloidosis (CA) is a rare, progressive, infiltrative cardiac disease. Light chain (AL) and transthyretin (ATTR) amyloidosis are in the background in almost all cases. New, easily available diagnostic tools and recently introduced novel therapies for both types of CA put this disease into the field of interest. Increased left ventricular wall thickness (IWT) detected by echocardiography is generally thought to be a necessary part of the diagnosis. We aimed to determine the proportion of CA patients without IWT, and to define the clinical characteristics of this cohort. Methods: In an academic tertiary center for CA, we identified patients diagnosed and treated for CA between January 2009 and February 2022. In a retrospective analysis we defined the proportion of patients with (≥12 mm) and without (<12 mm) IWT, and described their clinical features. Results: We identified 98 patients suitable for the analysis. In total, 70 had AL and 27 ATTR CA; 89 patients had CA with IWT and 9 patients (9%) had CA without IWT. All non-IWT patients had AL type CA. Both group of patients had clinically significant disease, which is supported by the relevant elevation in cardiac biomarker levels. There was no difference between the outcome of the two groups. Conclusion: Patients without IWT form a relevant subgroup among those with CA. Our results suggest that diagnostic algorithms and criteria should take these individuals into consideration, and, therefore, give them access to effective treatments.

Association between Left Ventricular Wall Thickness and Heart Rate Variability with Complex Ventricular Arrhythmia in Hypertrophic Cardiomyopathy

Objective: To demonstrate the association between the maximal left ventricular (LV) wall thickness and the late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR) and heart rate variability (HRV) with complex ventricular arrhythmia (VA) in patients with hypertrophic cardiomyopathy (HCM). Materials and Methods: The present study was a retrospective study. Fifty-seven HCM patients who underwent CMR and Holter monitoring at Siriraj Hospital, Bangkok, Thailand, were identified and included. Complex VA was defined as Lown grading system type 4a or 4b as couplet or non-sustained ventricular tachycardia. Standard deviation of normal RR-interval (SDNN) was used to assess HRV. Results: The authors studied 57 patients, 40 (70.2%) patients had LGE, and 13 (22.8%) patients had complex VA. Complex VA was demonstrated in 11 (27.5%) patients in the LGE group compared with two (11.8%) in those without (p=0.304), and four (57.1%), and nine (18.0%) in patients had a maximal LV wall thickness of 25 mm or more and less than 25 mm, respectively (p=0.041). SDNN was 100.98±29.82 ms versus 123.85±35.12 ms (p=0.015) in the LGE group compared with the no-LGE group, and 89.08±25.39 ms versus 113.34±33.06 ms (p=0.018) in patients with and without complex VA. Multivariate analysis showed significant associations of maximal LV wall thickness of 25 mm or more and SDNN of less than 105 ms with complex VA with odds ratios of 6.71 (95% confidence interval [CI] 1.09 to 41.14; p=0.040) and 5.15 (95% CI 1.14 to 23.30; p=0.033), respectively. Conclusion: In HCM patients, increased LV wall thickness and a reduction in SDNN are associated with complex VA. The present study supports the utility of CMR and HRV for risk stratification of patients with HCM. Keywords: Heart rate variability; Maximal left ventricular wall thickness; Complex ventricular arrhythmia; Hypertrophic cardiomyopathy

Eosinophils protect pressure overload- and β-adrenoreceptor agonist-induced cardiac hypertrophy.

Blood eosinophil (EOS) counts and EOS cationic protein (ECP) levels associate positively with major cardiovascular disease (CVD) risk factors and prevalence. This study investigates the role of EOS in cardiac hypertrophy. A retrospective cross-section study of 644 consecutive inpatients with hypertension examined the association between blood EOS counts and cardiac hypertrophy. Pressure overload- and β-adrenoreceptor agonist isoproterenol-induced cardiac hypertrophy was produced in EOS-deficient ΔdblGATA mice. This study revealed positive correlations between blood EOS counts and left ventricular (LV) mass and mass index in humans. ΔdblGATA mice showed exacerbated cardiac hypertrophy and dysfunction, with increased LV wall thickness, reduced LV internal diameter, and increased myocardial cell size, death, and fibrosis. Repopulation of EOS from wild-type (WT) mice, but not those from IL4-deficient mice ameliorated cardiac hypertrophy and cardiac dysfunctions. In ΔdblGATA and WT mice, administration of ECP mEar1 improved cardiac hypertrophy and function. Mechanistic studies demonstrated that EOS expression of IL4, IL13, and mEar1 was essential to control mouse cardiomyocyte hypertrophy and death and cardiac fibroblast TGF-β signalling and fibrotic protein synthesis. The use of human cardiac cells yielded the same results. Human ECP, EOS-derived neurotoxin, human EOS, or murine recombinant mEar1 reduced human cardiomyocyte death and hypertrophy and human cardiac fibroblast TGF-β signalling. Although blood EOS counts correlated positively with LV mass or LV mass index in humans, this study established a cardioprotective role for EOS IL4 and cationic proteins in cardiac hypertrophy and tested a therapeutic possibility of ECPs in this human CVD.

