scholarly journals Genetics of Myocardial Interstitial Fibrosis in the Human Heart and Association with Disease

2021 ◽  
Author(s):  
Victor Nauffal ◽  
Paolo Di Achille ◽  
Marcus D. R. Klarqvist ◽  
Jonathan W. Cunningham ◽  
James P. Pirruccello ◽  
...  
Keyword(s):  
Machine Learning ◽  
Heart Failure ◽  
Atrial Fibrillation ◽  
Human Heart ◽  
Iron Homeostasis ◽  
Interstitial Fibrosis ◽  
Association Studies ◽  
Interventricular Septum ◽  
Myocardial Interstitial Fibrosis ◽  
Myocardial T1

Myocardial interstitial fibrosis is a common thread in multiple cardiovascular diseases including heart failure, atrial fibrillation, conduction disease and sudden cardiac death. To investigate the biologic pathways that underlie interstitial fibrosis in the human heart, we developed a machine learning model to measure myocardial T1 time, a marker of myocardial interstitial fibrosis, in 42,654 UK Biobank participants. Greater T1 time was associated with impaired glucose metabolism, systemic inflammation, renal disease, aortic stenosis, cardiomyopathy, heart failure, atrial fibrillation and conduction disease. In genome-wide association analysis, we identified 12 independent loci associated with native myocardial T1 time with evidence of high genetic correlation between the interventricular septum and left ventricle free wall (r2g = 0.82). The identified loci implicated genes involved in glucose homeostasis (SLC2A12), iron homeostasis (HFE, TMPRSS6), tissue repair (ADAMTSL1, VEGFC), oxidative stress (SOD2), cardiac hypertrophy (MYH7B) and calcium signaling (CAMK2D). Transcriptome-wide association studies highlighted the role of expression of ADAMTSL1 and SLC2A12 in human cardiac tissue in modulating myocardial tissue characteristics and interstitial fibrosis. Harnessing machine learning to perform large-scale phenotyping of interstitial fibrosis in the human heart, our results yield novel insights into biologically relevant pathways for myocardial fibrosis and prioritize investigation of pathways for the development of anti-fibrotic therapies.

Histomolecular fibrotic profile and an extent of the atrial and ventricular electroanatomical substrate in patients with atrial fibrillation and heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V Orshanskaya ◽  
V.S Orshanskaya ◽  
A.V Kamenev ◽  
L.B Mitrofanova ◽  
L.A Belyakova ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Plasma Level ◽  
Serum Level ◽  
Interstitial Fibrosis ◽  
Myocardial Interstitial Fibrosis ◽  
Relative Extent ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Background and purpose The aim of this pilot study was to investigate the association between an extent of the atrial and ventricular electroanatomical substrate, serum fibrotic biomarkers and histological and immune-histochemical myocardial characteristics in ipatients with atrial fibrillation and heart failure. Methods We prospectively analyzed electroanatomical ultra-high density bipolar maps (HDBM) in 72 patients with AF and CHF, who underwent circular pulmonary veins (PVs) isolation. LA areas outside PVs ostia with bipolar signals ≤0.75mV, associated with local conduction velocity delay were considered as EAS and measured. Relative area of low voltage zones in right (RV) and left ventricles (RV) with bipolar signals in range of 0,5–1,5 mV were also consistently measured. Endomyocardial biopsy samples were taken from low, mediate and high septal areas of RV; histological and immune-histochemical staining was performed and an extent of myocardial interstitial fibrosis (MIF) was calculated. Before the operation we measured plasma MMP2, MMP9, TIMP, MMPs/TIMPs, galectin 3 (Gal3), TGF, soluble ST2 and the cross-linked collagen I/III synthesis and degradation product levels. The patients were divided into groups according to their ejection fraction Simpson (EF) (groups 1: EF≥50%, groups 2: EF 40–49%, and groups 3: EF<40%). Results The data of electroanatomical mapping, serum biomarkers and myocardial expression are presented in the table. According to results of correlation analysis, an extent of LA EAS were correlated with Gal3 and PIIICP plasma level and Gal3 myocardial expression and MIF extent (Rs=0,40, 0,45 and 0,42 respectively). The relative extent of LV EAS was correlated with MMP9 serum level (Rs=0,38); LV volume (LVV) was correlated with sST2 serum level and RVV was correlated with CD 133 myocardial expression (Rs=0,42) (picture 1). The patients with lower EF had larger extent of the LA EAS, (group 3: 28±12.4% vs. 1: 17.7±11.6%, p=0.03), an extent of LV EAS and LVV (group 3: 8,4±4,5% vs. 1: 5,1±3,8% p=0.02; group 3 vs group 1 p=0,05 relatively),higher Gal3 plasma level (group 1: 7,1±2 vs. group 2: 8,9±1,5, p=0.05) and higher MIF extent (group 2: 134±56 vs. 3: 151±30 p=0.04) (picture 2). Conclusion Our data suggest that relative extent of LA EAS in patients with atrial fibrillation is associated with Gal3 plasma level and Gal3 myocardial expression; severity of myocardial remodeling is connected to CD 3/133 myocardial expression and myocardial interstitial fibrosis extent, especially in patients with HF with restricted LV ejection fraction. Funding Acknowledgement Type of funding source: None

