The Role of Oncostatin M and Its Receptor Complexes in Cardiomyocyte Protection, Regeneration, and Failure.

Oncostatin M (OSM), a member of the interleukin-6 family, functions as a major mediator of cardiomyocyte remodeling under pathological conditions. Its involvement in a variety of human cardiac diseases such as aortic stenosis, myocardial infarction, myocarditis, cardiac sarcoidosis, and various cardiomyopathies make the OSM receptor (OSMR) signaling cascades a promising therapeutic target. However, the development of pharmacological treatment strategies is highly challenging for many reasons. In mouse models of heart disease, OSM elicits opposing effects via activation of the type II receptor complex (OSMR/gp130). Short-term activation of OSMR/gp130 protects the heart after acute injury, whereas chronic activation promotes the development of heart failure. Furthermore, OSM has the ability to integrate signals from unrelated receptors that enhance fetal remodeling (dedifferentiation) of adult cardiomyocytes. Because OSM strongly stimulates the production and secretion of extracellular proteins, it is likely to exert systemic effects, which in turn, could influence cardiac remodeling. Compared with the mouse, the complexity of OSM signaling is even greater in humans because this cytokine also activates the type I leukemia inhibitory factor receptor complex (LIFR/gp130). In this article, we provide an overview of OSM-induced cardiomyocyte remodeling and discuss the consequences of OSMR/gp130 and LIFR/gp130 activation under acute and chronic conditions.

Long-term results after mitral valve surgery using minimally invasive versus sternotomy approach: a propensity matched comparison of a large single-center series.

BACKGROUND: Mitral valve (MV) surgery has traditionally been performed by conventional sternotomy (CS), but more recently minimally invasive surgery (MIS) has become another treatment option. The aim of this study is to compare short- and long-term results of MV surgery after CS and MIS. METHODS: This study was a retrospective propensity-matched analysis of MV operations between January 2005 and December 2015. RESULTS: Among 1357 patients, 496 underwent CS and 861 MIS. Matching resulted in 422 patients per group. The procedure time was longer with MIS than CS (192 vs. 185 min; p = 0.002) as was cardiopulmonary bypass time (133 vs. 101 min; p < 0.001) and X-clamp time (80 vs. 71 min; p < 0.001). 'Short-term' successful valve repair was higher with MIS (96.0% vs. 76.0%, p < 0.001). Length of hospital stay was shorter in MIS than CS patients (10 vs. 11 days; p = 0.001). There was no difference in the overall 30-day mortality rate. Cardiovascular death was lower after MIS (1.2%) compared with CS (3.8%; OR 0.30; 95%CI 0.11-0.84). The difference did not remain significant after adjustment for procedural differences (aOR 0.40; 95%CI 0.13-1.25). Pacemaker was required less often after MIS (3.3%) than CS (11.2%; aOR 0.31; 95%CI 0.16-0.61), and acute renal failure was less common (2.1% vs. 11.9%; aOR 0.22; 95%CI 0.10-0.48). There were no significant differences with respect to rates of stroke, myocardial infarction or repeat MV surgery. The 7-year survival rate was significantly better after MIS (88.5%) than CS (74.8%; aHR 0.44, 95%CI 0.31-0.64). CONCLUSION: This study demonstrates that good results for MV surgery can be obtained with MIS, achieving a high MV repair rate, low peri-procedural morbidity and mortality, and improved long-term survival.

Comparison of flexible, open with semi-rigid, closed annuloplasty-rings for mitral valve repair.

