Desmin expression in cardiomyocytes - a good predictor of development of chronic heart failure.

Transcription

1 Desmin expression in cardiomyocytes - a good predictor of development of chronic heart failure. Department of Invasive Cardiology, Central Hospital of Internal Affairs and Administration Ministry, Warsaw, Poland Institute of Experimental and Clinical Medicine Polish Academy of Science, Warsaw, Poland Department of Pathology The Children Memorial Health Institute, Warsaw, Poland Agnieszka Pawlak A.Nasierowska-Guttmejer, E.Czarnowska, J.Rzezak, R.J.Gil

2 Desmin protein features Arrangement of myofibrils Function of desmin forms a scaffold around the Z-disk connects the Z-disk to the subsarcolemmal cytoskeleton connects the contractile apparatus to the cell nucleus, mitochondria links the myofibrils laterally by connecting the Z-disks Maintenance of structural and mechanical integrity during contraction helping in force transmission and longitudinal load bearing Regulatory function: intracellular sygnalisation, mitochondrial function (distribution, number, morphology and function) myofibrilogenesis gene expression Intercaleted disc Linea Z Desmin Nucleus

3 Desmin in clinical study High expression of desmin Confirmation that abnormal desmin accumulation and migration are due to a desmin gene mutation in a familial cardiomyopathy and distal myopathy Dunand M et all. Neuromuscul Disord Nov;19(11):802. Epub 2009 Aug 28. Low expression of desmin Desmin-free cardiomyocytes and myocardial dysfunction in end stage heart failure Di Somma S et all Eur J Heart Fail Jun;6(4): Expression of desmin Cardiomiocytes desmin abnormalities an accurate predictor of long- term survival in patients with chronic heart failure Pawlak A et al Kardiol Pol.2009 Jul; 67(7):724-33

4 Aim- verification of hypothesis Remodeling of desmin cytoskeleton -precedes development of heart failure and -might be an adverse predictor of disease.

5 Material and methods (1) Study population 195 patients [87.7% males, mean age 48.4±13.5 years] With clinical symptoms of heart failure With reduced EF below 45% Without coronary artery disease in coronaroangiography Unknown origin Endomyocardial biopsy Diagnostic endomyocardial biopsy (EMB) was performed on all patients by femoral approach. Four tissue specimens were taken from right or left ventricle Indication: IDCM

6 Material and methods (2) Baseline characteristic of patients Variables Study population (n=195) Gender, m/f (%) 169/26 (87,7/12,3) Age (years) a 48,36±13,5 NYHA (class) a Class I [n/%] Class II [n/%] Class III [n/%] Class IV [n/%] 2,08±0,83 53/27,18 81/41,54 54/27,69 7/3,59 LVEF (%) a 30,23±9,6 LVEDD (mm) a 65,17±10,1 Variables Diseases Hypertention (n/%) Hyperlipidemia (n/%) Diabetes (n/%) Renal failure (MDRD < 40 ml/min/1.73 m 2 ) Smoking history Medication ACE-inhiobitors (n/%) Angiotensin receptor blockers (n/%) Beta-blockers (n/%) Aldosteron receptor blockers (n/%) Diuretics (n/%) Statin (n/%) Digoxin (n/%) Study population (n=195) 87/(44,62) 57/(29,23) 29/(14,87) 21/(10,77) 55/(28,21) 174/(89,23) 9/(4,62) 176/(90,26) 131/(67,18) 142/(72,82) 94/(48,21) 61/(31,28) a Mean ± standard deviation

7 Normal expression I Slide expression with normal distribution (positive reaction in Z lines, intercalated discs) High expression IIA Increased and regular distribution Methods (3) Evaluation of desmin Desmin was analysed immunohistochemically in cardiomyocytes and Western -Blot High expression IIB Increased and irregular accumulation with formation of aggregates Low expression III Weak with abnormal distribution and lack in Z lines or lack expression

8 Methods (4) Echo examination Diameter of left ventricle LVEDD, LVESD Ejection fraction of LV LVEF Pressure in LV was calculated by ECHO as early mitral inflow(e)/propagation velocity (Vp) (E/Vp)

