Left Ventricular Myocardial Fibrosis Research Articles

#1311 Cardiac damage in a multifactorial DKD/CKD mouse model resembles HFpEF and can be reduced by standard-of-care treatment

Abstract Background and Aims We developed a diet-induced hypertension-accelerated mouse model of diabetic kidney disease characterized by progressive loss of GFR resulting in chronic kidney disease. Since cardiovascular disease is the major cause of death in CKD, we characterized the functional and structural cardiac damage in this model. Additionally, we studied the efficacy of combination therapy with an ACE-inhibitor (Lisinopril) and SGLT2-inhibitor (Dapagliflozin) on cardiac histopathology. Method Male KKAy mice underwent uninephrectomy. After recovery mice received high fat diet (45% LARD) and drinking water with or without 50 mg/L LNNA (wk0). At 12 weeks, imaging was performed to study cardiac function and mice were terminated at week 13. In the intervention study, at week 4, lisinopril (2.5 mg/kg/day; drinking water) and at week 8 dapagliflozin (5 and 20 mg/kg/day; foodadmix) treatment were started. At week 16 mice were terminated and lung and heart weight and cardiac histology were determined. Results Upon termination, macroscopic evaluation of the hearts showed extensive scar tissue formation on the outside of the left ventricle. Histological evaluation showed the presence left ventricular hypertrophy, coronary calcification and myocardial fibrosis in male KKAy mice with UNX, HFD and LNNA. KKAy mice with UNX and HFD but without LNNA also showed myocardial fibrosis, monocyte infiltration and focal mineralization. Imaging showed preserved ejection fraction, a significant reduction, increased left ventricle posterior wall thickness and decrease left ventricle inner diameter. Treatment with combination therapy reduced lung wet weight, significantly reduced heart weight and significantly decreased cardiac fibrosis. Macroscopically, less scar tissue was observed after treatment. Conclusion This multifactorial mouse model shows cardiac damage on a background of hypertension, diabetes, renal dysfunction and obesity. Functional measurement including preserved ejection fraction, left ventricle hypertrophy, diastolic dysfunction and increased fibrosis resembling the clinical HFpEF phenotype. Combination therapy with Lisinopril and Dapagliflozin reduced cardiac weight and cardiac fibrosis. This indicates cardiac involvement in the DKD mouse model which confirms that this multifactorial model is clinically relevant.

Assessing Regurgitation Severity, Adverse Remodeling, and Fibrosis with CMR in Primary Mitral Regurgitation.

This review offers an evidence-based analysis of established and emerging cardiovascular magnetic resonance (CMR) techniques used to assess the severity of primary mitral regurgitation (MR), identify adverse cardiac remodeling and its prognostic effect. The aim is to provide different insights regarding clinical decision-making and enhance the clinical outcomes of patients with MR. Cardiac remodeling and myocardial replacement fibrosis are observed frequently in the presence of substantial LV volume overload, particularly in cases with severe primary MR. CMR serves as a useful diagnostic imaging modality in assessing mitral regurgitation severity, early detection of cardiac remodeling, myocardial dysfunction, and myocardial fibrosis, enabling timely intervention before irreversible damage ensues. Incorporating myocardial remodeling in terms of left ventricular (LV) dilatation and myocardial fibrosis with quantitative MR severity assessment by CMR may assist in defining optimal timing of intervention.

Relationship of interleukin-16 with different phenogroups in acute heart failure with preserved ejection fraction.

Interleukin-16 (IL-16) has been reported to mediate left ventricular myocardial fibrosis and stiffening in patients with heart failure with preserved ejection fraction (HFpEF). We sought to elucidate whether IL-16 has a distinct impact on pathophysiology and prognosis across different subphenotypes of acute HFpEF. We analysed 211 patients enrolled in a prospective multicentre registry of acute decompensated HFpEF for whom serum IL-16 levels after stabilization were available (53% female, median age 81 [interquartile range 75-85] years). We divided this sub-cohort into four phenogroups using our established clustering algorithm. The study endpoint was all-cause death. Patients were subclassified into phenogroup 1 ('rhythm trouble' [n=69]), phenogroup 2 ('ventricular-arterial uncoupling' [n=49]), phenogroup 3 ('low output and systemic congestion' [n=41]), and phenogroup 4 ('systemic failure' [n=52]). After a median follow-up of 640days, 38 patients had died. Among the four phenogroups, phenogroup 2 had the highest IL-16 level. The IL-16 level showed significant associations with indices of cardiac hypertrophy, diastolic dysfunction, and congestion only in phenogroup 2. Furthermore, the IL-16 level had a significant predictive value for all-cause death only in phenogroup 2 (C-statistic 0.750, 95% confidence interval 0.606-0.863, P=0.017), while there was no association between the IL-16 level and the endpoint in the other phenogroups. Our results indicated that the serum IL-16 level had a significant association with indices that reflect the pathophysiology and prognosis of HFpEF in a specific phenogroup in acute HFpEF.

