End-stage Idiopathic Dilated Cardiomyopathy Research Articles

Myocardial expression analysis of osteopontin and its splice variants in patients affected by end-stage idiopathic or ischemic dilated cardiomyopathy

Myocardial expression analysis of osteopontin and its splice variants in patients affected by end-stage idiopathic or ischemic dilated cardiomyopathy

Induction of Ankrd1 in Dilated Cardiomyopathy Correlates with the Heart Failure Progression.

Progression of idiopathic dilated cardiomyopathy (IDCM) is marked with extensive left ventricular remodeling whose clinical manifestations and molecular basis are poorly understood. We aimed to evaluate the clinical potential of titin ligands in monitoring progression of cardiac remodeling associated with end-stage IDCM. Expression patterns of 8 mechanoptotic machinery-associated titin ligands (ANKRD1, ANKRD2, TRIM63, TRIM55, NBR1, MLP, FHL2, and TCAP) were quantitated in endomyocardial biopsies from 25 patients with advanced IDCM. When comparing NYHA disease stages, elevated ANKRD1 expression levels marked transition from NYHA < IV to NYHA IV. ANKRD1 expression levels closely correlated with systolic strain depression and short E wave deceleration time, as determined by echocardiography. On molecular level, myocardial ANKRD1 and serum adiponectin correlated with low BAX/BCL-2 ratios, indicative of antiapoptotic tissue propensity observed during the worsening of heart failure. ANKRD1 is a potential marker for cardiac remodeling and disease progression in IDCM. ANKRD1 expression correlated with reduced cardiac contractility and compliance. The association of ANKRD1 with antiapoptotic response suggests its role as myocyte survival factor during late stage heart disease, warranting further studies on ANKRD1 during end-stage heart failure.

PKCα-Specific Phosphorylation of the Troponin Complex in Human Myocardium: A Functional and Proteomics Analysis

AimsProtein kinase Cα (PKCα) is one of the predominant PKC isoforms that phosphorylate cardiac troponin. PKCα is implicated in heart failure and serves as a potential therapeutic target, however, the exact consequences for contractile function in human myocardium are unclear. This study aimed to investigate the effects of PKCα phosphorylation of cardiac troponin (cTn) on myofilament function in human failing cardiomyocytes and to resolve the potential targets involved.Methods and ResultsEndogenous cTn from permeabilized cardiomyocytes from patients with end-stage idiopathic dilated cardiomyopathy was exchanged (∼69%) with PKCα-treated recombinant human cTn (cTn (DD+PKCα)). This complex has Ser23/24 on cTnI mutated into aspartic acids (D) to rule out in vitro cross-phosphorylation of the PKA sites by PKCα. Isometric force was measured at various [Ca2+] after exchange. The maximal force (Fmax) in the cTn (DD+PKCα) group (17.1±1.9 kN/m2) was significantly reduced compared to the cTn (DD) group (26.1±1.9 kN/m2). Exchange of endogenous cTn with cTn (DD+PKCα) increased Ca2+-sensitivity of force (pCa50 = 5.59±0.02) compared to cTn (DD) (pCa50 = 5.51±0.02). In contrast, subsequent PKCα treatment of the cells exchanged with cTn (DD+PKCα) reduced pCa50 to 5.45±0.02. Two PKCα-phosphorylated residues were identified with mass spectrometry: Ser198 on cTnI and Ser179 on cTnT, although phosphorylation of Ser198 is very low. Using mass spectrometry based-multiple reaction monitoring, the extent of phosphorylation of the cTnI sites was quantified before and after treatment with PKCα and showed the highest phosphorylation increase on Thr143.ConclusionPKCα-mediated phosphorylation of the cTn complex decreases Fmax and increases myofilament Ca2+-sensitivity, while subsequent treatment with PKCα in situ decreased myofilament Ca2+-sensitivity. The known PKC sites as well as two sites which have not been previously linked to PKCα are phosphorylated in human cTn complex treated with PKCα with a high degree of specificity for Thr143.

