微电极阵列芯片技术研究48h房颤犬左、右心耳电生理特性

目的应用微电极阵列芯片（microelectrode arrays chip,MEA）技术评价48 h房颤（atrial fibrillation,AF）犬左、右心耳（LAA、RAA）的电生理特性。方法随意来源犬12只,以600次/分起搏右心房建立AF模型,分为48 h AF组（n=6）和对照组（n=6）。造模成功后迅速开胸剪取LAA、RAA,置于盛有台式液的MEA中,分别记录AF组及对照组LAA、RAA场电位（field action potential,FAP）形态、振幅、放电频率及激动传导情况。结果 AF组LAA、RAA组织FAP节律绝对不齐,LAA（185.22±25.62）次/分,较对照组（156.44±8.88）次/分增加15.67%（P〈0.01）,RAA（102.39±16）次/分,较对照组（156.44±8.88）次/分减慢34.62%（P〈0.01）。48 h AF组LAA组织电压（458.33±26.73）μV较对照组（740.55±18.93）μV降低38.11%（P〈0.01）,RAA（504.83±39.93）μV较对照组（840.56±18.93）μV明显降低（P〈0.01）,48 h房颤组LAA组织FAP时程（45.28±8.59）ms较对照组（70.77±6.98）ms缩短15 ms（P〈0.01）。RAA（61.78±7.1）ms较对照组（75.83±7.63）ms缩短14 ms（P〈0.01）。48 h AF组LAA、RAA FAP传导异质性增加。结论应用MEA技术可反映心肌组织片场电位电生理特性,48 h AF后LAA放电频率增加,频率绝对不齐,LAA、RAA电压降低,场电位时程延长。     

Decreased expression of small-conductance Ca2+-activated K+ channels SK1 and SK2 in human chronic atrial fibrillation

AimsSmall-conductance Ca^2 +-activated K⁺ (SK) channels are recognized as new ion channel candidates in atrial fibrillation (AF), with pivotal implications as novel drug targets due to their atrial-selective distribution in humans. The purpose of this study was to investigate whether SK channels and the Ca^2 +-activated K⁺ current (I_K,Ca) are involved in electrical remodeling of human chronic AF (cAF) and whether they display the differential distribution between the right (RA) and left atria (LA).Main methodsThe right (RAA) and left atrial appendage (LAA) myocytes were obtained from 29 sinus rhythm (SR) and 22 cAF patients. The I_K,Ca and action potential (AP) were recorded using the patch-clamp technique. Three SK channel subtypes (SK1–3) expressions were assayed by western blot and real-time quantitative PCR analysis.Key findingsThe I_K,Ca was decreased and its role in AP repolarization was attenuated in cAF, concomitant with a significant decrease in protein and mRNA levels of SK1 and SK2. In either SR or cAF, there was no difference in the I_K,Ca density and protein and mRNA expression levels of SK1–3 between RAA and LAA myocytes.SignificanceOur results demonstrated that SK1 and SK2 are involved in electrical remodeling of cAF. SK1–3 and I_K,Ca do not display the inter-atrial differential distribution in SR or cAF. These findings provide a new insight into mechanisms of electrical remodeling of human cAF.     

Impact of left atrial appendage location on risk of thrombus formation in patients with atrial fibrillation

Biomechanics and Modeling in Mechanobiology - Most strokes in patients with atrial fibrillation (AF) are thought to arise from thrombus formation in the left atrial appendage (LAA). Assessing the...     

Evaluating the novel parameters for assessing the LAA function and thrombus formation with nonvalvular atrial fibrillation