Associations of Circulating Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 With Long-Term Cardiac Function.

Although VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) have been associated with incident heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), the associations of VCAM-1 and ICAM-1 with sensitive measures of cardiac structure/function are unclear. The objective of this study is to evaluate associations between VCAM-1, ICAM-1, and measures of cardiac structure and function as potential pathways through which cellular adhesion molecules promote HFpEF and AF risk. In MESA (Multi-Ethnic Study of Atherosclerosis), we evaluated the associations of circulating VCAM-1 and ICAM-1 at examination 2 (2002-2004) with measures of cardiac structure/function on cardiac magnetic resonance imaging at examination 5 (2010-2011) after multivariable adjustment. Mediation analysis of left atrial (LA) strain on the association between VCAM-1 or ICAM-1 and AF or HFpEF was also performed. Overall, 2304 individuals (63±10 years; 47% men) with VCAM-1 or ICAM-1, cardiac magnetic resonance imaging, and covariate data were included in analysis. Higher VCAM-1 and ICAM-1 were associated with lower LA peak longitudinal strain and worse global circumferential left ventricular strain but were not associated with left ventricular myocardial scar or interstitial fibrosis. Lower LA peak longitudinal strain mediated 8% (95% CI, 2-30) of the relationship between VCAM-1 and HFpEF and 9% (95% CI, 2-21) of the relationship between VCAM-1 and AF. Higher VCAM-1 and ICAM-1 were associated with lower LA function and left ventricular systolic function but were not associated with myocardial scar or interstitial fibrosis. VCAM-1 and ICAM-1 may promote HFpEF and AF risk through impaired LA reservoir function.

Evaluation the relationship between myocardial fibrosis and left ventricular torsion measured by cardiac magnetic resonance feature-tracking in hypertrophic cardiomyopathy patients with preserved ejection fraction.

The relationship between left ventricular (LV) torsion and myocardial fibrosis (MF) in hypertrophic cardiomyopathy (HCM) patients with preserved ejection fraction was still not well understood. New developments in cardiac magnetic resonance (CMR) enable a much fuller assessment of cardiac characteristics. This study sought to assess the impact of HCM on myocardial function as assessed by LV torsion and its relationship with MF. HCM (n = 79) and healthy controls (n = 40) underwent CMR. According to whether there was late gadolinium enhancement (LGE), patients were divided into LGE+ group and LGE- group. LV torsion and torsion rate were measured by CMR feature-tracking (CMR-FT). MF was quantitatively evaluated through LGE imaging. LGE was present in 44 patients (56%). Compared with healthy controls, torsion increased in the LGE- group (P < 0.001). Compared with LGE+ group, torsion was higher in the LGE- group (P < 0.001). There was no significant difference in torsion between LGE+ group and healthy controls. Correlation analysis showed that torsion was correlated with LGE% (r= -0.443) and LGE mass (r= -0.435) respectively. On multivariable logistic regression analysis, LV torsion was the only feature that was independently associated with the presence of LGE (OR 0.130; 95% CI 0.040 to 0.420, P = 0.01). The best torsion value associated with MF was 1.91 (sensitivity 60.0%, specificity 77.3%, AUC = 0.733). In HCM patients with preserved ejection fraction, CMR-FT derivedLV torsion analysis holds promise for myocardial fibrosis detection.

Insights into the effects of Friedreich ataxia on the left ventricle using T1 mapping and late gadolinium enhancement.