Native T1 mapping for the diagnosis of cardiac amyloidosis in patients with left ventricular hypertrophy

BackgroundCardiac magnetic resonance (CMR) with parametric mapping can improve the characterization of myocardial tissue. We studied the diagnostic value of native T1 mapping to detect cardiac amyloidosis in patients with left ventricular (LV) hypertrophy.MethodsOne hundred twenty-five patients with increased LV wall thickness (≥ 12 mm end-diastole) who received clinical CMR in a 3 T scanner between 2017 and 2020 were included. 31 subjects without structural heart disease served as controls. Native T1 was measured as global mean value from 3 LV short axis slices. The study was registered at German clinical trial registry (DRKS00022048).ResultsMean age of the patients was 66 ± 14 years, 83% were males. CA was present in 24 patients, 21 patients had hypertrophic cardiomyopathy (HCM), 80 patients suffered from hypertensive heart disease (HHD). Native T1 times were higher in patients with CA (1409 ± 59 ms, p < 0.0001) compared to healthy controls (1225 ± 21 ms), HCM (1266 ± 44 ms) and HHD (1257 ± 41 ms). HCM and HHD patients did not differ in their native T1 times but were increased compared to control (p < 0.01). ROC analysis of native T1 demonstrated an area under the curve for the detection of CA vs. HCM and HHD of 0.9938 (p < 0.0001), which was higher than that of extracellular volume (0.9876) or quantitative late gadolinium enhancement (0.9406; both p < 0.0001). The optimal cut-off value of native T1 to diagnose CA was 1341 ms (sensitivity 100%, specificity 97%).ConclusionNon-contrast CMR imaging with native T1 mapping provides high diagnostic accuracy to diagnose cardiac amyloidosis in patients with left ventricular hypertrophy.

High-Throughput Precision Phenotyping of Left Ventricular Hypertrophy With Cardiovascular Deep Learning

Early detection and characterization of increased left ventricular (LV) wall thickness can markedly impact patient care but is limited by under-recognition of hypertrophy, measurement error and variability, and difficulty differentiating causes of increased wall thickness, such as hypertrophy, cardiomyopathy, and cardiac amyloidosis. To assess the accuracy of a deep learning workflow in quantifying ventricular hypertrophy and predicting the cause of increased LV wall thickness. This cohort study included physician-curated cohorts from the Stanford Amyloid Center and Cedars-Sinai Medical Center (CSMC) Advanced Heart Disease Clinic for cardiac amyloidosis and the Stanford Center for Inherited Cardiovascular Disease and the CSMC Hypertrophic Cardiomyopathy Clinic for hypertrophic cardiomyopathy from January 1, 2008, to December 31, 2020. The deep learning algorithm was trained and tested on retrospectively obtained independent echocardiogram videos from Stanford Healthcare, CSMC, and the Unity Imaging Collaborative. The main outcome was the accuracy of the deep learning algorithm in measuring left ventricular dimensions and identifying patients with increased LV wall thickness diagnosed with hypertrophic cardiomyopathy and cardiac amyloidosis. The study included 23 745 patients: 12 001 from Stanford Health Care (6509 [54.2%] female; mean [SD] age, 61.6 [17.4] years) and 1309 from CSMC (808 [61.7%] female; mean [SD] age, 62.8 [17.2] years) with parasternal long-axis videos and 8084 from Stanford Health Care (4201 [54.0%] female; mean [SD] age, 69.1 [16.8] years) and 2351 from CSMS (6509 [54.2%] female; mean [SD] age, 69.6 [14.7] years) with apical 4-chamber videos. The deep learning algorithm accurately measured intraventricular wall thickness (mean absolute error [MAE], 1.2 mm; 95% CI, 1.1-1.3 mm), LV diameter (MAE, 2.4 mm; 95% CI, 2.2-2.6 mm), and posterior wall thickness (MAE, 1.4 mm; 95% CI, 1.2-1.5 mm) and classified cardiac amyloidosis (area under the curve [AUC], 0.83) and hypertrophic cardiomyopathy (AUC, 0.98) separately from other causes of LV hypertrophy. In external data sets from independent domestic and international health care systems, the deep learning algorithm accurately quantified ventricular parameters (domestic: R2, 0.96; international: R2, 0.90). For the domestic data set, the MAE was 1.7 mm (95% CI, 1.6-1.8 mm) for intraventricular septum thickness, 3.8 mm (95% CI, 3.5-4.0 mm) for LV internal dimension, and 1.8 mm (95% CI, 1.7-2.0 mm) for LV posterior wall thickness. For the international data set, the MAE was 1.7 mm (95% CI, 1.5-2.0 mm) for intraventricular septum thickness, 2.9 mm (95% CI, 2.4-3.3 mm) for LV internal dimension, and 2.3 mm (95% CI, 1.9-2.7 mm) for LV posterior wall thickness. The deep learning algorithm accurately detected cardiac amyloidosis (AUC, 0.79) and hypertrophic cardiomyopathy (AUC, 0.89) in the domestic external validation site. In this cohort study, the deep learning model accurately identified subtle changes in LV wall geometric measurements and the causes of hypertrophy. Unlike with human experts, the deep learning workflow is fully automated, allowing for reproducible, precise measurements, and may provide a foundation for precision diagnosis of cardiac hypertrophy.

