Dilated Cardiomyopathy Heart Research Articles

Right ventricular systolic function and the manner of transformation of the right ventricle in patients with dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is generally considered to be accompanied by both left and right ventricular dysfunction, but most studies only analyze the left ventricular function. Biplane right ventriculography was performed in 13 control subjects and 13 patients with DCM and New York Heart Association functional class II. Three dimensions of the right ventricle (RV) (the long axis dimension (LA), the anterior - posterior dimension (AP), and the septum -free wall dimension (SF)) and 2 dimensions of the left ventricle (LV) (LA and AP) were examined to assess regional function. The group with DCM had a lower stroke volume index and RV ejection fraction. In the RV dimensional analysis, the group with DCM had a smaller SF and a larger AP at end-diastole, and larger AP and LA at end-systole. There was a significant linear negative correlation between SF of RV and AP of LV at end-diastole. In clinically well-controlled cases of DCM, RV systolic function is depressed, and the RV is compressed by the LV, becoming less thick than in the controls. This transformation results from some parallel interaction between the RV and a markedly enlarged LV.

HIV-related cardiovascular disease and drug interactions.

HIV infection is a global public health issue that is frequently associated with cardiovascular involvement. These HIV-associated cardiovascular manifestations are often clinically occult or attributed incorrectly to other non-cardiac disease processes. A heightened awareness and routine screening for cardiovascular involvement in HIV-infected patients leads to earlier detection and the hope for a reduction in associated morbidity and mortality. Left ventricular dysfunction, an independent predictor of mortality in HIV-infected patients, is the result of many causes in this population and may result in dilated cardiomyopathy and congestive heart failure in about 10% of patients. Other HIV-associated cardiovascular problems include infective endocarditis, cardiovascular malignancy, pulmonary arterial hypertension, vasculitis, pericardial effusion, premature atherosclerosis, and arrhythmias. HIV-associated cardiovascular emergencies include congestive heart failure, pulmonary edema, supraventricular and ventricular arrhythmias, endocarditis, and tamponade. Anti-infective and immunomodulatory therapies may be particularly helpful in this population to reduce associated cardiovascular disease. Highly active antiretroviral therapy may result in lipodystrophy, hyperlipidemia, truncal adiposity, and insulin resistance that can be improved by physical activity and training programs. Cardiovascular complications of therapeutic drugs in HIV-infected patients include torsade de pointes, congestive heart failure, dyslipidemia, accelerated atherosclerosis, and myocardial infarction. In summary, cardiovascular complications are important contributors to morbidity and mortality in HIV-infected patients that can be detected early in many cases and treated effectively.

Cardiology patient page. Familial dilated cardiomyopathy.

Cardiology patient page. Familial dilated cardiomyopathy.

Changes in myocardial oxidative metabolism after biventricular pacing as evaluated by [11C]acetate positron emission tomography

A 70-year-old woman with dilated cardiomyopathy and recurrent severe heart failure was admitted for biventricular pacing (BVP), which was recently reported to have clinical efficacy for severe heart failure with intraventricular conduction delay. An electrocardiogram showed complete left bundle branch block, and the QRS interval was markedly prolonged at 195 msec. Echocardiogram showed marked dilatation, diffuse hypokinesis and dyssynchrony of the left ventricle, and grade III mitral valve regurgitation. The patient underwent implantation of an atriobiventricular pacemaker and three pacing leads transvenously. The QRS interval shortened to 165 msec immediately after the BVP therapy, and improvements in echocardiographic parameters were seen at 5 months after BVP therapy. Myocardial oxidative metabolism was assessed by the monoexponential clearance rate of [11C]acetate (Kmono) as measured by positron emission tomography (PET), and myocardial efficiency was assessed by the work metabolic index (WMI) at 1 and 5 months after the BVP therapy. The PET images obtained 5 months after BVP therapy showed a decrease in the clearance of [11C]acetate compared with that obtained 1 month after BVP therapy. The Kmono of the whole left ventricle decreased from 0.051 at 1 month to 0.038 min-1 at 5 months after BVP therapy, and that of the septum, anterior wall, lateral wall and posterior wall also decreased. The WMI increased from 4.2 x 10(6) to 6.8 x 10(6) mmHg. ml/m2. These results suggest that BVP improved left ventricular function without increasing myocardial oxidative metabolism, resulting in improved myocardial efficiency, and that BVP may improve the long-term prognosis of heart failure patients with ventricular dyssynchrony. [11C]acetate PET is a useful method of evaluating global and regional myocardial oxidative metabolism in patients who have undergone BVP therapy.