The left ventricular (LV) changes which occur in Friedreich ataxia (FRDA) are incompletely understood. Cardiac magnetic resonance (CMR) imaging was performed using a 1.5T scanner in subjects with FRDA who are homozygous for an expansion of an intron 1 GAA repeat in the FXN gene. Standard measurements were performed of LV mass (LVM), LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF). Native T1 relaxation time and the extracellular volume fraction (ECV) were utilised as markers of left ventricular (LV) diffuse myocardial fibrosis and late gadolinium enhancement (LGE) was utilised as a marker of LV replacement fibrosis. FRDA genetic severity was assessed using the shorter FXN GAA repeat length (GAA1). There were 93 subjects with FRDA (63 adults, 30 children, 54% males), 9 of whom had a reduced LVEF (<55%). A LVEDV below the normal range was present in 39%, a LVM above the normal range in 22%, and an increased LVM/LVEDV ratio in 89% subjects. In adults with a normal LVEF, there was an independent positive correlation of LVM with GAA1, and a negative correlation with age, but no similar relationships were seen in children. GAA1 was positively correlated with native T1 time in both adults and children, and with ECV in adults, all these associations independent of LVM and LVEDV. LGE was present in 21% of subjects, including both adults and children, and subjects with and without a reduced LVEF. None of GAA1, LVM or LVEDV were predictors of LGE. An association between diffuse interstitial LV myocardial fibrosis and genetic severity in FRDA was present independently of FRDA-related LV structural changes. Localised replacement fibrosis was found in a minority of subjects with FRDA and was not associated with LV structural change or FRDA genetic severity in subjects with a normal LVEF.

Kiosk 6R-TB-04 - Correlation of Left Ventricular Strain and Myocardial Fibrosis in Patients with Severe Aortic Valve Disease and Preserved Ejection FBaction: A Magnetic Resonance and Histology Study

Kiosk 6R-TB-04 - Correlation of Left Ventricular Strain and Myocardial Fibrosis in Patients with Severe Aortic Valve Disease and Preserved Ejection FBaction: A Magnetic Resonance and Histology Study

Left ventricular fibrosis as a main determinant of filling pressures and left atrial function in advanced heart failure.

Advanced heart failure (AdHF) is characterized by variable degrees of left ventricular (LV) dysfunction, myocardial fibrosis, and raised filling pressures which lead to left atrial (LA) dilatation and cavity dysfunction. This study investigated the relationship between LA peak atrial longitudinal strain (PALS), assessed by speckle-tracking echocardiography (STE), and invasive measures of LV filling pressures and fibrosis in a group of AdHF patients undergoing heart transplantation (HTX). We consecutively enrolled patients with AdHF who underwent HTX at our Department. Demographic and basic echocardiographic data were registered, then invasive intracardiac pressures were obtained from right heart catheterization, and STE was also performed. After HTX, biopsy specimens from explanted hearts were collected to quantify the degree of LV myocardial fibrosis. Sixty-four patients were included in the study (mean age 62.5 ± 11 years, 42% female). The mean LV ejection fraction (LVEF) was 26.7 ± 6.1%, global PALS was 9.65 ± 4.5%, and mean pulmonary capillary wedge pressure (PCWP) was 18.8 ± 4.8 mmHg. Seventy-three % of patients proved to have severe LV fibrosis. Global PALS was inversely correlated with PCWP (R = -0.83; P < 0.0001) and with LV fibrosis severity (R = -0.78; P < 0.0001) but did not correlate with LVEF (R = 0.15; P = 0.2). Among echocardiographic indices of LV filling pressures, global PALS proved the strongest [area under the curve 0.955 (95% confidence interval 0.87-0.99)] predictor of raised (>18 mmHg) PCWP. In patients with AdHF, reduced global PALS strongly correlated with the invasively assessed LV filling pressure and degree of LV fibrosis. Such relationship could be used as non-invasive indicator for optimum patient stratification for therapeutic strategies.

Is myocardial fibrosis appropriately assessed by 2D strain derived integrated backscatter?