Mitral valve repair and redo repair for mitral regurgitation in a heart transplant recipient

A 37-year-old man with end-stage idiopathic dilated cardiomyopathy underwent an orthotopic heart transplant followed by a reoperation with mitral annuloplasty for severe mitral regurgitation. Shortly thereafter, he developed severe tricuspid regurgitation and severe recurrent mitral regurgitation due to annuloplasty ring dehiscence. The dehisced annuloplasty ring was refixated, followed by tricuspid annuloplasty through a right anterolateral thoracotomy. After four years of follow-up, there are no signs of recurrent mitral or tricupid regurgitation and the patient remains in NYHA class II. Pushing the envelope on conventional surgical procedures in marginal donor hearts (both before and after transplantation) may not only improve the patient’s functional status and reduce the need for retransplantation, but it may ultimately alleviate the chronic shortage of donor hearts.

Protein Kinase Cα Mediated Phosphorylation of Cardiac Troponin Reduces Maximal Force and Exerts Dual Effects on Ca 2+-Sensitivity in Human Cardiomyocytes

Alpha-adrenergic receptor activated protein kinase Cα (PKCα) modifies cardiac contractile function and is implicated in heart failure. Aim of the study: To determine the specific effects of PKCα-mediated phosphorylation of cardiac troponin (cTn) on myofilament function in failing cardiomyocytes. Methods: Endogenous cTn in Triton-permeabilized cardiomyocytes from patients with end-stage idiopathic dilated cardiomyopathy was partially exchanged (∼69%) with PKCα-treated recombinant human cTn(DD), in which the PKA-sites Ser23/24 on cTnI were mutated into aspartic acids (D). cTn(DD) was used to rule out in-vitro cross-phosphorylation of the PKA-sites by PKCα. A comparison was made between the effects of PKCα-treated and untreated cTn(DD). Isometric force was measured at various [Ca2+] to determine the maximum isometric force per cross-sectional area (Fmax) and the calcium sensitivity of force (pCa50). Results: Fmax after exchange with PKCα-treated cTn(DD) (17.1±1.9 kN/m2) was significantly reduced in comparison with untreated cTn(DD) (26.1±1.9 kN/m2). Subsequent incubation of the cardiomyocytes with activated PKCα in the PKCα-treated cTn(DD) group did not restore Fmax. Cardiomyocytes exchanged with PKCα-treated cTn(DD) were more sensitive to Ca2+ (pCa50=5.59±0.02) than cells exchanged with untreated cTn(DD) (pCa50=5.51±0.02). Surprisingly, subsequent PKCα-incubation of cardiomyocytes exchanged with PKCα-treated cTn(DD) caused a reduction in pCa50 to 5.45±0.02. Western blot analysis of PKCα-treated cTn showed phosphorylation of Ser42 and Thr143 on cTnI. Mass spectrometry revealed two novel phosphorylation sites: Ser198 on cTnI and Ser179 on cTnT. Conclusions: Specific in vitro PKCα-mediated phosphorylation of cTn increases Ca2+-sensitivity and decreases maximal force. Subsequent PKCα-mediated phosphorylation of the myofilaments in situ decreases Ca2+-sensitivity, without affecting Fmax. These results demonstrate the dual, site-specific effects of PKCα-mediated phosphorylation in human myocardium.

Use of CoSeal in a Patient With a Left Ventricular Assist Device

A 45-year-old man with end-stage idiopathic dilatated cardiomyopathy had previously undergone two left anterolateral thoracotomies for implantation and explantation of a left ventricular epicardial lead for biventricular pacing. Because of worsening heart failure and a predicted long delay to heart transplantation, a left-ventricular assist device was implanted, with application of CoSeal surgical sealant (Baxter Healthcare Corp, Fremont, CA) on the cardiac surface. At re-sternotomy for heart transplantation, surgical dissection of the left-ventricular assist device was greatly facilitated by the presence of avascular, very loose adhesions. CoSeal (Baxter Healthcare Corp) seems to be useful for the inhibition of adhesion formation after left-ventricular assist device implantation, although further clinical experience with this approach is required.