BACKGROUND: Mitral regurgitation is a frequent valvular disease, with an increasing prevalence. We analysed the long-term outcomes of mitral valve repair procedures conducted over the last 10 years in our clinic using almost exclusively two different annuloplasty ring types. METHODS: A single-centre, retrospective analysis of mitral valve surgeries conducted between January 2005 and December 2015 for patients undergoing first-line mitral valve repair with either open (Cosgrove) or closed (CE Physio / Physio II) annuloplasty (OA or CA, respectively) rings. RESULTS: In total, 1120 patient documentations were available of which 528 underwent OA and 592 patients CA. The median age of patients was 64.0 years and 41.1% were female. The majority of these patients underwent the procedure because of degenerative valve disease. Rates of successful repair were about 90%, 72 h procedural mortality was 0.6% and the rate of re-intervention was 0.6% within the first 30 days. Functional (mitral regurgitation, left ventricular ejection fraction, left ventricular end-diastolic and systolic diameter and New York Heart Association class) as well as hard outcomes were comparable. 77.7 and 74.4% of patients were alive at the 10-year follow-up in the OA and CA groups, respectively. Upon multivariable adjustment, the hazard ratio was 0.926 (95% CI: 0.642-1.3135; p = 0.681). CONCLUSIONS: The functional outcome and survival rates up to 10 years after mitral valve repair were comparable using open and closed annuloplasty rings. Whether this means these rings are interchangeable or a carefully selection of the best-for-the-patient devices will be subject of future investigations.

Minimally invasive left atrial appendage (LAA) clip insertion after challenging LAA occluder implantation to minimize the risk of stroke.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, requiring lifelong anticoagulation or interventional, transseptal left atrial appendage (LAA) occluder implantation to minimize stroke risk. Incomplete LAA closure post implantation is a frequent observation. Incomplete LAA occlusion after transseptal occluder implantation necessitates anticoagulation in cases of persistent AF to minimze risk of embolism and/or apoplexy. Patients with contraindications to lifelong anticoagulation therapy are challenging to treat and alternative options are needed. We present a case of a patient with persistent AF who underwent frustraneous LAA occluder implantation. The patient's anatomy necessitated surgical closure of the LAA, which was accomplished with an LAA clip 4 weeks after implantation. The patient was discharged in excellent clinical status 5 days after the surgery. No further complications were observed within the following year.

Pulmonary herniation after minimally invasive cardiac surgery: review and implications from a series of 20 cases.

Minimally invasive cardiac surgery (MICS) via right lateral mini thoracotomy is the gold standard treatment approach for mitral and tricuspid valve disorders. Other selected procedures (e.g. transapical aortic valve implantation, MIDCAB) require a left lateral mini thoracotomy for surgical access. Advantages of MICS over complete sternotomy are well known, but access-related complications post MICS, such as pulmonary herniation, are often underestimated/overlooked. In males, a pulmonary herniation in the proximity of the former thoracotomy is often clinically visible, especially when the intrathoracic pressure rises (e.g. during coughing). In females, clinical symptoms may be hidden by the breast and patients often have unspecific complaints or occasional pain when coughing, making identification of a lung herniation more difficult. Chest computed tomography is the diagnostic tool of choice for pulmonary herniations. Using a series of 20 patients with pulmonary herniation post MICS, we report our findings in diagnosis and treatment of this condition.

Long-term results of endoclamping in patients undergoing minimally invasive mitral valve surgery where external aortic clamping cannot be used - a propensity matched analysis.

BACKGROUND: Minimally invasive mitral valve surgery is standard of care in many centres and it is commonly associated with the need for cardiopulmonary bypass. Conventional external aortic clamping (exoclamping) is not always feasible, so endoaortic clamping (endoclamping) has evolved as a viable alternative. The aim of this study is to compare endoclamping (Intraclude™, Edwards Lifesciences) with exoclamping (Chitwood) during minimally invasive mitral valve procedures. METHODS: This single-centre study included 822 consecutive patients undergoing minimally invasive mitral valve procedures. The endoclamp was used in 64 patients and the exoclamp in 758. Propensity-score (PS) matching was performed resulting in 63 patients per group. Outcome measures included procedural variables, length of intensive care unit (ICU) and hospital stay, major adverse cardiac and cerebrovascular events (MACCE) and repeat surgery. RESULTS: The mean age was similar in the two group (62.2 [endoclamp] vs. 63.5 [exoclamp] years; p = 0.554), as were the cardiopulmonary bypass (145 vs. 156 min; p = 0.707) and the procedure time (203 vs. 211 min; p = 0.648). The X-clamp time was significantly shorter in the endoclamp group (88 vs. 99 min; p = 0.042). Length of ICU stay (25.0 vs. 23.0 h) and length of hospital stay (10.0 vs. 9.0 days) were slightly longer in the endoclamp group, but without statistical significance. There were nominal but no statistically significant differences between the groups in the rates of stroke, vascular complications, myocardial infarction or repeat mitral valve surgery. The conversion rate to open sternotomy approach was 2.4% without difference between groups. The estimated 7-year survival rate was similar for both groups (89.9% [endoclamp]; 84.0% [exoclamp]) with a hazard ratio of 1.291 (95% CI 0.453-3.680). CONCLUSIONS: Endoaortic clamping is an appropriate and reasonably safe alternative to the conventional Chitwood exoclamp for patients in which the exoclamp cannot be used because the ascending aorta cannot be safely mobilised.