Abstract Introduction Calibrated integrated backscatter (cIB) may be obtained from bidimensional (2D) strain echocardiography as a quantification measurement of myocardial ultrasound reflectivity. Increased collagen content of the myocardium modifies tissue reflectivity and cIB is suggested as a marker of left ventricular (LV) fibrosis. However, its diagnostic accuracy is not fully established. Aim To assess the correlation between cIB by 2D strain and LV myocardial fibrosis (MF), as evaluated by non-invasive imaging and histopathology. Methods Correlation study from a cohort of 157 patients with severe symptomatic aortic stenosis (AS) referred for surgical aortic valve replacement (AVR). Patients with complete preoperative transthoracic echocardiography, cardiac magnetic resonance (CMR) and endomyocardial biopsy (EMB) obtained from the anterior basal septum at the time of AVR were selected. Two groups of 30 patients were evaluated, with and without late gadolinium enhancement (LGE) at CMR. Integrated Backscatter was obtained at QRS peak in decibels (dB) from both parasternal long axis (PLAX) and apical-three-chamber (A3C) cine clips at Qanalysis. cIB was calculated by subtracting the pericardial intensity from the average of the anteroseptal and basal inferolateral wall values. Correlation analysis was performed for the whole group of patients with global and segmental (anterior basal septum) values of native T1 and extracellular volume (ECV), and EMB collagen volume fraction (CVF) from Masson´s Trichrome staining. IBS values were compared in both group of patients. Results 60 patients (74 [36-74] years, 45% male) with high gradient (mean gradient: 63±20mmHg), normal flow (45±10mL/m2), preserved ejection fraction (60±9%) AS were included. Basal septal cIB was –9.17±9.45dB and –17.45 (–31.2–10.95) dB from A3C and PLAX views, respectively. These indexes did not correlate with basal septum thickness or global LV mass. Absolute and cIB did not correlate neither with global and regional T1 and ECV values, nor with CVF at EMB. These were not significantly different in both groups of patients and there was no correlation between cIB values and mass of replacement MF in patients with LGE. Conclusion In these cohort of patients with classical severe AS, there was no correlation of cIB with imaging markers of both replacement and diffuse MF. cIB also didn´t correlate with CVF at histopathology. These findings suggest that reflectivity indexes are not suitable for myocardial tissue characterization in this setting.

Assessment of left ventricular myocardial fibrosis in adult patients with Ebstein's anomaly: a retrospective cohort study based on cardiac magnetic resonance and histopathological samples

Abstract Background The relationship between Ebstein's Anomaly (EA) and myocardial fibrosis in the left ventricle (LV) has been debated. This study aimed to determine the prevalence of replacement fibrosis in the LV using cardiac magnetic resonance (CMR) imaging and correlate it with histopathological findings. The study also investigated whether LV fibrosis is an independent risk factor for cardiovascular disease (CVD) mortality and developed a risk score for this purpose. Methods We performed a twelve-years (2009-2021) retrospective cohort study of adult patients with EA who underwent CMR. The CMR evaluation included a comprehensive assessment of myocardial fibrosis by late gadolinium enhancement (LGE). Four post-mortem samples were obtained from our cohort and stained using Masson trichrome to characterize LV-fibrosis. We used Cox-Regression analysis to identify and derive a prediction score that associates LV-fibrosis with CVD-mortality. Results We included 57 adults with EA (52% male, median age 29.52, IQR: 21.24-39.17 years). LGE prevalence by CMR was observed in 52.6% (95% CI: 39.9%-66.0%) in any chamber; LGE-LV in 29.8% (95% CI: 19.5%-42.7%). Histopathological findings revealed a mid-wall pattern with predominantly interstitial fibrosis and minimal replacement fibrosis. LV-fibrosis was associated with increased risk for CVD mortality (HR: 6.02, 95% CI: 1.22-19.91) attributable to lateral and mid-wall LV segment involvement. Our mortality score achieved an overall good prediction capacity (C-statistic: 0.93, Dxy= 0.86). Conclusions There is a high prevalence of replacement LV fibrosis in adults with EA, characterized by specific CMR and histological patterns. Furthermore, LV fibrosis is an independent predictor of CVD mortality, which could be integrated into a risk assessment in clinical management.Figure 1.CMR and pathological imagesFigure 1.Kaplan-Meier analysis

Abstract 14836: Left Ventricular Extracellular Volume on Computed Tomography is Useful for Predicting Reverse Remodeling After Catheter Ablation for Atrial Fibrillation

Introduction: In the CAMERA-MRI study, restoring sinus rhythm with catheter ablation (CA) for atrial fibrillation (AF) significantly improved left ventricular (LV) ejection fraction (EF), particularly in the absence of LV myocardial fibrosis, determined by magnetic resonance imaging (MRI). LV extracellular volume fraction (ECV) on MRI correlates with myocardial fibrosis. Recently analysis of LVECV on computed tomography (CT) has been feasible and LVECV on CT and MRI correlate well. Little is known about what predicts achieving LV reverse remodeling (LVRR) after CA. Hypothesis: LVECV on pre-ablation planning CT could predict LVRR after CA in patients with AF and reduced LVEF. Methods: One thousand three hundred twenty patients underwent CA for AF in our institutions from Apr 2014 to Aug 2022. Of these, 50 patients (4%) with LVEF under 50% on transthoracic echocardiography (TTE) were included. All patients underwent cardiac CT using 320-detector or 256-detector row CT before the CA. LVECV was measured by CT using non-contrast and late-phase cardiac images (Figure A). We defined LVRR as an LV end-systolic volume decrease of 15% or more, an increase in LVEF to 50% or more, or an absolute LVEF increase of 15% or more. We evaluated the utility of LVECV for the prediction of LVRR after CA. Results: LVRR was achieved in 31 patients (62%) after CA, and LVECV was significantly lower in them than in the others (31.3 ± 3.3% vs. 35.9 ± 6.6%, P &lt; 0.01) (Figure B). On receiver operating characteristic curve analysis, the best cut-off of LVECV for the prediction of LVRR was 34.8%, and the sensitivity and specificity of LVECV for the prediction of RR were 90 and 68% (the area under the curve was 0.72, Figure C). On multivariate logistic regression analysis, LVECV less than or equal to 34.8% was the only significant predictor of LVRR. Conclusion: LVECV on CT is useful for predicting LVRR in patients with AF after CA.