scholarly journals Myocardial Interstitial Fibrosis in Heart Failure

2018 ◽  
Vol 71 (15) ◽  
pp. 1696-1706 ◽  
Author(s):  
Arantxa González ◽  
Erik B. Schelbert ◽  
Javier Díez ◽  
Javed Butler
Keyword(s):  
Heart Failure ◽  
Interstitial Fibrosis ◽  
Myocardial Interstitial Fibrosis

P3793Spironolactone in patients with permanent atrial fibrillation, possible heart failure protective potential

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
R Dabrowski ◽  
T Chwyczko ◽  
I Kowalik ◽  
E Smolis-Bak ◽  
A Borowiec ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Beta Blocker ◽  
Interstitial Fibrosis ◽  
Randomized Study ◽  
Treated Group ◽  
Control Treatment ◽  
Permanent Atrial Fibrillation ◽  
Minute Walk

Abstract Background Atrial fibrillation (AF) promotes electrical, neurohormonal and structural remodeling of atria and ventricles. Long lasting AF leads to atrial interstitial fibrosis, apoptosis, loss of myofibrils and finally to heart failure (HF). Purpose The aim of the study was impact of aldosterone antagonist, spironolactone, on exercise tolerance and neurohormonal activity in patients with permanent AF without symptoms of HF. Methods In prospective, randomized study patients with permanent AF at least for 1 year, no signs and symptoms of HF and stable clinical condition were included. Patients were randomized to: beta-blocker plus spironolactone (dose: 25 mg) treatment and rate-control treatment with only beta-blocker. Propranolol, metoprolol and bisoprolol were used, doses were adjusted to achieve resting heart rate 60–80/min. Ergospirometry (CPX) and 6-minute walk (6-MWT) tests were performed during separate days. Results Study group consisted of 49 patients, 69% men, mean age 62.1±9.6 without structural and chronic active diseases, mean time of arrhythmia was 5.5 years, Q1: 2, Q3: 8 years. Follow-up was 11.2 months. All patients were treated with beta-blockers, 27 patients were treated with 25 mg spironolactone. Surprisingly physical capacity in 6-minute walk test (6-MWT) in studied patients was not significantly reduced in comparison with values ranges for healthy volunteers. After 11.2 months follow-up significantly longer exercise time (433±113 vs. 367±162 sec, p<0.05) and lower maximal HR (159±25 vs. 165±22 beats/min, p<0.0550) were observed in spironolactone treated group. Other CPX variables did not differ significantly between groups after 11,2 months: VO2: 20.7±5.1 vs. 20.1±4.8 [ml/kg/min]; VO2 as % of normal value: 78.4±15.2 vs. 76.8±15.2; O2 pulse: 12±2.8 vs. 12.7±3.6 [ml/beat]; AT: 1.4±0.3, 1.6±0.5 [L/min]; VE: 74.9±20.0, 72.6±17.9 [L/min]. All spirometric variables worsened after 11.2 months: VC: 4.3±1.1 vs. 3.8±0.8 [L], p<0.0005, FVC: 4.2±1.1 vs. 3.8±1.0 p<0.005 [L], FEV1: 3.1±0.8 vs. 2.8±0.7 [L], p<0.01. In spironolactone treated group after 11.2 months BNP concentrations were significantly lower: Q1: 54, Q2: 83, Q3: 100 vs. Q1: 42, Q2: 93; Q3: 184 ng/L (p=0.025) and aldosterone levels were markedly increased: Q1: 216, Q2: 266; Q3:443 vs. Q1: 169; Q2: 228; Q3:294 ng/dL (p=0.0007). Conclusions In patients with permanent atrial fibrillation cardiopulmonary exercise responses were markedly abnormal, but exercise capacity was increased after spironolactone treatment. Deterioration of spirometry results might be due to beta-blocker treatment. In spironolactone treated group BNP levels were significantly lower what may correspond to its heart failure protective activity.