The dysfunction of left atrial appendage (LAA) is prone to form thrombus when atrial fibrillation (AF) sustained more than 48 h. Traditional 2D-TEE (transesophageal echocardiography) can not accurate evaluate the function of LAA. The purpose of this study is to analyze the relationship of LAA function parameters and thrombus formation in patients with non-valvular atrial fibrillation (NVAF) by real-time three-dimensional transesophageal echocardiography (RT-3D-TEE). High risk patients can be identified according to the characteristics of ultrasonic index in patients with left atrial appendage thrombosis, which has important clinical value and significance in the risk assessment, guiding treatment and judging prognosis. We examined the relationship between the echocardiographic parameters of LAA function and the incidence of thrombus in 102 NVAF patients. They underwent RT-3D-TEE and left atrial appendage thrombus (LAAT)/severe spontaneous echocardiographic contrast (SSEC) was found in 67 patients (thrombus group) but absent in the remaining 35 patients (non-thrombus group). After measured by QLAB software, the LAA functional parameters were significantly associated with LAAT/SEC formation. Univariate analysis indicated that AF time, LAD, LVEF, LAA-OAmax, LAAVmax, LAAVI and LAAEF demonstrated a positive association (P < 0.05). However, logistic regression analysis identified that AF time (OR:1.73, P < 0.05)、LAAEF (OR:4.09, P < 0.01)and LAAVI (OR:3.28, P < 0.01) were independent predictors of LAAT/SSEC. In patients with nonvalvular atrial fibrillation, echocardiographic parameters of LAA function are significantly associated with LAAT/SSEC.     

Angiotensin II receptor blockade improves matrix metalloproteinases/tissue inhibitor of matrix metalloproteinase-1 balance and restores fibronectin expression in rat infarcted myocardium

Matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs) have been recognized to play a pivotal role in matrix remodeling following myocardial infarction (MI). The aims of the present study were to examine the expression profile of MMPs/TIMP-1 after MI and to determine whether angiotensin II receptor (ATR) blockade improves MMPs/TIMP-1 balance. Compared with sham-operated rats, in vivo MI-induced a significant elevation of MMP-2, MMP-3 and MMP-9 levels and a marked reduction of TIMP-1 and fibronectin (FN) expressions in infarcted left ventricular free wall (LVFW) and hypertrophic interventricular septum (IS) but not in non-infarcted right ventricle (RV). In addition, regional MI increased MMP-2, MMP-3 and MMP-9, while decreased TIMP-1 and FN in infarcted LVFW and hypertrophic IS compared with the non-infarcted RV. Compared with vehicle-treated MI rats, oral valsartan, but not PD123319, limited infarct size, normalized MMPs/TIMP-1 balance and restored FN level. The present findings might further our understanding of the regulatory mechanisms of valsartan in myocardial remodeling after MI.     

Digitalis Does not Improve Left Atrial Mechanical Dysfunction After Successful Electrical Cardioversion of Chronic Atrial Fibrillation

This study was designed to investigate whether administration of digitalis could improve mechanical function of left atrial appendage (LAA) and left atrium prospectively in patients with atrial stunning. Fifty-four consecutive patients in whom atrial stunning was observed immediately after cardioversion of chronic atrial fibrillation (AF) were randomized into digitalis or control group for 1 week following cardioversion. Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) were performed prior to, immediately following, 1 day after and 1 week after cardioversion to measure transmitral flow velocity and LAA flow velocity. Electrical cardioversion of AF elicited significantly slower left atrial appendage peak emptying velocity (LAA-PEV) and peak filling velocity (LAA-PFV) immediately following cardioversion in both groups. 1 day post cardioversion, there were no significant differences in transmitral E wave, A wave, E/A ratio, LAA-PEV, LAA-PFV or left atrial appendage ejection fraction (LAA-EF) between digitalis and control groups. 1 week post cardioversion, no significant differences were found in transmitral E wave, A wave, E/A ratio, LAA-PEV, LAA-PFV or LAA-EF between the two groups. The occurrence rates of spontaneous echo contrast were not significantly different between digitalis and control groups one day and one week post cardioversion. In conclusion, digitalis did not improve left atrial and appendage mechanical dysfunction following cardioversion of chronic AF. Digitalis did not prevent the development of spontaneous echo contrast in left atrial chamber and appendage. This may be due to the fact that digitalis aggravates intracellular calcium overload induced by chronic AF and has a negative effect on ventricular rate.     