The impact of age on ablation outcomes in AF-mediated cardiomyopathy.

The absence of ventricular scar in patients with atrial fibrillation (AF) and systolic heart failure (HF) predicts left ventricular (LV) recovery following AF ablation. It is unknown whether age impacts the degree of LV recovery, reverse remodeling, or AF recurrence following catheter ablation (CA) among this population. To evaluate the impact of age on LV recovery and AF recurrence in a population with AF and systolic HF without fibrosis (termed AF-mediated cardiomyopathy) following CA. Consecutive patients undergoing CA between 2013 and 2021 with LV ejection fraction (LVEF) < 45% and absence of cardiac magnetic resonance imaging (CMR) detected LV myocardial fibrosis were stratified by age (<65 vs. ≥65 years). Following CA, participants underwent remote rhythm monitoring for 12 months with repeat CMR for HF surveillance. The study population consisted of 70 patients (10% female, mean LVEF 33 ± 9%), stratified into younger (age < 65 years, 63%) and older (age ≥ 65 years, 37%) cohorts. Baseline comorbidities, LVEF(34 ± 9 vs. 33 ± 8 ≥65 years, p = .686), atrial and ventricular dimensions (left atrial volume index:55 ± 21 vs. 56 ± 14 mL/m2 age ≥ 65, p = .834; indexed left ventricular end-diastolic volume: 108 ± 40 vs. 104 ± 28 mL/m2 age ≥ 65, p = .681), pharmacotherapy and ablation strategy (pulmonary vein isolation in all; posterior wall isolation in 27% vs. 19% age ≥ 65, p = .448; cavotricuspid isthmus in 9% vs. 11.5% age ≥ 65) were comparable (all p > .05) albeit a higher CHADS2 VASc score in the older cohort (2.7 ± 0.9 vs. 1.6 ± 0.6 age < 65, p < .001). Freedom from AF was comparable (hazard ratio: 0.65, 95% confidence interval: 0.38-1.48, LogRank p = .283) as was AF burden [0% (interquartile range, IQR: 0.0-2.1) vs. age ≥ 65: [0% (IQR 0.0-1.7), p = .516], irrespective of age. There was a significant improvement in LV systolic function in both groups (ΔLVEF + 21 ± 14% vs. +21 ± 12% age ≥ 65, p = .913), with LV recovery in the vast majority (73% vs. 69%, respectively, p = .759) at 13 (IQR: 12-16) months. This was accompanied by comparable improvements in functional status (New York Heart Association class p = .851; 6-min walk distance 50 ± 61 vs. 93 ± 134 min age ≥ 65, p = .066), biomarkers (ΔN-terminal-pro brain natriuretic peptide -139 ± 246 vs. -168 ± 181 age ≥ 65,p = .629) and HF symptoms (Short Form-36 survey Δphysical component summary p = .483/Δmental component summary, p = .841). In patients undergoing CA for AF with systolic HF in the absence of ventricular scar, comparable improvements in ventricular function, symptoms, and freedom from AF are achieved irrespective of age.

Electrocardiographic Markers of Adverse Left Ventricular Remodeling and Myocardial Fibrosis in Severe Aortic Stenosis.