scholarly journals Prognostic Impact of Myocardial Interstitial Fibrosis in Non-Ischemic Heart Failure

2011 ◽  
Vol 75 (11) ◽  
pp. 2605-2613 ◽  
Author(s):  
Tatsuo Aoki ◽  
Yoshihiro Fukumoto ◽  
Koichiro Sugimura ◽  
Minako Oikawa ◽  
Kimio Satoh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Interstitial Fibrosis ◽  
Ischemic Heart ◽  
Prognostic Impact ◽  
Ischemic Heart Failure ◽  
Myocardial Interstitial Fibrosis

Differential regulation of protein phosphatase 1 (PP1) isoforms in human heart failure and atrial fibrillation

2017 ◽  
Vol 112 (4) ◽  
Author(s):  
Stefanie Meyer-Roxlau ◽  
Simon Lämmle ◽  
Annett Opitz ◽  
Stephan Künzel ◽  
Julius P. Joos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Protein Phosphatase ◽  
Human Heart ◽  
Differential Regulation ◽  
Protein Phosphatase 1 ◽  
Human Heart Failure

P1596Interaction of CaMKII and NaV1.8 modulates cardiac electrophysiology in human heart failure

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
P Tirilomis ◽  
S Ahmad ◽  
P Bengel ◽  
S Pabel ◽  
L Maier ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Electrophysiology ◽  
Human Heart ◽  
Association Studies ◽  
Cardiac Conduction ◽  
Epifluorescence Microscopy ◽  
Genome Wide Association Studies ◽  
Human Heart Failure ◽  
Human Cardiomyocytes ◽  
Ventricular Cardiomyocytes

Abstract Introduction In human heart failure, electrical remodeling contributes to the risk of arrhythmia generation. Increased expression of Ca/Calmodulin-dependent protein kinase IIδ (CaMKIIδ) and an enhanced persistent Na current (INaL) have been linked to arrhythmogenesis. CaMKIIδ increases INaL via regulation of sodium channels thereby contributing to arrhythmias through early- and delayed-afterdepolarizations (EADs and DADs). Genome-wide association studies (GWAS) have described the implication of the neuronal sodium channel isoform NaV1.8 (SCN10A) in cardiac electrophysiology showing modulation in cardiac conduction. We showed that the expression of the isoform Nav1.8 is significantly increased in human failing cardiomyocytes and contributes substantially to the enhanced INaL. Purpose We investigated a potential interaction of CaMKIIδ and NaV1.8 and thereby its role in arrhythmia generation and electrophysiology in human and murine failing hearts. Methods Cardiomyocytes were isolated from explanted failing hearts and CaMKIIδ transgenic (TG) mice. We performed immunostainings and co-immunoprecipitation (Co-IP) to show interactions of CaMKIIδ and Nav1.8 in isolated cardiomyocytes and homogenates. Whole-cell patch clamp experiments were conducted in isolated human and murine ventricular cardiomyocytes. Additionally, Ca2+ transients were measured using epifluorescence microscopy with the Ca2+ dye fura-2 (10μmol/L) whereas Ca2+ sparks measurements were performed by using confocal microscopy with the Ca2+ dye fluo-4 (10μmol/L). PF-01247324 is a novel specific NaV1.8 inhibitor (orally bioavailable; 1 μmol/L) and autocamtide inhibitory peptide (AIP, 1 μmol/L) was used to inhibit CaMKIIδ. Results Co-immunoprecipitation experiments revealed an association of CaMKIIδ and Nav1.8 in human homogenates compared to healthy controls. Furthermore, immunohistochemistry stainings in isolated human cardiomyocytes showed a co-localization of CaMKIIδ and NaV1.8 at the intercalated disc and t-tubules. We observed a significant reduction of INaL integral and proarrhythmic SR-Ca2+ spark frequency (CaSpF) after addition of either PF-01247324 or the CaMKIIδ inhibitor AIP in failing human and murine ventricular cardiomyocytes. When PF-01247324 and AIP were added together, the decrease in INaL integral and CaSpF was comparable to PF-01247324 alone in human failing cardiomyocytes. Inhibition of NaV1.8 did not show an effect on Ca2+ transient amplitude or Ca2+ transient decay at different stimulation frequencies in CaMKIIδ TG cardiomyocytes. Conclusion Our results demonstrate the significance of both CaMKIIδ and NaV1.8 in INaL generation and their detrimental interaction. This data suggest that increased CaMKIIδ activity plays a substantial role for the activation of NaV1.8-mediated late sodium current and SR-Ca2+ leak.