Long-term outcomes of concomitant tricuspid valve repair in patients undergoing mitral valve surgery.

BACKGROUND: We aimed to find out how the concomitant performance of tricuspid valve repair (TVR) affects outcomes of patients undergoing mitral valve surgery (MVS). METHODS: Single-centre, retrospective analysis of 1357 patients who underwent MVS between January 2005 and December 2015, including 1165 patients with isolated MVS and 192 patients with MVS plus TVR. We used propensity scores to match patients for baseline characteristics other than valve related parameters and arrived at a matched sample of 182 patients per group. RESULTS: The overall procedure duration was longer in the MVS + TVR (224 min) versus the MVS group (176 min; p < 0.001), as were the duration of mechanical ventilation (13 vs. 11 h; p < 0.001), X-clamp (90.5 vs. 66 min; p < 0.001) and cardiopulmonary bypass time (136 vs. 95.5 min; p < 0.001). Rates of procedural complications were not different between groups with the exception of pacemaker rates which were 16.0% in the MVS + TVR group and 8.8% in the isolated MVS group (p = 0.037). There was no difference in death rates within 30 days, stroke, myocardial infarction or repeat MVS. The long-term survival rate was 60.8% in the MVS + TVR vs. 57.5% in the isolated MVS group (HR 1.048; 95%CI 0.737-1.492; p = 0.794). The rate of grade III/IV tricuspid regurgitation (TR) remained low after MVS + TVR during long-term follow-up while the rate of grade ≥ II TR increased slightly in the isolated MVS group. CONCLUSION: The data show that the concomitant performance of TVR in patients undergoing MVS is a safe and effective procedure with good long-term outcomes. Patients can undergo MVS + TVR with confidence as it improves their prognosis up to the level of patients undergoing isolated MVS.

Mitral valve repair for posterior leaflet prolapse: Long-term comparison of loop implantation vs resection.

BACKGROUND: Resection (triangular or quadrangular) is considered the gold standard for the treatment of posterior leaflet prolapse and loop implantation a more recent alternative. We aimed to compare the long-term outcomes of triangular or quadrangular resection vs loop implantation. METHODS: Single-centre, retrospective analysis of mitral valve (MV) surgeries conducted from January 2005 to December 2015. Propensity score matching was based on seven key baseline variables. RESULTS: Data from 721 patients were analyzed; 358 patients received loop implantation and 363 patients underwent resection. Patients had a mean age of 62 years, 33.0% were female and 50.6% had hypertension. Propensity score matching resulted in a matched group of 263 patients who received loop implantation or underwent resection, respectively. Postoperatively, the patients' mitral insufficiency was reduced from grade III/IV to either zero or trace (45.8%) or I (49.8%) and New York Heart Association class reduced from 66.9% in class III/IV preoperatively to 8.3% with no significant differences between groups. Fewer patients receiving loops had procedure-related complications. Fewer patients in the loop implantation group required permanent pacemaker implantation at 30 days (8.4% vs 2.3%; P = .002). The 10-year survival for patients in the resection (88.0%) and loop implantation (89.3%) groups had a hazard ratio of 1.224 (95% confidence interval, 0.633-2.367). CONCLUSION: Our study showed that both loop implantation and resection were associated with comparable long-term survival in patients with posterior leaflet prolapse. Loop implantation is associated with a significantly higher rate of a successful repair, a significantly lower rate of MV replacement after repair failure, fewer procedure-related complications and better 30-day at comparable long-term outcomes.