The optimal timing for aortic valve replacement (AVR) in aortic stenosis (AS) is still controversial and may be guided by markers of adverse left ventricular (LV) remodeling. We aim to assess electrocardiographic (ECG) strain in relation to LV remodeling and myocardial fibrosis. 83 severe AS patients underwent surgical AVR, with preoperative 12-lead ECG, cardiovascular magnetic resonance with T1 mapping and echocardiography with global longitudinal strain analysis. Collagen volume fraction (CVF) was measured in myocardial biopsies sampled during AVR. Patients with ECG strain had more severe AS, more advanced LV remodeling and evidence of heart failure. Patients with ECG strain had more diffuse fibrosis, as evident by higher mean native T1 values (974.8 ± 34 ms vs. 946.5 ± 28 ms, p < 0.001). ECG strain was the only predictor of increased LV mass index on multivariate regression analysis (OR = 7.10, 95% CI 1.46-34.48, p = 0.02). Patients with persistent ECG strain at 1 year following AVR had more advanced LV remodeling and more histological fibrosis (CVF 12.5% vs. 7.3%, p = 0.009) at baseline assessment. Therefore, ECG strain is a marker of adverse LV remodeling and interstitial myocardial fibrosis. Lack of improvement in ECG strain following AVR indicates more advanced baseline LV injury and higher levels of myocardial fibrosis.

Canagliflozin Ameliorates Ventricular Remodeling through Apelin/Angiotensin-Converting Enzyme 2 Signaling in Heart Failure with Preserved Ejection Fraction Rats

Introduction: The aim of this study was to investigate the effect of canagliflozin (CANA) on ventricular remodeling in patients with preserved ejection fraction (HFpEF) heart failure and to further investigate its possible molecular mechanisms. Methods: A high-salt diet was used to induce the formation of HFpEF model in salt-sensitive rats. The rats were fed with CANA and irbesartan, respectively. The mice were divided into control group, model group, CANA group, irbesartan group, and combined drug group. After 12 weeks of feeding, the rats were evaluated by measuring the relevant indexes and echocardiography for cardiac function. Histological analysis was performed using Masson trichrome staining and immunohistochemical staining. RT-qPCR and Western blot were used to quantify the relevant genes and proteins. Results: In this study, CANA exhibited diuresis, decreased blood pressure, weight loss, and increased food and water intake. Following a high-salt diet, Dahl salt-sensitive rats developed hypertension followed by left ventricular diastolic dysfunction, myocardial fibrosis, and left ventricular remodeling. Myocardial hypertrophy and fibrosis were reduced, and left ventricular diastolic function and ventricular remodeling improved after CANA treatment. The combination of CANA and irbesartan was superior to monotherapy in reducing blood pressure and improving cardiac insufficiency and left ventricular diastolic dysfunction in rats. CANA improves myocardial fibrosis, left ventricular diastolic dysfunction, and ventricular remodeling by upregulating apelin, activating angiotensin-converting enzyme 2 (ACE2), and increasing ACE2/Ang (1–7)/MASR axis levels. Conclusion: CANA improves myocardial fibrosis, left ventricular diastolic dysfunction, and ventricular remodeling in HFpEF rats through upregulation of apelin/ACE2 signaling.

Hypertrophic cardiomyopathy in patients with a normal electrocardiogram: A view from the east side of the Atlantic Ocean

BackgroundAlthough the 12‑lead electrocardiogram (ECG) is abnormal in most patients with hypertrophic cardiomyopathy (HCM), some present normal ECG. This study aimed to analyse the baseline characteristics, clinical presentation and outcomes of HCM patients with normal ECG and to compare them with those with abnormal ECG. Methods and resultsBaseline characteristics, clinical presentation, data from complementary exams and clinical outcomes of 1070 consecutive patients included in the Portuguese Registry of HCM (Pro-HCM registry) were compared between two groups of patients: normal Vs. abnormal ECG. Among this population, 98 (9.2%) patients had normal ECG at presentation; they were significantly younger and had lower frequency of hypertension, symptoms at presentation, heart failure, angina, cardiac and non-cardiac diseases. ESC and AHA risk scores for Sudden Cardiac Death (SCD) were not significantly different between the two groups. Patients with normal ECG had higher prevalence of family history of SCD and lower degree of left ventricular (LV) hypertrophy, LV systolic dysfunction, LV outflow tract obstruction and myocardial fibrosis. The combined endpoint of cardiac death, SCD, cardiac arrest, appropriate ICD shocks or evolution to systolic dysfunction, during a mean follow-up of 5 years was significantly less frequent in patients with normal ECG (2.1% Vs. 6.5%; p = 0.043). ConclusionsA normal ECG is not a marker of an overall benign profile in HCM patients. Though a normal ECG at presentation is associated with a less severe phenotype and a lower probability of evolution to heart failure at 5-years, this finding did not show a protective effect in other clinical outcomes.

