scholarly journals The Physiology and Pathophysiology of T-Tubules in the Heart

2021 ◽  
Vol 12 ◽  
Author(s):  
Ingunn E. Setterberg ◽  
Christopher Le ◽  
Michael Frisk ◽  
Jia Li ◽  
William E. Louch
Keyword(s):  
Heart Failure ◽  
Close Contact ◽  
Ryanodine Receptors ◽  
Wall Stress ◽  
Regulatory Proteins ◽  
Ventricular Wall ◽  
Preserved Ejection Fraction ◽  
Ec Coupling ◽  
T Tubules ◽  
Review Current

In cardiomyocytes, invaginations of the sarcolemmal membrane called t-tubules are critically important for triggering contraction by excitation-contraction (EC) coupling. These structures form functional junctions with the sarcoplasmic reticulum (SR), and thereby enable close contact between L-type Ca2+ channels (LTCCs) and Ryanodine Receptors (RyRs). This arrangement in turn ensures efficient triggering of Ca2+ release, and contraction. While new data indicate that t-tubules are capable of exhibiting compensatory remodeling, they are also widely reported to be structurally and functionally compromised during disease, resulting in disrupted Ca2+ homeostasis, impaired systolic and/or diastolic function, and arrhythmogenesis. This review summarizes these findings, while highlighting an emerging appreciation of the distinct roles of t-tubules in the pathophysiology of heart failure with reduced and preserved ejection fraction (HFrEF and HFpEF). In this context, we review current understanding of the processes underlying t-tubule growth, maintenance, and degradation, underscoring the involvement of a variety of regulatory proteins, including junctophilin-2 (JPH2), amphiphysin-2 (BIN1), caveolin-3 (Cav3), and newer candidate proteins. Upstream regulation of t-tubule structure/function by cardiac workload and specifically ventricular wall stress is also discussed, alongside perspectives for novel strategies which may therapeutically target these mechanisms.

Abstract 17200: Plasma BNP Declines in the First Two Years After Transplant and is Elevated at the Time of Treated Rejection

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Tom J Valikodath ◽  
Neal Jorgensen ◽  
Erin Albers ◽  
Borah Hong ◽  
Joshua Friedland-Little ◽  
...  
Keyword(s):  
Heart Failure ◽  
Natriuretic Peptide ◽  
Ventricular Dysfunction ◽  
Multivariable Analysis ◽  
Wall Stress ◽  
Ventricular Wall ◽  
The Relationship ◽  
Pediatric Recipients ◽  
Over Time

Introduction: Plasma B-type natriuretic peptide (BNP) is a biomarker used to diagnose and monitor ventricular dysfunction and heart failure. However, the response of the allograft to produce BNP from ventricular wall stress and inflammation may be different, particularly in an understudied population such as pediatric recipients. Hypothesis: BNP levels decrease over time after transplant as the allograft recovers; but BNP will be higher during rejection. Methods: Enrolled all heart recipients from January 2007 to December 2016. Rejection surveillance included serial echocardiography, annual biopsy, and BNP q 1-3 months. Rejection is defined as requiring augmentation of immunosuppression from biopsy grade ≥ 2R or ≥ pAMR2 or from clinical diagnosis. Results: Among 114 patients studied, 60% were male with age at transplant 5.8 ± SD 6.5 yrs. Follow-up was 3.7 ± 2.7 yrs and 37 patients (32%) experienced 75 episodes of rejection. A total of 8358 BNP samples were obtained. BNP decreased linearly after transplant leveling off after 2 years (Fig 1). BNP was 671 ± 1115 (n=75) at rejection vs. 187 ± 423 pg/mL (n=501) without rejection confirmed by biopsy. By multivariable analysis, Ln BNP was associated with rejection (RR 1.56; 95% CI 1.35-1.80). Figure 2 shows the relationship between change in BNP and risk of rejection. Multivariable longitudinal Cox proportional model incorporating BNPs leading to 1 st rejection showed Ln BNP to be associated with rejection (HR 2.22; 95% CI 1.53-3.23, p<0.001). Conclusion: BNP continues to decrease in the 1 st 2 years after transplant. At rejection, BNP is elevated, and this test can be further developed to screen for rejection.

scholarly journals Pachymic Acid Attenuated Doxorubicin-Induced Heart Failure by Suppressing miR-24 and Preserving Cardiac Junctophilin-2 in Rats