P-18 Matrix Metalloproteinases and Late Gadolinium-Enhancement with Cardiovascular Magnetic Resonance in Patients with Dilated Cardiomyopathy

Enteroviruses have been implicated in the pathogenesis of idiopathic dilated cardiomyopathy (IDC). Recently, adenovirus and parvovirus have been proposed as etiological agents of IDC. Viral Infection in the myocardium of patients with end-stage IDC was evaluated. Myocardial specimens from 30 American IDC patients, obtained during heart transplants, and from 47 Japanese IDC patients, obtained during partial left ventriculectomy, were analyzed for the presence of viruses. Established RT-PCR or PCR was used to detect genomic sequences of enterovirus, influenza virus, mumps virus, adenovirus, herpes simplex virus, varicellazoster virus, and Epstein-Barr virus. Enteroviral RNA was detected in 7 (23%) of the 30 American patients and in 15 (32%) of the 47 Japanese patients. Sequence analysis revealed that the viruses detected were coxsackieviruses, such as coxsackievirus B3. No genomic sequences of other viruses were detected in the myocardium. A highly sensitive real-time LightCycler PCR assay was developed for the quantification of coxsackieviral genome in the myocardium. The linear dynamic range, spanning from 10 to 1010 copies, can detect viral genome in the myocardium of patients at all stages of the disease process. Low copy number of coxsackieviral RNA was detected in the myocardium of both American and Japanese patients. Conclusion: Low level of coxsackieviral RNA in the myocardium was demonstrated in a significant proportion of patients with end-stage IDC. There was no evidence of infection by other viruses in the myocardium of IDC patients.

Prediction of Short-Term Outcomes in Patients With Idiopathic Dilated Cardiomyopathy Referred for Transplantation Using Standard Echocardiography and Strain Imaging

Objective We sought to evaluate the short-term prognostic value of echocardiography including two-dimensional (2D) strain imaging in patients with end-stage idiopathic dilated cardiomyopathy (IDCM). Methods To evaluate the short-term (6-month) prognostic value of different parameters used for the assessment of IDCM patients referred for heart transplantation, we performed at the baseline transthoracic echocardiography including 2D strain imaging, N-terminal pro-BNP measurements, and exercise testing for all patients included in the study. After 6 months, all parameters, including endsystolic strain (ESS), peak systolic strain rate (SSR max), early and late diastolic strain rates, their ratio (diastolic strain rate E [DSR E], dialostolic strain rate A [DSR A], diastolic strain rate E and A wave ratio [DSR E/A]), and systolic intraventricular dyssynchrony indexes (IVDSI) were tested for their prognostic value to predict a patient's outcome. Results At the baseline stable patients had significantly lower transmitral E and A wave ratio (E/A), DSR E/A, higher DSR A values, longer transmitral E wave deceleration time (DcT), higher longitudinal ESS and SSR max values, lower systolic circumferential and longitudinal IVDSI. Conclusion The highest sensitivity for rapid heart failure progression was shown by DcT <100 ms, E/A > 1.5, DSR A < 0.3/s, circumferential IVDSI > 0.16, and longitudinal IVDSI > 0.22 (91%, 78%, 94%, 83%, and 75%, respectively).

Immunoglobulin adsorbtion therapy in patients with end-stage idiopathic dilated cardiomyopathy referred for heart transplantation

Immunoglobulin adsorbtion therapy in patients with end-stage idiopathic dilated cardiomyopathy referred for heart transplantation

Standard Echocardiography and Strain Imaging in Prediction of Short-Term Outcome in Patients with Idiopathic Dilated Cardiomyopathy Referred for Transplantation

Purpose: In the light of continuous prolongation of the waiting time on heart transplantation (HTx) lists, the need for reliable predictors of the time course of heart failure (HF) has become increasingly important. To optimize HTx-listing decisions, we evaluated the prognostic value of echocardiography including 2D strain imaging in patients with end-stage idiopathic dilated cardiomyopathy (IDCM).