Advanced CMR Techniques in Anderson-Fabry Disease: State of the Art.

Anderson-Fabry disease (AFD) is a rare multisystem X-linked lysosomal storage disorder caused by α-galactosidase A enzyme deficiency. Long-term cardiac involvement in AFD results in left ventricular hypertrophy and myocardial fibrosis, inducing several complications, mainly arrhythmias, valvular dysfunction, and coronary artery disease. Cardiac magnetic resonance (CMR) represents the predominant noninvasive imaging modality for the assessment of cardiac involvement in the AFD, being able to comprehensively assess cardiac regional anatomy, ventricular function as well as to provide tissue characterization. This review aims to explore the role of the most advanced CMR techniques, such as myocardial strain, T1 and T2 mapping, perfusion and hybrid imaging, as diagnostic and prognostic biomarkers.

Left ventricular deformation and myocardial fibrosis in pediatric patients with Duchenne muscular dystrophy

BackgroundLeft ventricular (LV) strain and rotation are emerging functional markers for early detection of LV dysfunction and have been associated with the burden of myocardial fibrosis in several disease states. This study examined the association between LV deformation (i.e., LV strain and rotation) and extent and location of LV myocardial fibrosis in pediatric patients with Duchenne muscular dystrophy (DMD). Methods and results34 pediatric patients with DMD underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) to assess LV myocardial fibrosis. Offline CMR feature-tracking analysis was used to assess global and segmental longitudinal and circumferential LV strain, and LV rotation. Patients with fibrosis (n = 18, 52.9%) were older than those without fibrosis (14 ± 3 years (yrs) vs 11 ± 2 yrs., p = 0.01). There was no significant difference in LV ejection fraction (LVEF) between subjects with and without fibrosis (54 ± 6% vs 56 ± 4%, p = 0.18). However, lower endocardial global circumferential strain (GCS), but not LV rotation, was associated with presence of fibrosis (adjusted Odds Ratio 1.25 [95% CI 1.01–1.56], p = 0.04). Both GCS and global longitudinal strain correlated with the extent of fibrosis (r = .52, p = 0.03 and r = .75, p < 0.01, respectively). Importantly, segmental strain did not seem to correspond to location of fibrosis. ConclusionA lower global, but not segmental, strain is associated with presence and extent of LV myocardial fibrosis in pediatric DMD patients. Therefore, strain parameters might detect structural myocardial alterations, however currently more research is needed to evaluate its value (e.g., prognostic) in clinical practice.

Ling-Gui-Qi-Hua formula alleviates left ventricular myocardial fibrosis in rats with heart failure with preserved ejection fraction by blocking the transforming growth factor-β1 /Smads signaling pathway

Ethnopharmacological relevanceLing-Gui-Qi-Hua (LGQH) decoction, composed of Poria cocos (Schw.) Wolf, Cinnamomum cassia (L.) J. Presl, Paeonia veitchii Lynch, and Atractylodes macrocephala Koidz., is a compound formula derived from Ling-Gui-Zhu-Gan decoction recorded in the Treatise on Febrile and Miscellaneous. It has shown cardioprotective effects on patients or rats with heart failure with preserved ejection fraction (HFpEF). Nevertheless, the active ingredients of LGQH and its anti-fibrotic mechanism remain unknown. Aim of the studyTo determine the active ingredients in LGQH decoction and verify that LGQH decoction may inhibit left ventricular (LV) myocardial fibrosis in HFpEF rats by blocking the transforming growth factor-β1 (TGF-β1)/Smads signaling pathway from the perspective of animal experiments. Materials and methodsFirst, liquid chromatography-mass spectrometry (LC-MS) technology was used to identify active components in the LGQH decoction. Secondly, a rat model of the metabolic syndrome-associated HFpEF phenotype was established and subsequently received LGQH intervention. The mRNA and protein expression of targets in the TGF-β1/Smads pathway were detected by quantitative real-time polymerase chain reaction and western blot analysis. Finally, molecular docking was conducted to examine the interactions between the active ingredients in the LGQH decoction and key proteins of the TGF-β1/Smads pathways. ResultsAccording to LC-MS analysis, the LGQH decoction contained 13 active ingredients. In animal experiments, LGQH attenuated LV hypertrophy, enlargement, and diastolic function in HEpEF rats. Mechanically, LGQH not only down-regulated TGF-β1, Smad2, Smad3, Smad4, α-SMA, Coll I, and Coll III mRNA expressions and TGF-β1, Smad2, Smad3, P-Smad2/Smad3, Smad4, α-SMA, and Coll I protein expressions, but also up-regulated Smad7 mRNA and protein expressions, which ultimately led to myocardial fibrosis. Furthermore, molecular docking confirmed that 13 active ingredients in the LGQH decoction have excellent binding activities to the critical targets of the TGF-β1/Smads pathway. ConclusionLGQH is a modified herbal formulation with multiple active ingredients. It might alleviate LV remodeling and diastolic dysfunction and inhibit LV myocardial fibrosis by blocking TGF-β1/Smads pathways in HFpEF rats.