A retrospective study of canine dilated cardiomyopathy (189 cases)

1997 ◽  
Vol 33 (6) ◽  
pp. 544-550 ◽  
Author(s):  
A Tidholm ◽  
L Jonsson
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Dilated Cardiomyopathy ◽  
Interstitial Fibrosis ◽  
Histopathological Changes ◽  
German Shepherd ◽  
Male Predominance ◽  
Doberman Pinschers ◽  
Mild Hyperglycemia ◽  
Canine Dilated Cardiomyopathy

The case records of 189 dogs (including 38 breeds) with congestive heart failure caused by dilated cardiomyopathy were studied retrospectively. Airedale terriers, boxers, Doberman pinschers, English cocker spaniels, Newfoundlands, St. Bernards, and standard poodles were over-represented. German shepherd dogs were under-represented. A male predominance was observed. Systolic murmurs were detected in 25% of the cases. Atrial fibrillation was the most common arrhythmia. Mild hyperglycemia and mild-to-moderate hypercholesterolemia were found in 38% and 33% of cases, respectively. Histopathological changes consisted of attenuated wavy fibers and interstitial fibrosis.

Dilated cardiomyopathy in the Newfoundland: a study of 37 cases (1983-1994)

1996 ◽  
Vol 32 (6) ◽  
pp. 465-470 ◽  
Author(s):  
A Tidholm ◽  
L Jonsson
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Congestive Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Clinical Diagnosis ◽  
Current Knowledge ◽  
Interstitial Fibrosis ◽  
Histopathological Changes ◽  
Homogeneous Population ◽  
Echocardiographic Findings

The case records of 37 Newfoundlands with congestive heart failure caused by dilated cardiomyopathy were reviewed in an attempt to compare current knowledge of dilated cardiomyopathy with findings in a large and homogeneous population. The clinical diagnosis was based on echocardiographic findings of reduced shortening fraction (FS) in the presence of clinical and radiographic signs or necropsy findings of left-sided or biventricular heart failure. Systolic murmurs were detected in only four cases. Atrial fibrillation was the most common arrhythmia. Histopathological changes consisted of attenuated wavy fibers and interstitial fibrosis. No significant sex predilection was observed.

Heart failure in chronic kidney disease: the emerging role of myocardial fibrosis

2020 ◽  
Author(s):  
Gregorio Romero-González ◽  
Arantxa González ◽  
Begoña López ◽  
Susana Ravassa ◽  
Javier Díez
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Current Knowledge ◽  
Interstitial Fibrosis ◽  
Collagen Fibres ◽  
Fibrotic Tissue ◽  
Myocardial Interstitial Fibrosis ◽  
New Strategy

Abstract Heart failure (HF) is one of the main causes of morbidity and mortality in patients with chronic kidney disease (CKD). Decreased glomerular filtration rate is associated with diffuse deposition of fibrotic tissue in the myocardial interstitium [i.e. myocardial interstitial fibrosis (MIF)] and loss of cardiac function. MIF results from cardiac fibroblast-mediated alterations in the turnover of fibrillary collagen that lead to the excessive synthesis and deposition of collagen fibres. The accumulation of stiff fibrotic tissue alters the mechanical properties of the myocardium, thus contributing to the development of HF. Accumulating evidence suggests that several mechanisms are operative along the different stages of CKD that may converge to alter fibroblasts and collagen turnover in the heart. Therefore, focusing on MIF might enable the identification of fibrosis-related biomarkers and targets that could potentially lead to a new strategy for the prevention and treatment of HF in patients with CKD. This article summarizes current knowledge on the mechanisms and detrimental consequences of MIF in CKD and discusses the validity and usefulness of available biomarkers to recognize the clinical–pathological variability of MIF and track its clinical evolution in CKD patients. Finally, the currently available and potential future therapeutic strategies aimed at personalizing prevention and reversal of MIF in CKD patients, especially those with HF, will be also discussed.

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