Comparative analysis of oncofetal fibronectin and tenascin-C expression in right atrial auricular and left ventricular human cardiac tissue from patients with coronary artery disease and aortic valve stenosis

Aortic valve stenosis (AVS) and coronary artery disease (CAD) are accompanied by changes in the cardiac extra cellular matrix (cECM) including the re-expression of oncofetal fibronectin (Fn) and tenascin-C (Tn-C) variants. Human antibodies against these variants are usable for targeted therapy. Aim of the study was the comparative analysis of cECM remodelling in tissue samples from right atrial auricle (RAA) and left ventricular septum (LVS). RAA and LVS specimens from 30 patients (17?×?AVS; 13?×?AVS+CAD) were analysed with respect to histological changes and ECM remodelling using PCR based ECM gene expression profiling. Re-expression of ED-A(+) Fn and A1(+) Tn-C was investigated on the mRNA and on the protein level. For immunofluorescence, human recombinant small immunoprotein (SIP) format antibodies were used. There was a positive correlation of the grade of histological changes in RAA and corresponding LVS samples (r?=?0.695). ECM gene expression levels were higher in LVS compared to RAA. For 24 genes, a corresponding relevant (>2.5-fold) up- or down-regulation in RAA and LVS occurred. Using SIP antibodies, a positive correlation of protein deposition levels in RAA and corresponding LVS (r?=?0.818) could be shown for ED-A(+) Fn. Cardiac tissue remodelling is likely a process involving the entire heart reflected by intra-individually comparable histology and cECM changes in RAA and LVS samples. ED-A(+) Fn might be an excellent target for an antibody-mediated delivery of diagnostic or therapeutic agents. The RAA is a valuable and representative tool to evaluate cardiac remodelling and to plan individualized therapy.     

Neural substrate for atrial fibrillation: implications for targeted parasympathetic blockade in the posterior left atrium

The parasympathetic (P) nervous system is thought to contribute significantly to focal atrial fibrillation (AF). Thus we hypothesized that P nerve fibers [and related muscarinic (M(2)) receptors] are preferentially located in the posterior left atrium (PLA) and that selective cholinergic blockade in the PLA can be successfully performed to alter vagal AF substrate. The PLA, pulmonary veins (PVs), and left atrial appendage (LAA) from six dogs were immunostained for sympathetic (S) nerves, P nerves, and M(2) receptors. Epicardial electrophysiological mapping was performed in seven additional dogs. The PLA was the most richly innervated, with nerve bundles containing P and S fibers (0.9 +/- 1, 3.2 +/- 2.5, and 0.17 +/- 0.3/cm(2) in the PV, PLA, and LAA, respectively, P < 0.001); nerve bundles were located in fibrofatty tissue as well as in surrounding myocardium. P fibers predominated over S fibers within bundles (P-to-S ratio = 4.4, 7.2, and 5.8 in PV, PLA, and LAA, respectively). M(2) distribution was also most pronounced in the PLA (17.8 +/- 8.3, 14.3 +/- 7.3, and 14.5 +/- 8 M(2)-stained cells/cm(2) in the PLA, PV, and LAA, respectively, P = 0.012). Left cervical vagal stimulation (VS) caused significant effective refractory period shortening in all regions, with easily inducible AF. Topical application of 1% tropicamide to the PLA significantly attenuated VS-induced effective refractory period shortening in the PLA, PV, and LAA and decreased AF inducibility by 92% (P < 0.001). We conclude that 1) P fibers and M(2) receptors are preferentially located in the PLA, suggesting an important role for this region in creation of vagal AF substrate and 2) targeted P blockade in the PLA is feasible and results in attenuation of vagal responses in the entire left atrium and, consequently, a change in AF substrate.     

The effects of alpha-lipoic acid on MMP-2 and MMP-9 activities in a rat renal ischemia and re-perfusion model

Matrix metalloproteinases (MMPs) are enzymes that are responsible for degradation of extracellular matrix (ECM); they are involved in the pathogenesis of ischemia-re-perfusion (I-R) injury. We investigated the possible preventive effect of alpha-lipoic acid (LA) in a renal I-R injury model in rats by assessing its reducing effect on the expression and activation of MMP-2 and MMP-9 induced by I-R. Rats were assigned to four groups: control, sham-operated, I-R (saline, i.p.) and I-R+ LA (100 mg/kg, i.p.). After a right nephrectomy, I-R was induced by clamping the left renal pedicle for 1 h, followed by 6 h re-perfusion. In the sham group, a right nephrectomy was performed and left renal pedicles were dissected without clamping and the entire left kidney was excised after 6 h. LA pretreatment was started 30 min prior to induction of ischemia. Injury to tubules was evaluated using light and electron microscopy. The expressions of MMP-2 and MMP-9 were determined by immunohistochemistry and their activities were analyzed by gelatin zymography. Serum creatinine was measured using a quantitative kit based on the Jaffe colorimetric technique. Malondialdehyde (MDA) and glutathione (GSH) were analyzed using high performance liquid chromatography. Tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-1 were assessed using enzyme-linked immunosorbent assay (ELISA). I-R caused tubular dilatation and brush border loss. LA decreased both renal dysfunction and abnormal levels of MDA and GSH during I-R. Moreover, LA decreased significantly both MMP-2 and MMP-9 expressions and activations during I-R. TIMP-1 and TIMP-2 levels were increased significantly by LA administration. LA modulated increased MMP-2 and MMP-9 activities and decreased TIMP-1 and TIMP-2 levels during renal I-R.     