Is myocardial fibrosis appropriately assessed by 2D strain derived integrated backscatter?

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Calibrated integrated backscatter (cIBS) may be obtained from bidimensional (2D) strain echocardiography as a quantification measurement of myocardial ultrasound reflectivity. Increased collagen content of the myocardium modifies tissue reflectivity and cIBS is suggested as a marker of left ventricular (LV) fibrosis. However, its diagnostic accuracy is not established. Aim To assess the correlation between cIBS by 2D strain and LV myocardial fibrosis (MF), as evaluated by non-invasive imaging and histopathology. Methods Correlation study from a cohort of 157 patients with severe symptomatic aortic stenosis (AS) referred for surgical aortic valve replacement (AVR). Patients with complete preoperative transthoracic echocardiography, cardiac magnetic resonance (CMR) and endomyocardial biopsy (EMB) obtained from the anterior basal septum at the time of AVR were selected. Two groups of 30 patients were evaluated, with and without late gadolinium enhancement (LGE) at CMR. IBS was obtained at QRS peak in decibels (dB) from both parasternal long axis (PLAX) and apical three chamber (A3C) cine clips at Qanalysis (Figure 1A). cIBS was calculated by subtracting the pericardial intensity from the average of the anteroseptal and basal inferolateral wall values. Correlation analysis was performed for the whole group of patients with global and segmental (anterior basal septum) values of native T1 and extracellular volume (ECV), and EMB collagen volume fraction (CVF) from Masson´s Trichrome staining. IBS values were compared in both group of patients. Results 60 patients (73 [68–74] years, 45% male) with high gradient (mean gradient: 64±20mmHg), normal flow (45±10mL/m2), preserved ejection fraction (60±9%) AS. Basal septal cIBS was −9.2±9.5dB and −16.3±7.9dB from A3C and PLAX views, respectively. These indexes did not correlate with basal septum thickness or global LV mass. Absolute and cIBS did not correlate neither with global and regional T1 and ECV values, nor with CVF at EMB (Figure 1B). These were not significantly different in both groups of patients and there was no correlation between cIBS values and mass of replacement MF in patients with LGE. Conclusion In these cohort of patients with classical severe AS, there was no correlation of cIBS with imaging markers of both replacement and diffuse MF. cIBS also didn´t correlate with CVF at histopathology. These findings suggest that reflectivity indexes are not suitable for myocardial tissue characterization in this setting.

Obesity blunts amelioration of cardiac hypertrophy and fibrosis by human mesenchymal stem/stromal cell-derived extracellular vesicles.

Renovascular hypertension (RVH) can induce cardiac damage that is reversible using adipose tissue-derived mesenchymal stromal/stem cells (A-MSCs). However, A-MSCs isolated from patients with obesity are less effective than lean-A-MSC in blunting hypertensive cardiomyopathy in mice with RVH. We tested the hypothesis that this impairment extends to their obese A-MSC-extracellular vesicles (EVs) progeny. MSCs were harvested from the subcutaneous fat of obese and lean human subjects, and their EVs were collected and injected into the aorta of mice 2 wk after renal artery stenosis or sham surgery. Cardiac left ventricular (LV) function was studied with MRI 2 wk later, and myocardial tissue ex vivo. Blood pressure, LV myocardial wall thickness, mass, and fibrosis that were elevated in RVH mice were suppressed only by lean EVs. Hence, human A-MSC-derived lean EVs are more effective than obese EVs in blunting hypertensive cardiac injury in RVH mice. These observations highlight impaired paracrine repair potency of endogenous MSCs in patients with obesity.NEW & NOTEWORTHY Injection of A-MSC-derived EVs harvested from patients who are lean can resolve myocardial injury in mice with experimental renovascular hypertension more effectively than A-MSC-derived EVs from patients with obesity. These observations underscore and might have important ramifications for the self-healing capacity of patients with obesity and for the use of autologous EVs as a regenerative tool.