Multimodality Imaging in Cardiomyopathies with Hypertrophic Phenotypes.

Multimodality imaging is a comprehensive strategy to investigate left ventricular hypertrophy (LVH), providing morphologic, functional, and often clinical information to clinicians. Hypertrophic cardiomyopathy (HCM) is defined by an increased LV wall thickness not only explainable by abnormal loading conditions. In the context of HCM, multimodality imaging, by different imaging techniques, such as echocardiography, cardiac magnetic resonance, cardiac computer tomography, and cardiac nuclear imaging, provides essential information for diagnosis, sudden cardiac death stratification, and management. Furthermore, it is essential to uncover the specific cause of HCM, such as Fabry disease and cardiac amyloidosis, which can benefit of specific treatments. This review aims to elucidate the current role of multimodality imaging in adult patients with HCM.

Electrocardiographic Characteristics and Their Correlation with Echocardiographic Alterations in Fabry Disease.

Fabry disease (FD) is an X-linked disorder with α-galactosidase A deficiency. Males (>30 years) and females (>40 years) often present with cardiac manifestations, predominantly left ventricular hypertrophy (LVH). The aim of this study was to evaluate electrocardiographic (ECG) characteristics within FD patients to identify gender related differences, and to additionally explore the association of ECG parameters with structural and functional alterations on transthoracic echocardiography (TTE). Retrospective cross-sectional analysis of 45 FD patients with contemporaneous ECG and TTE was performed and compared to age and gender matched healthy controls. FD patients demonstrated alterations in several ECG parameters particularly in males, including prolonged P-wave duration (91 vs. 81 ms, p = 0.022), prolonged QRS duration (96 vs. 84 ms, p < 0.001), increased R-wave amplitude in lead I (8.1 vs. 5.7 mV, p = 0.047), increased Sokolow–Lyon index (25 vs. 19 mV, p = 0.002) and were more likely to meet LVH criteria (31% vs. 7%, p = 0.006). FD patients with impaired basal longitudinal strain (LS) on TTE were more likely to meet LVH criteria (41% vs. 0%, p = 0.018). Those with more advanced FD (increased LV wall thickness on TTE) were more likely to meet LVH criteria but additionally demonstrated prolonged ventricular depolarization (QRS duration 101 vs. 88 ms, p = 0.044). Therefore, alterations on ECG demonstrating delayed atrial activation, delayed ventricular depolarization and evidence of LVH were more often seen in male FD patients. Impaired basal LS, a TTE marker of early cardiac involvement, correlated with ECG abnormalities. Increased LV wall thickness on TTE, a marker of more advanced FD, was associated with more severe ECG abnormalities.