P1144 Validation of criteria for non-compacted myocardium in dilated cardiomyopathy, valvular and hypertensive heart disease

P1144 Validation of criteria for non-compacted myocardium in dilated cardiomyopathy, valvular and hypertensive heart disease

Alterations in Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling in patients with end-stage dilated cardiomyopathy.

Experimental studies indicate that interleukin-6 (IL-6)-related cytokines, signaling via the shared receptor gp130, Janus kinases (JAKs), and signal transducers and activators of transcription (STATs), provide a critical cardiomyocyte survival pathway in vivo. Little is known about the activation of this signaling pathway in the myocardia of patients with end-stage dilated cardiomyopathy (DCM). We performed a comprehensive expression and activation analysis of IL-6-related cytokines, receptors, signal transducers, and signal transduction inhibitors in left ventricular (LV) myocardia from patients with DCM (n=10) and non-failing (NF) donor hearts (n=5). Differential expression (DCM versus NF) was observed by immunoblotting at each level of the signaling cascade, including receptor ligands (IL-6: -59%, P<0.01; leukemia inhibitory factor [LIF]: +54%, P<0.05), receptor subunits (LIF receptor: -16%, P<0.05), signaling molecules (the Janus kinase TYK2: -48%, P<0.01; STAT3: -47%, P<0.01), and suppressors of cytokine signaling (SOCS1: +97%, P<0.05; SOCS3: -49%, P<0.01). Tyrosine-phosphorylation status of gp130 was increased (+60%, P<0.05), whereas tyrosine-phosphorylation status of JAK2 was reduced in DCM (-72%, P<0.01). Moreover, as shown by immunohistochemistry, the number of STAT3-positive cardiomyocytes was reduced in DCM (-42%, P<0.01). Signaling via gp130 and JAK-STAT is profoundly altered in DCM. Importantly, tyrosine-phosphorylation of JAK2 is reduced in the face of increased gp130 phosphorylation, indicating impaired downstream activation of this critical pathway in DCM.

Hyperubiquitination of proteins in dilated cardiomyopathy.

Protein degradation by the ubiquitin-proteasome pathway plays an important role in a variety of fundamental cellular processes, including cell cycle regulation, transcription, antigen processing and muscle remodelling. Research into disorders associated with the ubiquitin-proteasome system has been mainly in the field of neurodegenerative diseases. It is however becoming increasingly apparent that defects in the system are responsible for a number of non-neurological pathologies. Based on initial observations made as part of a proteomic analysis of an animal model of dilated cardiomyopathy (DCM) which indicated increased activity of the ubiquitin-proteasome system, we sought to determine whether this system was perturbed in hearts of human DCM patients. We studied explanted hearts from 12 DCM, 9 ischaemic (IHD) and 12 unused donor hearts. Protein expression was examined using two-dimensional polyacrylamide gel electrophoresis, Western blotting and immunohistochemistry. Expression of mRNA was examined using real-time quantitative polymerase chain reaction. Ubiquitinated proteins were affinity purified using a ubiquitin-binding column and identified using peptide mass fingerprinting. All DCM hearts showed significantly higher expression of certain key enzymes of the ubiquitin-proteasome pathway. mRNA expression of ubiquitin carboxyl-terminal hydrolase (UCH) was significantly higher (5.4-fold) in DCM hearts than in control hearts. Myocytes in sections from DCM hearts stained positively for UCH, whereas control hearts were negative. Overall protein ubiquitination was increased two-fold in DCM relative to IHD hearts and five-fold relative to donor hearts. The ubiquitination of a number of distinct proteins was greatly enhanced in DCM hearts as revealed by anti-ubiquitin Western blots. A number of these proteins were identified using affinity purification and matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry.

Non-transplant cardiac surgery for end-stage dilated cardiomyopathy in small children

Between October 1997 and December 2000, a total of 7 pediatric patients with end-stage dilated cardiomyopathy (DCM) were referred to our service for heart transplantation; non-transplant cardiac surgery was offered as a biologic bridge. Two patients died before surgery and the in-hospital surgical mortality rate was 50%: 75% in 4 patients who received emergency surgery and 0% in 2 patients who received urgent surgery. Non-transplant cardiac surgery improved clinical outcome and acted as a biologic bridge, instead of a mechanical bridge, to heart transplantation in small children with DCM and severe heart failure.