Etiology and Quantitative Evaluation of Viral Infection in the Myocardium of Patients With End-stage Idiopathic Dilated Cardiomyopathy

Enteroviruses have been implicated in the pathogenesis of idiopathic dilated cardiomyopathy (IDC). Recently, adenovirus and parvovirus have been proposed as etiological agents of IDC. Viral Infection in the myocardium of patients with end-stage IDC was evaluated. Myocardial specimens from 30 American IDC patients, obtained during heart transplants, and from 47 Japanese IDC patients, obtained during partial left ventriculectomy, were analyzed for the presence of cardiotropic viruses. Established RT-PCR or PCR was used to detect genomic sequences of enterovirus, influenza virus, mumps virus, adenovirus, herpes simplex virus, varicella-zoster virus, and Epstein-Barr virus.

Substituição da valva mitral com tração dos músculos papilares em pacientes com miocardiopatia dilatada

This study aimed at evaluating results of mitral valve replacement using a new technique of complete chordae tendineae adjustment for left ventricular remodeling. Twenty end-stage idiopathic dilated cardiomyopathy patients with severe functional mitral valve regurgitation underwent mitral valve replacement. Seventeen (85%) were in functional class IV. Both anterior and posterior leaflets of the mitral valve were divided to obtain 4 pillars of chordae tendineae. These were displaced with traction toward the left atrium and anchored between the mitral annulus and a valvular prosthesis. To evaluate the left ventricular remodeling, Doppler echocardiography was performed. For statistical analysis, variance analysis and the Friedman's test were employed. Two (10%) early deaths occurred. Kaplan-Meyer showed survival at one year post-operative was 85%, 2 years it was 44%, at 3 years 44%, at 4 years 44% and at 5 years it was 44%. In the 48- and 54-month follow-ups, the McNemar test showed improvement in the functional class (p<0.001). In the third month of follow-up, variance analysis showed improvement in the ejection fraction (p=0.008) and reductions of the end diastolic diameter (p=0.038), end systolic diameter (p=0.008), end systolic volume (p=0.029) and end diastolic volume (p=0.009). No statistical differences were noted in the systolic volume. Comparing pre-operative and third- and six-month follow-ups, the Friedman test showed no statistical differences for all studied variables. Variance analyses between pre, three-month and final evaluations showed no significant differences. This technique of mitral valve replacement improved the left ventricle ejection fraction and decreased the end diastolic and systolic diameters and the end systolic diastolic volumes up to the third month of follow-up. From then on the variables stabilized.

Resting and 24-Hour Electrocardiographic Changes during Left Ventricular Assist Device Support

Introduction: Ventricular unloading during chronic left ventricular assist device (LVAD) has been shown to cause structural and functional “reverse remodeling” of the failing heart. Our aim was to investigate the effect of LVAD support on specific electrocardiograhic (ECG) parameters in patients with end-stage idiopathic dilated cardiomyopathy (IDC). Methods: Eight patients, age 47 ± 13 years, with end-stage IDC underwent LVAD implantation (Heartmate XVE). The impact of LVAD support on the frequency of ventricular arrhythmias and specific ECG parameters [QRS, QT and QT corrected (QTc)] were evaluated after analyzing a total of 149 electrocardiograms and 39 24-hour ECG monitorings performed both before and after LVAD implantation. Results: These observations were performed from day 7th to day 180th during a follow-up period of 892 patient days. QTc decreased from 575 ± 65 ms pre-LVAD implantation to 446 ± 53 ms after the completion of the first week of LVAD support (23% decrease, p = 0.001). The QTc continued to decrease during LVAD support and by the completion of the sixth LVAD support month was QTc 387 ± 66 ms (p = 0.007). The pre-implant QRS duration decreased from 153 ± 50 to 128 ± 31 ms after the first week of LVAD support (16% decrease, p = 0.024) and continued to decrease until the fourth month of support. The frequency of ventricular arrhythmias compared to the pre-implant values significantly decreased after the completion of 2 months of LVAD support (premature ventricular contractions from 3044 ± 2904/24h to 137 ± 94/24h, p = 0.068, ventricular couplets from 49 ± 24/24h to 7.7 ± 8.3/24h, p = 0.037, ventricular runs from 12 ± 7/24h to 1.5 ± 1.7/24h, p = 0.035). No incidence of symptomatic arrhythmias or sudden death was observed during the follow-up period. Conclusion: LVAD support induced early and continuous decrease of QTc and QRS duration suggesting a form of electrical reverse remodeling of the failing heart which was accompanied by a more delayed decrease in the frequency of ventricular arrhythmias.

