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从风湿性心脏病致心力衰竭的病例看心肌重构

从风湿性心脏病致心力衰竭的病例看心肌重构. 褚祎、姜岚、王晶、夏雪、曹洁. Compensatory Mechanisms to Heart Failure. 1. Neurohumoral Activation 2. Functional Adjustment 3. Structural Adaptation 4. Extracardial Compensation. Neurohumoral Activation. (1) Activation of Sympathetic Nervous System

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从风湿性心脏病致心力衰竭的病例看心肌重构

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  1. 从风湿性心脏病致心力衰竭的病例看心肌重构 褚祎、姜岚、王晶、夏雪、曹洁

  2. Compensatory Mechanisms to Heart Failure 1. Neurohumoral Activation 2. Functional Adjustment 3. Structural Adaptation 4. Extracardial Compensation

  3. Neurohumoral Activation (1) Activation of Sympathetic Nervous System (2) Activation of Renin-Angiotensin System

  4. Functional Adjustment (1) Increased Heart Rate (2) Increased Preload (3) Increased Contractility

  5. Structural Adaptation (1) Myocyte Remodeling a. Myocardial Hypertrophy Concentric Hypertrophy Eccentric Hypertrophy b. Changes in Myocyte Phenotype (2) Changes in Non-Myocytes

  6. Extracardial Compensation (1) Redistribution of Blood Flow (2) Increase in Red Cells (3) Increase Ability of Cells to Use Oxygen

  7. 病例 • 病史：患者31年前于重体力劳动后出现心悸、喘憋，伴夜间憋醒，需坐起。诊断“风湿性心脏病”。其后间断出现喘憋，多于感冒后发生，发作时轻微活动即可发 生喘憋，伴夜间不能平卧。后来发现二尖瓣狭窄，心房颤动，心力衰竭。近2年来，患者运动明显受限，经常喘憋，夜间坐位入睡。3天来，受凉后喘憋加重，不能自行行走，夜间坐位入睡，伴咳血痰，暗红色为主，偶有鲜红色血痰。自发 病来，精神、睡眠差，食欲不佳，小便次数增多，尤其夜尿增多，6~7次/夜，大便如常。 • 查体：BP：160/90mmHg，P：64次/分，口唇略发绀，双肺可闻及满肺哮鸣音及少量细湿罗音。心尖搏动弥散，位于第Ⅴ肋间腋中线上。心尖部触及震颤。叩诊心界扩大。心律不齐，S1强弱不等，A2=P2，心尖部可闻及III级收缩期杂音，舒张期隆隆样杂音。腹部膨隆，腹软，无压痛，肝脾触诊不满意，双下肢轻度可凹性水肿。

  8. Rheumatic heart disease: Mitral verrucous endocarditis ---- thickening of valves and chordae tendinea

  9. Valve Impairment and Compensation • Mitral stenosis: • fibrosis and thickening of valves, shortening of chordae tendinea • Compensation: elevated transmitral pressure • LA pressure PV pressure congestion of lungDyspnea • LV contractionPalpitation • From functional compensation to constructional compensation smaller gap

  10. Venous pulmonary hypertension Infernalcircle Pulmonary artery hypertension congestion of lung Increased RV postload HEART FAILURE Heart remodeling LV failure Damage to myocardial cell Impaired compliance Increased LV postload Impaired systolic and diastolic function Congestion of systemic circulation Anorexy, Ascites, Extremitas inferior edema Right heart failure

  11. Myocardial remodeling

  12. Cellular hypertrophy • Collagen :amount, phenotype ,cross-linking. • Cell death :apoptosis, necrosis

  13. Hypertrophy In the transition to failure centric hypertrophy eccentric hypertrophy cross-sectional area and diameter balanced increase length than thick increasing wall thickness pump function myocardial compliance diastolic properties myocardial fibrosis lethal arrhythmias overall wall thickness and LV volume

  14. Collagen change Fibrillar collagens : type I (>50%) type III (10%~45%) type V(5%~10%) Increased I and III Hypertension, infarction Dilated cardiomyopathy Decreased I Infarction (within 24h) Papillary muscles Type Disease states

  15. Balance between cardiomyocyte hypertrophy and apoptosis • GPCR signaling • Gp130 receptor-coupled signaling • The PI3K–Akt axis • Calcium-dependent signaling • TNFα–NF-κB

  16. Fig. 2. G-protein-coupled receptor (GPCR) agonists (e.g. catecholamines, angiotensin II, prostaglandin F2α or endothelin-1), bind to transmembrane GPCRs which leads to activation of cytoplasmic signaling through the alpha subunit of the heterotrimeric guanine nucleotide-binding proteins (G proteins) of the Gq family (Gαq), which activate protein kinase C (PKC) members and transcriptionally activate a pro-apoptotic Bcl-2 member called Nix. In addition, Gαq is a potent hypertrophic signal transducer, and enhances (as calcineurin, see Fig. 5) transcript initiation via a cyclin T-cdk9 complex that phosphorylates RNA polymerase II.

  17. Changes in ECM MMPs

  18. Bioactive molecules operative in CHF • Renin-angiotensin-aldosterone system • Oxidative stress • Endothelin-1

  19. Renin-angiotensin-aldosterone system AngⅡ----AT1 receptor----JAK-STAT----STATS and NF-κB cause induction of MMPs Aldosterone----zinc-finger intracellular receptor affect MMP types

  20. Oxidative stress • Oxidative stress is defined as an imbalance between oxidants and antioxidants resulting in oxidative damage to cellular and extracellular components. • Reactive oxygen and nitrogen species (ROS) can directly activate pro-MMPs as well as cause the activation of key transcription factors such as NF-κB,AP-1 and Ets.

  21. Endothelin-1 • Endothelin-1 increases MMP-1 mRNA in vascular smooth muscle cells.

  22. Sympathetic activation • Levels of the catecholamine, norepinephrine (NE), has been identified to be increased in patients with CHF • Increased MMP-2 levels is positively correlated with NE levels.

  23. Cytokines/chemokines Tumor necrosis factor-а(MMPs with TIMPs) Interleukin-1β(NF-κB)

  24. Matricellular factors in CHF • Osteoponin (OPN) • Transforming growth factor-β (TGF- β) • Thrombospondin (TSP)

  25. TGF-β has been demonstrated to be increased during heart failure and contributes to the hypertrophy of myocytes and fibrosis.

  26. Thank you!

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