A STUDY ON CARDIOVASCULAR DISEASE PATTERN OF ADMITTED CASES IN NEWLY EMERGED NATIONAL HEART CENTRE

Cardiovascular disease is one of the global leading causes of death . Although indeveloped countries overall cardiovascular death is declining due to long term declineof rheumatic heart disease (RHD), cerebro vascular and hypertensive heart disease,heart disease is still the leading cause of death. In developing countries prevalence ofcoronary heart disease (CHD) is in increasing trend and cardiovascular disease patternis changing. Cardiovascular disease pattern of this region is revealed in this study.Total 300 study subjects, admitted from May 2000 to April 2001, 174 (58%) male and126 (42%) female and age ranged from 5 to 83 years were analyzed retrospectively.Proportionate distribution of all admitted cases was calculated and arranged inaccording with sequence order.Rheumatic heart disease was found the commonest, which constituted 27.3%, followedby coronary heart disease (21.7%) and hypertension (20.7%) respectively. Chronicobstructive pulmonary disease (COPD) with cor pulmonale (7.7%) was fourth insequence order then respectively came diabetes mellitus (DM) coexisted with CHD orhypertension, dilated cardiomyopathy (DCM), cardiac arrhythmia without organicheart disease, congenital heart disease, infective endocarditis, rheumatic fever,pericardial effusion etc. Readmission rate within one year was 12.3% and mortalityrate was 2.7%. Conclusion: Rheumatic heart disease is the commonest heart diseasefollowed by coronary heart disease and hypertension. COPD with cor pulmonale,diabetes coexisted with CHD or hypertension, DCM and cardiac arrhythmia withoutorganic heart disease are also common heart diseases.Key Words: Cardiovascular diseases, Disease pattern.

TREATMENT OF HEART FAILURE PATIENTS IN UNIVERSITY AND GENERAL HOSPITAL IN 1997

Background. Chronic heart failure is a serious condition with high morbidity and mortality. Prognosis can be improved with early diagnosis and adequate nonpharmacologic and pharmacologic treatment. Aims of the study. Aim of the study was a comparison of diagnostic and therapeutic management of patients who were hospitalized in the University or Community hospital. Methods. The hospital records of patients, hospitalized for heart failure, from University hospital (UH, Internal clinic, Department of angiology, Department of hypertension) and Community hospital (CH, Department of Internal medicine) were reviewed retrospectively. We included all consecutive patients in the period from January 1, 1997 to June 30, 1997 (CH) and December 31, 1997 (UH) who were discharged or died with diagnosis of a heart failure. Results. Six hundred and twenty-five patients (307 from CH and 318 from UH), aged 76 ± 11 years, were included in the survey. In 308 (49%) patients heart failure was diagnosed prior to index hospitalization. Rehospitalization rate was 42%. Etiology of heart failure was ischemic heart disease (36%), arterial hypertension (37%), dilated cardiomyopathy (16%) and valvular heart disease (15%). The hospital stay was 14 ± 10 days in UH and 10 ± 6 days in CH (p < 0.001). Overall in-hospital mortality reached 16% (98 patients) and was 8% in UH and 24% in CH (< 0.001). Echocardiography was performed in UH in 45% and in CH in 13% of all patients and in 50% vs. 22% of patients, hospitalized for the first time. At the discharge the following drugs were prescribed (UH vs. CH): diuretics (82% vs. 73%), ACE inhibitors (61% vs. 33%), digoxin (54% vs. 71%) beta-adrenergic blockers (3% vs. 0%) and antiarrhytmics (7% vs. 32%). Among the patients with systolic dysfunction 69% from UH and 32% of patients from CH received ACE inhibitors. In patients with atrial fibrillation, warfarin was prescribed to 34% and 5% UH and CH patients, respectively. The advice regarding lifestyle changes in discharge records was found in only 21% and 3% from UH and CH patients. Conclusions. Our survey showed a considerable gap between guidelines and clinical practice in hospital management of patients with heart failure. This gap is more evident in CH. Most prominent features are underuse of echocardiography in diagnostic algorhytm, underuse of ACE inhibitors in treatment of systolic dysfunction, non-use of beta-adrenergic blockers and unsufficient nonpharmacologic advices in discharge records.