Concomitant epicardial left atrial appendage ligation and left atrial ablation of atrial fibrillation: Safety,feasibility and outcome

IntroductionWe present initial results of patients undergoing a combined procedure of epicardial LAA ligation in addition to left atrial ablation for AF.Methods9 patients were included for additional use of LARIAT as an individual treatment approach for AF. First an epicardial LAA ligation was performed, in the same procedure left atrial ablations consisting of PVI and additional substrate based modifying ablations were performed. Follow–up at 3 months and 12 months was performed.ResultsThere was only 1 minor procedural complication (11%) involving epicardial bleeding and 2 late adverse events of pericardial tamponade and stroke. At the final follow-up (median 20 months) 7 patients were in stable sinus rhythm (78%) and 2 pts had reduced AF burden.ConclusionConcomitant epicardial LAA ligation and ablation is feasible in selected patients with a reasonable risk profile. More prospective data are required to validate the safety and efficacy.     

Decreased expression of matrix metalloproteinase-9 and increased expression of tissue inhibitors of matrix metalloproteinase-1 in paratuberculosis-infected cattle in the ELISA-negative subclinical stage

We investigated the gene expression of matrix metalloproteinases-9 (MMP-9) and tissue inhibitors of matrix metalloproteinases-1 (TIMP-1) in peripheral blood cells from infected cattle with Mycobacterium avium subsp. paratuberculosis (Map) in the ELISA-negative subclinical stage compared with uninfected control cattle. Significant decreased MMP-9 expression and increased TIMP-1 expression were found in peripheral blood cells from Map-infected cattle after stimulation with Map lysate and Map purified protein derivative (PPD) than in control cattle by real-time RT-PCR analysis. In contrast to the uninfected controls, the activity of MMP-9 was also decreased in peripheral blood cell culture supernatants from Map-infected cattle at 24?hr after Map lysate and MapPPD stimulation by gelatin zymography analysis. As a result, the MMP-9 may play an important role in the development of Mycobacterium avium subsp. paratuberculosis disease.     

Latent MMP-9 is bound to TIMP-1 before secretion

Expression patterns of matrix metalloproteinase-9 (MMP-9) and its specific inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1), are closely correlated with physiological and pathological processes characterized by the degradation and accumulation of the extracellular matrix (ECM). Both, activated MMP-9 and pro-MMP-9 can bind to TIMP-1, and most cell types secrete MMP-9 in complex with TIMP-1. Utilizing immunofluorescence, we observed intracellular co-localization of MMP-9 and TIMP-1 in stimulated human fibrosarcoma cells. In the present study we searched for the origin of the complex formation between the latent enzyme and its specific inhibitor on a subcellular level. Fluorescence resonance energy transfer (FRET) between the fluorescently labeled enzyme and its inhibitor in co-transfected cells were measured. MMP-9 and TIMP-1 were fused to cyan (CFP) and yellow (YFP) variants of the green fluorescent protein and transiently expressed in human hepatoma cells. The intracellular distribution of fluorescently labeled TIMP-1 and MMP-9 was analyzed by confocal laser scanning microscopy. Intracellular complex formation in the Golgi apparatus was verified, demonstrating FRET between MMP-9-CFP and TIMP-1-YFP. Our data provide evidence that the proMMP-9-TIMP-1 complex is already present in the Golgi apparatus. This may be of significance for a number of intracellular and extracellular biochemical processes involving proMMP-9. However, the magnitude and functional relevance of this finding remain unknown.     