2021 ◽  
Vol 22 (19) ◽  
pp. 10710
Author(s):  
Nahla N. Younis ◽  
Alaa Salama ◽  
Mohamed A. Shaheen ◽  
Rana G. Eissa
Keyword(s):  
Electron Microscopy ◽  
Heart Failure ◽  
Fiber Diameter ◽  
Ryanodine Receptors ◽  
Cardiac Contractility ◽  
Histological Assessment ◽  
Contraction Coupling ◽  
Pachymic Acid ◽  
T Tubules ◽  
Mitochondrial Number

Defects in cardiac contractility and heart failure (HF) are common following doxorubicin (DOX) administration. Different miRs play a role in HF, and their targeting was suggested as a promising therapy. We aimed to target miR-24, a suppressor upstream of junctophilin-2 (JP-2), which is required to affix the sarcoplasmic reticulum to T-tubules, and hence the release of Ca2+ in excitation–contraction coupling using pachymic acid (PA) and/or losartan (LN). HF was induced with DOX (3.5 mg/kg, i.p six doses, twice weekly) in 24 rats. PA and LN (10 mg/kg, daily) were administered orally for four weeks starting the next day of the last DOX dose. Echocardiography, left ventricle (LV) biochemical and histological assessment and electron microscopy were conducted. DOX increased serum BNP, HW/TL, HW/BW, mitochondrial number/size and LV expression of miR-24 but decreased EF, cardiomyocyte fiber diameter, LV content of JP-2 and ryanodine receptors-2 (RyR2). Treatment with either PA or LN reversed these changes. Combined PA + LN attained better results than monotherapies. In conclusion, HF progression following DOX administration can be prevented or even delayed by targeting miR-24 and its downstream JP-2. Our results, therefore, suggest the possibility of using PA alone or as an adjuvant therapy with LN to attain better management of HF patients, especially those who developed tolerance toward LN.

scholarly journals Association between Diastolic Wall Stress in Severe Aortic Stenosis with Preserved Ejection Fraction and Heart Failure

2018 ◽  
Vol 86 (3) ◽  
pp. 163-170
Author(s):  
Ricardo E. Migliore ◽  
María E. Adaniya ◽  
Guillermo Miramont ◽  
Miguel Barranco ◽  
Silvia González ◽  
...  
Keyword(s):  
Heart Failure ◽  
Aortic Stenosis ◽  
Ejection Fraction ◽  
Severe Aortic Stenosis ◽  
Wall Stress ◽  
Preserved Ejection Fraction

scholarly journals Severe T-System Remodeling in Pediatric Viral Myocarditis

2021 ◽  
Vol 7 ◽  
Author(s):  
Dominik J. Fiegle ◽  
Martin Schöber ◽  
Sven Dittrich ◽  
Robert Cesnjevar ◽  
Karin Klingel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Acute Myocarditis ◽  
Viral Myocarditis ◽  
Left Ventricular ◽  
Length Ratio ◽  
Transverse Tubular System ◽  
Ec Coupling ◽  
T Tubules ◽  
T System

Chronic heart failure (HF) in adults causes remodeling of the cardiomyocyte transverse tubular system (t-system), which contributes to disease progression by impairing excitation-contraction (EC) coupling. However, it is unknown if t-system remodeling occurs in pediatric heart failure. This study investigated the t-system in pediatric viral myocarditis. The t-system and integrity of EC coupling junctions (co-localization of L-type Ca2+ channels with ryanodine receptors and junctophilin-2) were analyzed by 3D confocal microscopy in left-ventricular (LV) samples from 5 children with myocarditis (age 14 ± 3 months), undergoing ventricular assist device (VAD) implantation, and 5 children with atrioventricular septum defect (AVSD, age 17 ± 3 months), undergoing corrective surgery. LV ejection fraction (EF) was 58.4 ± 2.3% in AVSD and 12.2 ± 2.4% in acute myocarditis. Cardiomyocytes from myocarditis samples showed increased t-tubule distance (1.27 ± 0.05 μm, n = 34 cells) and dilation of t-tubules (volume-length ratio: 0.64 ± 0.02 μm2) when compared with AVSD (0.90 ± 0.02 μm, p &lt; 0.001; 0.52 ± 0.02 μm2, n = 61, p &lt; 0.01). Intriguingly, 4 out of 5 myocarditis samples exhibited sheet-like t-tubules (t-sheets), a characteristic feature of adult chronic heart failure. The fraction of extracellular matrix was slightly higher in myocarditis (26.6 ± 1.4%) than in AVSD samples (24.4 ± 0.8%, p &lt; 0.05). In one case of myocarditis, a second biopsy was taken and analyzed at VAD explantation after extensive cardiac recovery (EF from 7 to 56%) and clinical remission. When compared with pre-VAD, t-tubule distance and density were unchanged, as well as volume-length ratio (0.67 ± 0.04 μm2 vs. 0.72 ± 0.05 μm2, p = 0.5), reflecting extant t-sheets. However, junctophilin-2 cluster density was considerably higher (0.12 ± 0.02 μm−3 vs. 0.05 ± 0.01 μm−3, n = 9/10, p &lt; 0.001), approaching values of AVSD (0.13 ± 0.05 μm−3, n = 56), and the measure of intact EC coupling junctions showed a distinct increase (20.2 ± 5.0% vs. 6.8 ± 2.2%, p &lt; 0.001). Severe t-system loss and remodeling to t-sheets can occur in acute HF in young children, resembling the structural changes of chronically failing adult hearts. T-system remodeling might contribute to cardiac dysfunction in viral myocarditis. Although t-system recovery remains elusive, recovery of EC coupling junctions may be possible and deserves further investigation.