Titin: An endosarcomeric protein that modulates myocardial stiffness in DCM

Titin is the third myofilament of the cardiac muscle sarcomere, with a single molecule spanning the half sarcomere. Titin contains a molecular spring segment that generates passive force in sarcomeres stretched above the slack length and restoring forces in sarcomeres shortened below this length. The roles of titin in heart disease remain to be established. In this work we review recent developments in the understanding of titin's role in cardiac muscle. We focus on both short-term and long-term modulation of titin-based muscle stiffness, as well as on the recently discovered interplay between titin and actomysoin interaction, suggesting a possible role for titin in the Frank-Starling mechanism of the heart. Finally, we present evidence that suggests that titin plays a role in elevating passive stiffness of myocardium of dilated cardiomyopathy (DCM) hearts, via alterations in titin isoform expression.

Dilated cardiomyopathy

The management of patients with dilated cardiomyopathy (DCM) heart failure starts with the determination of the underlying diagnosis, definition of the hemodynamic character (eg, systolic, diastolic, valvular, right- and left-sided heart dysfunction), recognition of complicating factors (eg, atrial fibrillation, renal dysfunction), and consideration for any surgically remedial lesions (eg, severe valvular regurgitation, high-grade coronary artery occlusive disease). Angiotensin-converting enzyme inhibitors, beta-blocking agents, digoxin, and judicious diuretic administration make up the therapeutic plan for patients with symptomatic DCM heart failure. Angiotensin-converting enzymes are indicated for patients with DCM who have mild or no detectable symptoms; whether this subgroup would benefit from long-term beta-blockade remains to be established. Spirolactone also has been shown to be effective in patients with more advanced stages of heart failure. Biventricular pacing (cardiac resynchronization therapy) recently has been approved for use in patients with DCM and a left ventricular or intraventricular conduction defect and a QRS duration of longer than 140 msec. More intense pharmacotherapy, mechanical devices, and transplantation are directed at patients with severely symptomatic end-stage DCM. The effectiveness of any heart failure treatment plan is very much dependent on nonpharmacologic approaches, including dietary measures, exercise conditioning, and similar considerations, all of which are best delivered by dedicated heart failure programs.

Influence of nitric oxide synthase inhibition and endothelin-1 receptor blockade on acetylcholine-induced coronary artery contraction in vitro in dilated and ischemic cardiomyopathies.

The normal dilatory response to acetylcholine (ACH) is reduced in coronary vessels from patients with dilated cardiomyopathy (DCM) and reversed to a contraction in patients with coronary artery disease (CAD) and ischemic cardiomyopathy (ICM). This study investigated the influence of nitric oxide synthase inhibition and endothelin (ET)-1 receptor blockade on the reactivity to ACH of coronary arteries isolated from patients with end-stage congestive heart failure (CHF) associated or not with CAD. Small (approximately 400 microm) epicardial right coronary arteries were isolated from explanted hearts of patients undergoing transplantation for DCM or ICM. Segments were mounted on a wire myograph to record changes in isometric tension. ACH (1 microM) dilated pre-contracted vessels from DCM hearts but contracted pre-contracted vessels from ICM hearts. In the absence of pre-contraction, ACH (10(-9)-3 x 10(-5) M) induced a small contraction of rings from DCM hearts and a larger contraction (p < 0.05) of rings from ICM hearts. N(omega)-nitro-L-arginine (L-NNA, 100 microM), a NO synthase inhibitor, increased (p < 0.05) sensitivity and maximal response to ACH of vessels from DCM hearts only. In the presence of L-NNA, blockade of ET(A) with BQ123 (1 microM) prevented the effects of L-NNA in DCM, whereas blockade of ET(A/B) receptors with bosentan (10 microM) only reduced vascular sensitivity to ACH without significantly reducing the maximal contraction to ACH in DCM. The antagonists had no effects in vessels from ICM hearts. ACH, however, induced similar contractions of vessels without endothelium in DCM and ICM. These results suggest that ACH induces a contraction by stimulating smooth muscle muscarinic receptors. In coronary arteries isolated from DCM hearts, the contraction is regulated by NO and ET-1, whereas these factors seem to have little influence in ICM. This suggests that endothelial muscarinic receptors are either not expressed or uncoupled in ICM hearts.