Percutaneous left atrial appendage closure for stroke prevention in atrial fibrillation

Background

Percutaneous left atrial appendage (LAA) closure can be an alternative to coumadin treatment in patients with atrial fibrillation (AF) at high risk for thromboembolic events and/or bleeding complications. We report the initial experience with this new technique.

Methods

Patients were eligible if they had AF with a high stroke risk (CHADS₂ score >1), and/or contraindication for coumadin therapy. The procedure was performed under general anaesthesia, using biplane fluoroscopy and (3D) transoesophageal echocardiography (TEE) guidance. Patients were discharged on coumadin until a TEE was repeated at 45 days after closure to evaluate LAA occlusion. If LAA occlusion was achieved, oral anticoagulation was discontinued and aspirin started.

Results

Percutaneous LAA closure was performed in 10 patients (50% male, age 61.6 ± 9.6 years). The median CHADS₂ score was 3 (range 2–4), median CHA₂DS₂-VASc score 3.5 (range 2–6) and HAS-BLED score 1.5 (range 1–4). Nine patients had a history of stroke and 2 patients had a history of major bleeding while on coumadin. Concomitant pulmonary vein isolation was performed in 9 patients. The device was successfully placed in all patients within a median of 56 min (38–137 min). Asymptomatic catheter thrombus occurred in one patient. At 45-day follow-up, no thromboembolic events occurred, TEE showed minimal residual flow in the LAA in three patients. In one patient the LAA device was dislocated, requiring successful percutaneous retrieval.

Conclusion

Device closure of the LAA may provide an alternative strategy to chronic coumadin therapy in patients with AF and high risk of stroke and/or bleeding complications using coumadin.     

Heart extracellular matrix gene expression profile in the vitamin D receptor knockout mice

1,25-Dihydroxyvitamin D₃ [1,25D] deficiency and vitamin D receptor [VDR] genotypes are risk factors for several diseases and disorders including heart diseases. Extracellular matrix (ECM) remodeling mediated by matrix metalloproteinases [MMPs] contributes to progressive left ventricular remodeling, dilation, and heart failure. In the present study, we used high-density oligonucleotide microarray to examine gene expression profile in wild type [WT] and vitamin D receptor knockout mice (VDR KO) which was further validated by RT-PCR. Microarray analysis revealed tissue inhibitors of metalloproteinases [TIMP-1 and TIMP-3] were significantly under expressed in VDR KO mice as compared to WT mice which was further validated by RT-PCR. Zymography and RT-PCR showed that MMP-2 and MMP-9 were up regulated in VDR KO mice. In addition, cross-sectional diameter and longitudinal width of the VDR KO heart myofibrils showed highly significant cellular hypertrophy. Trichrome staining showed marked increase in fibrotic lesions in the VDR KO mice. Heart weight to body weight ratio showed 41% increase in VDR KO mice when compared to WT mice. This data supports a role for 1,25D in heart ECM metabolism and suggests that MMPs and TIMPs expression may be modulated by vitamin D.     

Incidence and predictors of left atrial thrombus in patients with atrial fibrillation prior to ablation in the real world of China

BackgroundThe present study was to evaluate the value of CHADS2 and CHA2DS2VASC scores on predicting left atrial (LA) or left atrial appendage (LAA) thrombus in atrial fibrillation (AF) patients prior to ablation in the real world of China.Methods and resultsA total of 397 patients with non-valvular AF were analyzed to determine the relationship between CHADS2 and CHA2DS2VASC scores and LA/LAA thrombus identified on transesophageal echocardiography prior to radiofrequency ablation(RFA). LA/LAA thrombus was present in 38 patients (9.6%). There was a strong association between higher CHADS2 score or CHA2DS2VASC score and LA/LAA thrombus. No thrombus was identified in patients with CHA2DS2VASC score of 0 regardless of anticoagulation status. However, LA/LAA thrombus was detected in 2.9% patients with CHADS2 score of 0 without adequate anticoagulation, while no thrombus was present in the patients with CHADS2 score of 0 with adequate anticoagulation. Univariate analysis showed that heart failure (LVEF＜50%), LA≥40 mm, diabetes mellitus, previous stroke or TIA, CAD, hypertension, inadequate anticoagulation therapy, CHADS2 score of ≥2 and CHA2DS2VASC score of ≥2 were significantly associated with LA/LAA thrombus. Multivariable Cox regression analysis demonstrated that CHA2DS2VASC score of ≥2 (p = 0.02) and previous stroke or TIA (p = 0.04) were independently associated with LA/LAA thrombus regardless of anticoagulation status. ROC curve analysis showed that higher CHADS2 score and CHA2DS2VASC score could be similarly used to predict the presence of LA thrombus.ConclusionsBoth higher CHA2DS2VASC and CHADS2 scores were associated with LA/LAA thrombus in non-valvular AF patients prior to ablation. Although CHA2DS2VASC score and CHADS2 score had similar value to predict LA/LAA thrombus, CHA2DS2VASc score was better to identify low-risk patients for LA/LAA thrombus than CHADS2 score without anticoagulation. There will be a possibility of performing AF ablation or cardioversion in patients with a CHA2DS2VASC of 0 without TEE or anticoagulation therapy. The safety need to be verified by more multicentre randomized controlled clinical trails.     

