P707Poor clinical outcome in patients with increased high-sensitive cardiac troponin T in dilated cardiomyopathy: in the context of left ventricular wall stress

Alterations in length-dependent activation (LDA) may constitute a mechanism by which cardiomyopathy mutations lead to deleterious phenotypes and compromised heart function, because LDA underlies the molecular basis by which the heart tunes myocardial force production on a beat-to-beat basis (Frank-Starling mechanism). In this study, we investigated the effect of DCM-linked mutation (R173W) in human cardiac troponin T (TnT) on myofilament LDA. R173W mutation is associated with left ventricular dilatation and systolic dysfunction and is found in multiple families. R173W mutation is in the central region (residues 80–180) of TnT, which is known to be important for myofilament cooperativity and cross-bridge (XB) recruitment. Steady-state and dynamic contractile parameters were measured in detergent-skinned guinea pig left ventricular muscle fibers reconstituted with recombinant guinea pig wild-type TnT (TnTWT) or mutant TnT (TnTR174W; guinea pig analog of human R173W mutation) at two different sarcomere lengths (SL): short (1.9 µm) and long (2.3 µm). TnTR174W decreased pCa50 (−log [Ca2+]free required for half-maximal activation) to a greater extent at long than at short SL; for example, pCa50 decreased by 0.12 pCa units at long SL and by 0.06 pCa units at short SL. Differential changes in pCa50 at short and long SL attenuated the SL-dependent increase in myofilament Ca2+ sensitivity (ΔpCa50) in TnTR174W fibers; ΔpCa50 was 0.10 units in TnTWT fibers but only 0.04 units in TnTR174W fibers. Furthermore, TnTR174W blunted the SL-dependent increase in the magnitude of XB recruitment. Our observations suggest that the R173W mutation in human cardiac TnT may impair Frank-Starling mechanism. NEW & NOTEWORTHY This work characterizes the effect of dilated cardiomyopathy mutation in cardiac troponin T (TnTR174W) on myofilament length-dependent activation. TnTR174W attenuates the length-dependent increase in cross-bridge recruitment and myofilament Ca2+ sensitivity.

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Left Ventricular Wall Stress Calculated from One-Plane Cineangiography

Circulation Research ◽

10.1161/01.res.26.1.71 ◽

1970 ◽

Vol 26 (1) ◽

pp. 71-83 ◽

Cited By ~ 147

Author(s):

HERMAN L. FALSETTI ◽

ROBERT E. MATES ◽

COLIN GRANT ◽

DAVID G. GREENE ◽

IVAN L. BUNNELL

Keyword(s):

Wall Stress ◽

Left Ventricular ◽

Left Ventricular Wall ◽

Ventricular Wall

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Mechanically Unloading the Left Ventricle Before Coronary Reperfusion Reduces Left Ventricular Wall Stress and Myocardial Infarct Size

Circulation ◽

10.1161/circulationaha.112.000029 ◽

2013 ◽

Vol 128 (4) ◽

pp. 328-336 ◽

Cited By ~ 90

Author(s):

Navin K. Kapur ◽

Vikram Paruchuri ◽

Jose Angel Urbano-Morales ◽

Emily E. Mackey ◽

Gerard H. Daly ◽

...

Keyword(s):

Left Ventricle ◽

Infarct Size ◽

Myocardial Infarct ◽

Wall Stress ◽

Left Ventricular ◽

Left Ventricular Wall ◽

Myocardial Infarct Size ◽

Ventricular Wall ◽

Coronary Reperfusion

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Reduction in Left Ventricular Wall Stress and Improvement in Function in Failing Hearts using Algisyl-LVR

Journal of Visualized Experiments ◽

10.3791/50096 ◽

2013 ◽

Cited By ~ 7

Author(s):

Lik Chuan Lee ◽

Zhang Zhihong ◽

Andrew Hinson ◽

Julius M. Guccione

Keyword(s):

Wall Stress ◽

Left Ventricular ◽

Left Ventricular Wall ◽

Ventricular Wall

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Association of High-Sensitivity Cardiac Troponin T and N-Terminal Pro-Brain-Type Natriuretic Peptide With Left Ventricular Structure: J-HOP Study

Journal of Clinical Hypertension ◽

10.1111/jch.12321 ◽

2014 ◽

Vol 16 (5) ◽

pp. 354-361 ◽

Cited By ~ 2

Author(s):

Satoshi Hoshide ◽

Michiaki Nagai ◽

Yuichiro Yano ◽

Joji Ishikawa ◽

Kazuo Eguchi ◽

...