Relationship between tumor necrosis factor-alpha production and oxidative stress in the failing hearts of patients with dilated cardiomyopathy

OBJECTIVESThis study evaluated oxidative stress in the failing ventricle in patients with dilated cardiomyopathy (DCM).BACKGROUNDOxidative stress appears to increase in the failing myocardium and may contribute to ventricular dysfunction in patients with DCM. Tumor necrosis factor-alpha (TNF-alpha), which is expressed in the failing heart, may stimulate oxidative stress.METHODSWe measured plasma oxidized low density lipoprotein (oxLDL) by sandwich enzyme-linked immunosorbent assay using specific antibodies against oxLDL in the aortic root (AO) and the coronary sinus (CS) in control subjects (n = 8) and in 22 patients with DCM and mild congestive heart failure. We also measured the plasma levels of TNF-alpha and angiotensin II.RESULTSThere was no difference in oxLDL between the AO and CS in control subjects. In contrast, plasma oxLDL was significantly higher in the CS than the AO in patients with DCM, suggesting that the transcardiac gradient of oxLDL reflects oxidative stress in the failing heart in these patients. Plasma TNF-alpha levels were significantly higher in the CS than the AO with a significant positive correlation of the transcardiac gradient of TNF-alpha and the transcardiac gradient of oxLDL. Moreover, a significant negative correlation existed between the transcardiac gradient of oxLDL and left ventricular ejection fraction. The transcardiac gradient of plasma oxLDL was significantly lower in 6 patients who received carvedilol than in 16 patients who did not receive carvedilol.CONCLUSIONSThese findings indicate that the transcardiac gradient of oxLDL may be a marker of oxidative stress in the heart and that left ventricular dysfunction may be partly due to the oxidative stress in patients with DCM. In addition, TNF-alpha may stimulate oxidative stress in the failing heart in patients with DCM.

Genetic complementation studies using genetically engineered mice have revealed the impact of phospholamban on progression of cardiomyopathy

It has been suggested that dilated cardiomyopathy and end-stage heart failure result in multiple defects in Ca(2+) cycling. By genetic ablation of a muscle specific sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) inhibitor, phospholamban, the broad phenotypes of murine model of dilated cardiomyopathy could be almost completely rescued. Thus, phospholamban inactivation or disruption of interaction between phospholamban and SERCA2a may provide a novel therapeutic approach for preventing the progression of heart failure.

Heart function challenged with beta-receptor agonism or antagonism in a heart failure model.

We have shown that chronic treatment with carteolol, a non-selective beta-adrenergic receptor antagonist, improved left ventricular (LV) function and survival in an avian model of dilated cardiomyopathy (DCM). The aim of the present study was to compare ex vivo heart function with and without beta-agonist and antagonist challenge. We investigated whether intracoronary infusion of a beta-blocker, carteolol or beta-agonist, isoproterenol decreased contractility. In the DCM group, isoproterenol resulted in a significantly greater increase in heart rate (71% vs. 28% compared to control hearts). To investigate the mechanism for the increase in heart rate, we exposed spontaneously beating neonatal cardiomyocytes to serum immunoglobulin (IgG) isolated from DCM animals. Serum IgG resulted in a significant increase in spontaneous beating rate in neonatal rat cardiomyocytes that was blocked by pre-treatment with a beta-blocker. Carteolol challenge did not significantly change heart rate but did significantly increase LV peak pressure in DCM hearts (62%) while coronary artery flow remained unchanged (2.7+/-0.1 vs 2.7+/-0.5 ml/min/g). These results show that 1) beta-receptor stimulation results in a greater tachycardic response in DCM animals, and 2) carteolol challenge improves myocardial contractility in hearts from DCM animals independent of heart rate or changes in coronary artery flow.

Autophagic degeneration as a possible mechanism of myocardial cell death in dilated cardiomyopathy.

In failing hearts, cardiomyocytes degenerate and interstitial fibrosis, which indicates cardiomyocyte loss, becomes more prominent in the myocardium. However, the precise mechanism of cardiomyocyte degeneration that leads to cell death is still unclear, although it is presumed that lysosomal function and autophagy play an important role because lysosomal activity increases under stress such as hypoxia. Myocardium that had been resected during partial left ventriculectomy performed in patients with dilated cardiomyopathy (DCM) was examined. Under light microscopy, some cardiomyocytes had a marked scarcity of myofibrils and had prominent cytoplasmic vacuolization. Atrophic and degenerated cardiomyocytes were often observed adjacent to replacement fibrotic tissue. Immunohistochemistry showed positivity for lysosome-associated membrane protein and a lysosomal catheptic enzyme in vacuoles of various sizes in the cardiomyocytes and these lysosomal markers were markedly increased in atrophic and degenerated cardiomyocytes. Electron microscopy revealed that degenerated cardiomyocytes had many vacuoles containing intracellular organelles, such as mitochondria, and were considered to be autophagic vacuoles. In DCM hearts, autophagy appeared to be associated not only with degradation of damaged intracellular organelles but also with progressive destruction of cardiomyocytes. It is possible that autophagic degeneration is one of the mechanisms of myocardial cell death.