Evidence of viral infection in the myocardium of American and Japanese patients with idiopathic dilated cardiomyopathy

Enteroviruses have been implicated in the pathogenesis of idiopathic dilated cardiomyopathy (IDC). Recently, the association of adenovirus or parvovirus with IDC has been reported. Viral infection in the myocardium of American and Japanese patients with end-stage IDC was evaluated. Myocardial specimens from 30 American patients with IDC and 47 Japanese patients with IDC were analyzed for the presence of cardiotropic viruses. The strand-specific detection of enteroviral ribonucleic acid (RNA) was performed to determine viral activity in hearts with IDC. Established reverse transcription-polymerase chain reaction (PCR) or PCR techniques were used to detect genomic sequences of influenza viruses, mumps virus, adenovirus, parvovirus, herpes simplex viruses, varicella-zoster virus, and Epstein-Barr virus. Enteroviral RNA was detected in 7 of the 30 American patients (23%) and in 15 of the 47 Japanese patients (32%). Minus-strand enteroviral RNA, an indicator of active enteroviral RNA replication, was demonstrated in 5 of 7 plus-strand-positive American patients (71%) and in 12 of 15 plus-strand-positive Japanese patients (80%). Sequence analysis revealed that the viruses detected were Coxsackie B viruses. No genomic sequences of other viruses were detected in the myocardium of either American or Japanese patients with IDC. Therefore, active group B Coxsackie virus RNA replication in the myocardium was demonstrated in a significant proportion of American and Japanese patients with end-stage IDC. There was no evidence of persistent infection by other viruses in hearts with IDC. Specific therapy should be designed for Coxsackie virus positive patients with IDC.

No evidence for persistent enterovirus infection in cattle with end-stage idiopathic dilated cardiomyopathy

No evidence for persistent enterovirus infection in cattle with end-stage idiopathic dilated cardiomyopathy

Frequency and associations of symptomatic deterioration after dual-chamber defibrillator implantation in patients with ischemic or idiopathic dilated cardiomyopathy

Sequential atrioventricular (AV) pacing has been proposed as a treatment for congestive heart failure (CHF) due to its ability to maintain chronotropic competence and optimal AV synchrony 1 Auricchio A. Sommariva L. Salo R.W. Scafuri A. Chiariello L. Improvement of cardiac function in patients with severe congestive heart failure and coronary artery disease by dual chamber pacing with shortened AV delay. Pacing Clin Electrophysiol. 1993; 16: 2034-2043 Crossref PubMed Scopus (131) Google Scholar , 2 Hochleitner M. Hortnagl H. Hortnagl H. Fridrich L. Gschnitzer F. Long-term efficacy of physiologic dual-chamber pacing in the treatment of end-stage idiopathic dilated cardiomyopathy. Am J Cardiol. 1992; 70: 1320-1325 Abstract Full Text PDF PubMed Scopus (170) Google Scholar ; it is increasingly being used in this patient population. Controlled studies have failed to confirm a significant improvement in left ventricular (LV) systolic function. 3 Innes D. Leitch J.W. Fletcher P.J. VDD pacing at short atrioventricular intervals does not improve cardiac output in patients with dilated heart failure. Pacing Clin Electrophysiol. 1994; 17: 959-965 Crossref PubMed Scopus (81) Google Scholar , 4 Gold M.R. Feliciano Z. Gottlieb S.S. Fisher M.L. Dual-chamber pacing with a short atrioventricular delay in congestive heart failure a randomized study. J Am Coll Cardiol. 1995; 26: 967-973 Abstract Full Text PDF PubMed Scopus (223) Google Scholar , 5 Linde C. Gadler F. Edner M. Nordlander R. Rosenqvist M. Rydén L. Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure. J Am Coll Cardiol. 1995; 75: 919-923 Abstract Full Text PDF Scopus (214) Google Scholar Anecdotal evidence exists that an exacerbation of symptomatic cardiac dysfunction may occur with right ventricular (RV) apical pacing, presumably due to dyssynchronous ventricular contraction. Although ventricular pacing is rarely used with single-chamber implantable cardioverter defibrillators, with dual-chamber systems many patients are paced in the ventricular chamber for much of the time. In this study we evaluated the effects of RV apical pacing in patients with heart failure who received dual-chamber defibrillators.