Keyword(s):

Natriuretic Peptide ◽

Cardiac Troponin ◽

Troponin T ◽

High Sensitivity ◽

Left Ventricular ◽

Cardiac Troponin T ◽

Left Ventricular Structure ◽

Ventricular Structure

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Prognostic Value of Combination of Cardiac Troponin T and B-Type Natriuretic Peptide after Initiation of Treatment in Patients with Chronic Heart Failure

Clinical Chemistry ◽

10.1373/clinchem.2003.021311 ◽

2003 ◽

Vol 49 (12) ◽

pp. 2020-2026 ◽

Cited By ~ 66

Author(s):

Junnichi Ishii ◽

Wei Cui ◽

Fumihiko Kitagawa ◽

Takahiro Kuno ◽

Yuu Nakamura ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Cardiac Troponin ◽

Troponin T ◽

Myocardial Damage ◽

Left Ventricular ◽

Functional Class ◽

Cardiac Troponin T ◽

Cardiac Events ◽

Nyha Functional Class

Abstract Background: Recent studies have suggested that cardiac troponin T (cTnT) and troponin I may detect ongoing myocardial damage involved in the progression of chronic heart failure (CHF). This study was prospectively designed to examine whether the combination of cTnT, a marker for ongoing myocardial damage, and B-type natriuretic peptide (BNP), a marker for left ventricular overload, would effectively stratify patients with CHF after initiation of treatment. Methods: We measured serum cTnT, plasma BNP, and left ventricular ejection fraction (LVEF) on admission for worsening CHF [New York Heart Association (NYHA) functional class III to IV] and 2 months after initiation of treatment to stabilize CHF (n = 100; mean age, 68 years). Results: Mean (SD) concentrations of cTnT [0.023 (0.066) vs 0.063 (0.20) μg/L] and BNP [249 (276) vs 753 (598) ng/L], percentage increased cTnT (>0.01 μg/L; 35% vs 60%), NYHA functional class [2.5 (0.6) vs 3.5 (5)], and LVEF [43 (13)% vs 36 (12)%] were significantly (P <0.01) improved 2 months after treatment compared with admission. During a mean follow-up of 391 days, there were 44 cardiac events, including 12 cardiac deaths and 32 readmissions for worsening CHF. On a stepwise Cox regression analysis, increased cTnT and BNP were independent predictors of cardiac events (P <0.001). cTnT >0.01 μg/L and/or BNP >160 ng/L 2 months after initiation of treatment were associated with increased cardiac mortality and morbidity rates. Conclusion: The combination of cTnT and BNP measurements after initiation of treatment may be highly effective for risk stratification in patients with CHF.

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Abstract 3809: Cardiac-Specific Overexpression of EcSOD Using an AAV9 Vector in Combination with the Cardiac Troponin-T Promoter Inhibits LV Remodeling after Myocardial Infarction

Circulation ◽

10.1161/circ.118.suppl_18.s_488-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Konkal-Matt R Prasad ◽

Ronald J Beyers ◽

Yaqin Xu ◽

Brent A French

Keyword(s):

Myocardial Infarction ◽

Cardiac Troponin ◽

Troponin T ◽

Left Ventricular ◽

The Body ◽

Cardiac Troponin T ◽

Sod Activity ◽

Western Blots ◽

Systemic Injection ◽

Lv Remodeling

Introduction: The wide tissue tropism exhibited by AAV provides for efficient gene transfer throughout the body, but targeting gene expression to cardiomyocytes is desirable for cardiac gene therapy. We hypothesized that targeted overexpression of extracellular superoxide dismutase (EcSOD) via the cardiac Troponin-T (cTnT) promoter would suffice to minimize left ventricular (LV) remodeling after myocardial infarction (MI). Methods: An AAV9 vector expressing EcSOD from the cTnT promoter (AcTnTEcSOD) was injected into 5 wk-old C57 mice via jugular vein (3x10 11 vp/mouse). Western blots, immunohistochemistry & in vitro SOD assays were used to measure EcSOD expression, distribution and activity. Cardiac magnetic resonance (CMR) imaging was performed at baseline (5 wks post-vector injection) and at days 1, 7 & 28 after MI to assess LV volumes (vol) & ejection fraction (EF) as compared to WT mice (n=4). Infarct (IF) sizes were also compared by DE on D1. Results: Systemic injection of the vector (AcTnTEcSOD) provided uniform EcSOD overexpression within cardiomyocytes (Panels A&B) and elevated total cardiac SOD activity by 5.6 fold (p<0.05). On D1 post-MI, IF sizes were similar in vector & WT groups (p=ns). The vector group had significantly lower end-diastolic vol at D7, D28 and lower end-systolic vol at D28 (all p<0.05 by ANOVA, Panels C&D), resulting in improved D28 EF over controls (p=0.02). Conclusions: Cardiac-specific overexpression of therapeutic genes can be achieved by combining highly-efficient AAV9 vectors with cardiac-specific promoters. AAV-mediated, cardiac-restricted overexpression of EcSOD from the cTnT promoter significantly reduces post-MI LV remodeling.

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