9 Results (1) Characteristic of study population. Variables Stage I (n=57) Stage IIA (n=40) Stage IIB (n=56) Stage III (n=42) P Gender, m/f (%) 51/6 (89,5/10,5) 34/6 (85,0/15,0) 49/7 (89,9/10,1) 35/7 (85,7/14,3) NS Age (years) a 50,6±15,4 47,9±11,7 47,8±12,1 48,3±14,3 NS NYHA (class) a 1,6±0,7 2,0±0,7 2,3±0,8 2,5±0,8 P=0.001 LVEF (%) a 35,2±10,1 31,0±8,9 27,2±8,4 26,8±8,2 P=0.001 LVEDD (mm) a 61,23±9,3 64,7±9,9 67,2±8,0 68,6±12,0 P=0.001 NYHA class New York Heart Association Class, LVEF left ventricle ejection fraction, LVEDD- left ventricle and diastolic diameter. a Mean ± standard deviation

10 Results (2) Desmin expression vs diseases and medication. Variables Stage I (n=57) Stage IIA (n=40) Stage IIB (n=56) Stage III (n=42) P Diseases Hypertention (n/%) Hyperlipidemia (n/%) Diabetes (n/%) Renal failure (MDRD < 40 ml/min/1.73 m2 Smoking history 28/(49,1) 15/(26,3) 7/(12,3) 7/(12,3) 16 (28,1) 15/(37,5) 12/(30,0) 6/(15,0) 0/(0) 12 (30,0) 24/(42,9) 16/(28,6) 8/(14,3) 8/(14,3) 14 (25,0) 20/(47,6) 14/(33,3) 8/(19,0) 6/(14,3) 13 (31,0) p=0,69 p=0,90 p=0,83 p=0,10 p=0,92 Medication ACE-inhiobitors (n/%) Angiotensin receptor blockers (n/%) Beta-blockers (n/%) Aldosteron receptor blockers (n/%) Diuretics (n/%) Statin (n/%) Digoxin (n/%) 47/(82,5) 1/(1,8) 46/(80,7) 28/(49,1) 40/(70,2) 25/(43,9) 15/(26,3) 35/(87,5) 4/(10,0) 38/(95,0) 29/(72,5) 24/(60,0) 23/(57,5) 7/(17,5) 52/(92,9) 4/(7,1) 53/(94,6) 48/(85,7) 41/(73,2) 21/(37,5) 25/(44,6) 40/(95,2) 0/(0,0) 39/(92,9) 26/(61,9) 37/(88,1) 25/(43,9) 14/(33,3) p=0,16 p=0,88 p=0,04 p=0.00 p=0.04 p=0,10 p=0.00

11 Results (3) Desmin expression and ultrastructural changes in cardiomyocyes. Immunohistochemical staining of desmin Stage I Stage IIA Stage IIB Stage III Electron microscopy

12 Integrated density (% of control) Results (4) Western Blot for Desmin Control 270/10 395/10 401/10 101/ , , , , Control III (270/10) IIB (395/10) IIA (401/10) I (101/09)

13 Results (5) Desmin vs clinical parameter 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% NYHA III IIB IIA I

14 Results (6) Desmin and biochemical parameter p<0,001 p=0,001 p=0,007 p=0,001

15 Results (7) Desmin and echocardiographic parameters p<0,001 p<0,001 p=0,03 p=0,004 NS NS NS p=0,02 p=0,08 p=0,05 p=0,63 p=0,06 NS p=0,08

16 Desmin expression vs survive in patient with IDCM The Kaplan-Meier estimate p<0,01 p<0,08 p<0,001 p<0,001 Log-rang p<0,0001 TIME [months]

17 Summary Abnormal expression of DESM in cardiomyocytes carries direct impact on biochemical, echocardographic parameters and survival of patients with heart failure. Initial increase of desmin expression ( IIA) is related with adaptive mechanism and does not influence long-term prognosis, while its further increase (maladaptive IIB) is associated with poor long prognosis. Decrease or lack immunohistochemical expression of DESM in cardiomyocytes is associated with the worst biochemical and echocardiographical parameters and long-term prognosis.

18 Conclusion The pattern of desmin can be an important factor of cellular remodeling and early diagnostic feature of progress of chronic HF

19 Thank you for your attention

20 Normal expression of desmin intercaleted disc mitochondrium nucleus linea Z