Abstract 5882: Myocardial Contractile Dysfunction in Heart Failure with Preserved Ejection Fraction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Barry A Borlaug ◽  
Carolyn S Lam ◽  
Veronique Roger ◽  
Richard J Rodeheffer ◽  
Margaret M Redfield
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Myocardial Contractility ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Wall Stress ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
Long Term Outcome

Background Patients with heart failure and preserved ejection fraction (HFpEF) have diastolic dysfunction, but are traditionally considered to have normal left ventricular (LV) systolic function. However, ventricular remodeling can result in preservation of EF despite abnormal myocardial contractility. Methods We performed echo-Doppler characterization of LV chamber and myocardial systolic properties in a population-based study, comparing patients with HFpEF (N=244) to healthy controls (CON, N=617), and hypertensives without HF (HTN, N=719), then examined long term outcome. Results All subjects had a normal EF (>50%). However, systolic chamber function, measured by wall stress-corrected endocardial fractional shortening (sc-eFS), was impaired in HFpEF (96±12%) compared to both CON (100±8%, p<0.0001) and HTN (108±11%, p<0.0001). Myocardial contractility, assessed by wall stress-corrected midwall shortening (sc-mFS), was also reduced in HFpEF (91±13%) compared to CON (100±10%, p<0.0001) and HTN (105±12%, p<0.0001). HTN had increased sc-eFS and sc-mFS compared with both HFpEF and CON (p<0.0001). In HFpEF, impaired sc-mFS was associated with increased mortality, independent of age (Figure ), while EF and sc- eFS were not. Conclusions Despite preservation of EF, unselected HFpEF patients from the community have significantly impaired systolic chamber function and depressed myocardial contractility. Abnormal myocardial contractility in HFpEF is associated with increased mortality. These data suggest that myocardial systolic dysfunction contributes to the pathophysiology of HFpEF and may represent a potential therapeutic target.

scholarly journals Effect of Transmural Differences in Excitation-Contraction Delay and Contraction Velocity on Left Ventricle Isovolumic Contraction: A Simulation Study

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
J. Vaverka ◽  
J. Burša ◽  
J. Šumbera ◽  
M. Pásek
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Wall Stress ◽  
Element Model ◽  
Ventricular Wall ◽  
Shortening Velocity ◽  
Electromechanical Delay ◽  
Contraction Coupling ◽  
Physiological Importance ◽  
Isovolumic Contraction

Recent studies have shown that left ventricle (LV) exhibits considerable transmural differences in active mechanical properties induced by transmural differences in electrical activity, excitation-contraction coupling, and contractile properties of individual myocytes. It was shown that the time between electrical and mechanical activation of myocytes (electromechanical delay: EMD) decreases from subendocardium to subepicardium and, on the contrary, the myocyte shortening velocity (MSV) increases in the same direction. To investigate the physiological importance of this inhomogeneity, we developed a new finite element model of LV incorporating the observed transmural gradients in EMD and MSV. Comparative simulations with the model showed that when EMD or MSV or both were set constant across the LV wall, the LV contractility during isovolumic contraction (IVC) decreased significantly (dp/dtmax⁡  was reduced by 2 to 38% and IVC was prolonged by 18 to 73%). This was accompanied by an increase of transmural differences in wall stress. These results suggest that the transmural differences in EMD and MSV play an important role in physiological contractility of LV by synchronising the contraction of individual layers of ventricular wall during the systole. Reduction or enhancement of these differences may therefore impair the function of LV and contribute to heart failure.

Assessment and relevance of ventricular wall stress in heart failure

2008 ◽  
Vol 29 (18) ◽  
pp. 2316-2316 ◽  
Author(s):  
P. Alter ◽  
H. Rupp ◽  
B. Maisch
Keyword(s):  
Heart Failure ◽  
Wall Stress ◽  
Ventricular Wall
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