The Batista procedure: fact, fiction and its role in the management of heart failure.

End-stage heart failure is associated with high rates of mortality. Obviously, heart transplantation is the ultimate surgical intervention for its treatment. However, this surgical option is severely limited by immunosuppressive drug morbidity and inadequate donor organ availability. Partial left ventriculectomy, the so called Batista procedure, has been proposed for the treatment of dilated cardiomyopathy and other end-stage heart failure. Although initial reports lacked significant information on the safety and efficacy of this procedure, overall clinical impression from the reports is that the operation may serve as a relatively inexpensive bridge to transplantation especially in the patients with idiopathic dilated cardiomyopathy. In order to select an exact procedure to resect appropriate amount of scar tissue, dobutamine echocardiographic study, intraoperative volume reduction test using cardiopulmonary bypass, positron emission tomography, or magnetic resonance imaging scans can be used. To avoid the late deterioration related to the development of significant mitral valve regurgitation, definitive mitral valve repair or replacement at the time of the partial left ventriculectomy may be advised. Further study is required to determine the procedure's exact role in the treatment of congestive heart failure. This would have to be a multicenter, randomized, and long-term follow-up study.

The role of inflammatory mediators in the failing heart: immunomodulation of cytokines in experimental models of heart failure.

Congestive heart failure may be produced by a variety of disorders, including dilated cardiomyopathy, hypertension, and ischemic heart disease. We have developed experimental models of these diseases, and found gene expressions of proinflammatory cytokines increased in the hearts of these animals. Various drugs for heart failure modulate the production of cytokines in experimental models of heart failure. Pimobendan, an inhibitor of phosphodiesterase III prolonged survival, attenuated inflammatory lesions, and decreased the production of cytokines and nitric oxide. Recent studies have shown that these inhibitory effects are due to inhibition of activation of NF-kappaB. In contrast, digitalis increased the production of cytokines and exacerbated myocarditis. Interleukin-10 prolonged survival, attenuated myocardial injury, and appears promising as a treatment of heart failure due to viral myocarditis. Endothelin-1 plays an important pathophysiological role in heart failure, and treatment with an endothelin antagonist had a cardioprotective effect in experimental models of heart failure.

Altered balance between matrix gelatinases (MMP-2 and MMP-9) and their tissue inhibitors in human dilated cardiomyopathy: potential role of MMP-9 in myosin-heavy chain degradation.

End-stage of human dilated cardiomyopathy (DCM) is characterized by myocyte loss and fibrosis, and associated with ventricular dilatation and reduced cardiac function. Matrix metalloproteinases (MMPs) and their natural tissue inhibitors (TIMPs) have been involved in the myocardial remodeling. To evaluate the potential role of matrix gelatinases (MMP-2 and MMP-9) in DCM, the balance between gelatinases and TIMPs and the gelatinase localization were investigated in left free wall ventricles from six normal donors and six patients with DCM at the transplantation time. TIMP-(1, 2, 3 and 4) mRNAs were analyzed by quantitative reverse transcription-polymerase chain reaction (RT-PCR). TIMP-1 and -2 protein content was assessed by ELISA. MMP-2 and MMP-9 expression were examined by zymography and immunological techniques. All TIMPs were down-regulated in DCM hearts, especially TIMP-1 (reduced by 80%). Gel zymography revealed similar activity of MMP-2 and MMP-9 in both tissues. By in situ zymography and immunohistochemistry, active and immunoreactive gelatinases were pericardiomyocyte in control hearts and intracardiomyocyte in DCM hearts. Intracellular MMPs were associated with sarcomeric structure in DCM. To estimate a putative role of these gelatinases, several sarcomeric contractile proteins were digested in vitro by purified active MMP-9. Only myosin-heavy chain was cleaved in vitro giving 180-, 120-, 80- and 20-kDa proteolytic fragments. In vivo, two major myosin-heavy chain proteolytic fragments (80 and 20 kDa) were detected by specific monoclonal antibody against myosin-heavy chain in DCM left ventricular homogenates, only. Taken together, these data highly suggest that MMP-2 and MMP-9 may be involved in the disorganization of the contractile apparatus in DCM hearts.