High-density activation map of atrial tachycardia within left atrial appendage

Identification of the critical isthmus of the reentrant tachycardia is essential to maximize the effect of catheter ablation (CA) and to minimize the myocardial injury of CA. An 81-year-old woman presented recurrent palpitations after CA of atrial fibrillation (AF) and atrial tachycardia (AT). She had moderate aortic valve stenosis and coronary artery disease. She had received a pulmonary vein isolation, left atrial (LA) posterior wall isolation, and LA anterior linear ablation for atrial fibrillation 1 year prior. At the start of the procedure, she was in sinus rhythm. Atrial burst pacing induced an AT (230msec). High-density mapping revealed a figure-of-eight activation pattern within the LA appendage (LAA), accounting for 99% of the tachycardia cycle length. The critical isthmus was identified at the mid LAA and the local electrogram of the critical isthmus was not fractionated. A single radiofrequency application at the critical isthmus of the AT, terminated the AT. She was free from any ATs for 28 months.Radiofrequency ablation of the localized reentrant AT was usually performed targeting long fractionated electrograms. In our case, the local electrogram at the critical isthmus was not fragmented compared with the LAA distal part. Long fractionated electrograms were recorded at a more distal part of the LAA than the common isthmus and we could avoid the potential risk of a perforation. A recent developed 3-dimensional electro-anatomical mapping system can identify the critical isthmus and allow us to select a new therapeutic strategy for a critical isthmus ablation of an AT within the LAA.     

Protein remodeling of extracellular matrix in rat myocardium during four-day hypoxia: the effect of concurrent hypercapnia

The combination of long-term hypercapnia and hypoxia decreases pulmonary vascular remodeling and attenuation of right ventricular (RV) hypertrophy. However, there is limited information in the literature regarding the first stages of acclimatization to hypercapnia/hypoxia. The purpose of this study was to investigate the effect of four-day hypoxia (10% O2) and hypoxia/hypercapnia (10% O2 + 4.4% CO2) on the protein composition of rat myocardium. Expression of the cardiac collagen types and activities of matrix metalloproteinases (MMPs) and of their tissue inhibitor TIMP-1 were followed. The four-day hypoxia changed protein composition of the right ventricle only in the hypercapnic condition; remodeling was observed in the extracellular matrix (ECM) compartments. While the concentrations of pepsin-soluble collagenous proteins in the RV were elevated, the concentrations of pepsin-insoluble proteins were decreased. Furthermore, the four-day hypoxia/hypercapnia increased the synthesis of cardiac collagen due to newly synthesized forms; the amount of cross-linked particles was not affected. This type of hypoxia increased cardiac collagen type III mRNA, while cardiac collagen type I mRNA was decreased. MMP-2 activity was detected on the zymographic gel through appearance of two bands; no differences were observed in either group. mRNA levels for MMP-2 in the RV were significantly lower in both the hypoxic and hypoxic/hypercapnic animals. mRNA levels for TIMP-1 were reduced in the RV of both the hypoxic and hypoxic/hypercapnic animals. Hypoxia with hypercapnia increased the level of mRNA (6.5 times) for the atrial natriuretic peptide (ANP) predominantly in the RV. The role of this peptide in remodeling of cardiac ECM is discussed.