Regulation of the angiotensin II AT1 receptor in patients with end-stage idiopathic dilated cardiomyopathy

Regulation of the angiotensin II AT1 receptor in patients with end-stage idiopathic dilated cardiomyopathy

Histopathologic findings in explanted heart tissue from patients with end-stage idiopathic dilated cardiomyopathy

Histopathologic findings in explanted heart tissue from patients with end-stage idiopathic dilated cardiomyopathy

Endothelin-1, endothelin-1 receptors and cardiac natriuretic peptides in failing human heart

Endothelin (ET)-1 is a potent vasoconstrictor peptide produced in the myocardium that can exert important effects on cardiac myocyte growth and phenotype; cardiac natriuretic peptides (ANP and BNP) are known to act as physiological antagonists of ET-1. In this study a comparative determination of ET-1 receptors and of the local productions of ET-1 and of ANP and BNP was made in different sites of failing and nonfailing hearts. Tissue from right and left atrium, right and left ventricle and interventricular septum from seven adult heart transplant recipients with end-stage idiopathic dilated cardiomyopathy (functional class III and IV, with ejection fraction < 35%) and from four post-mortem subjects without cardiac complications was analyzed. In failing hearts we observed a tendency to increase of density of binding sites, most evident in left ventricle (62.6 ± 22.6 fmol/mg protein vs. 29.0 ± 3.3, mean ± SEM, p = ns). A prevalence of ET-A subclass, observed in all samples, resulted more pronounced in failing hearts where this increase, found in all the cardiac regions, was more evident in left ventricle (p = 0.0007 vs nonfailing hearts). The local concentrations of ET-1, ANP and BNP resulted significantly increased in failing hearts with respect to controls in all sides of the heart. In failing hearts we have observed a tendency to increase in endothelin receptor density mainly due to a significant upregulation of ET-A subtype and a parallel increase of the tissue levels of ANP, BNP and ET-1 indicating an activation of these systems in heart failure.

Midterm follow-up of patients who underwent removal of a left ventricular assist device after cardiac recovery from end-stage dilated cardiomyopathy.

Cardiac recovery in end-stage idiopathic dilated cardiomyopathy recently occurred after temporary support with a left ventricular assist device. We report the case histories of patients who underwent removal of the device more than 4 years ago. Since June 1994, 23 patients with end-stage idiopathic dilated cardiomyopathy who were supported by a left ventricular assist device or biventricular assist device for 1 to 26 months (mean, 6 months) underwent removal of the device after complete or extensive cardiac recovery, as revealed by echocardiography. Seven patients (group A) had recurrent cardiac failure after 4 to 24 months. Transplantation was performed in 6 patients, and one died while on the waiting list. Three patients died of noncardiac causes within a period of 4 months and 3 days after removal of the assist device. Stable cardiac recovery occurred in 13 patients (group B) for 3 to 49 months (mean, 23 months). At the time of implantation, there were no significant differences between the groups with regard to age, hemodynamics, left ventricular ejection fraction, left ventricular internal diameter in diastole, and autoantibody levels. The increase of ejection fraction and the decrease of left ventricular internal diameter in diastole after 2 months were highly significant. The patients in group A had longer histories of heart failure and first cardiac symptoms and duration of assist when compared with group B. Group B demonstrated a quicker cardiac recovery on the assist device, and thus support was shorter. Also, the degree of recovery at assist device explantation was more complete in group B. The age at the time of device placement was the only influencing factor for duration on the assist device. The probability of recurrence of heart failure was influenced by the duration of heart failure. In selected patients with idiopathic dilated cardiomyopathy, lasting recovery can be achieved after unloading with a left ventricular assist device. Lasting cardiac recovery seems to be related to functional normalization and a more rapid recovery during the unloading period.