Explantation and reimplantation of a breast implant to facilitate minimally invasive mitral valve surgery and cryoablation of atrial fibrillation.

Clinicians can feel confident about performing mitral repair/replacement in patients who have previously undergone mammoplasty. It may also have applications in performing atrial septal defect closure, Maze procedures for atrial fibrillation, and tricuspid valve surgery in patients with breast implants.

Long-term outcome after mitral valve replacement using biological versus mechanical valves.

BACKGROUND: This study compared long-term outcomes of biological and mechanical mitral valve replacement (MVR) in patients requiring replacement of the mitral valve where repair was not feasible. METHODS: A single-centre registry of patients receiving MVR between 2005 and 2015 was established. Thirty-day mortality and long-term outcomes were analysed and compared. RESULTS: Three hundred twenty four patients underwent MVR (265 biological; 59 mechanical valves). Patients receiving biological valves were older (p < 0.001), had a higher log EuroSCORE (p < 0.001) and received less minimally invasive surgery (p < 0.001). Immediate procedural mortality was 1.9%, which only occurred in the biological valve group. At 30 days, 9.0% of patients had died, 4.0% experienced stroke, 8.0% received a pacemaker and 10.5% suffered an acute renal failure. The rate of re-thoracotomy (14.2%) was lower in the biological (12.5%) than in the mechanical valve group (22.0%; adjOR 0.45 [0.20-1.00]; p = 0.050). Frequent long-term complications were stroke (9.2%) and bleeding (4.8%), with bleeding complications being higher in the mechanical valve group (p = 0.009). During the follow-up period biological valves showed a numerically higher survival rate during the first years, which shifted after 3 years in favour of mechanical valves. At 10 years, survival rates were 62.4% vs. 77.1% in the biological and mechanical valve groups (p = 0.769). Hazard ratio after adjustment was 0.833 (95% CI 0.430-1.615). CONCLUSION: These data confirm that mechanical valve implantation is associated with an increased risk of bleeding. While there was a potential survival benefit during the first years after surgery for patients receiving a biological valves the difference became insignificant after a follow-up of 10 years.

Numerical Investigation of Roughness Effects on Transition on Spherical Capsules.

To address the hitherto unknown mechanism of boundary-layer transition on blunt reentry capsules, the role of roughness-induced disturbance growth on a spherical-section forebody is assessed via optimal transient growth theory and direct numerical simulations (DNS). Optimal transient-growth studies have been performed for the blunt capsule experiments at Mach 5.9 in the Hypersonic Ludwieg tube Braunschweig (HLB) of the Technische Universität Braunschweig, which included measurements behind a patch of controlled, distributed micron-sized surface roughness. Transient-growth results for the HLB capsule indicate similar trends as the corresponding numerical data for a Mach 6 experiment in the Actively Controlled Expansion (ACE) facility of the Texas A&M University (TAMU) at a lower Reynolds number. Both configurations indicate a similar dependence on surface temperature ratio, and more important, rather low values of maximum energy gain. DNS are performed for the conditions of the HLB experiment to understand the generation of stationary disturbances by the roughness patch and the accompanying evolution of unsteady perturbations. However, no evidence of either modal or nonmodal disturbance growth in the wake of the roughness patch is found in the DNS data; thus, the physical mechanism underlying the observed onset of transition still remains unknown.

Oncostatin M is a major mediator of cardiomyocyte dedifferentiation and remodeling.

Cardiomyocyte remodeling, which includes partial dedifferentiation of cardiomyocytes, is a process that occurs during both acute and chronic disease processes. Here, we demonstrate that oncostatin M (OSM) is a major mediator of cardiomyocyte dedifferentiation and remodeling during acute myocardial infarction (MI) and in chronic dilated cardiomyopathy (DCM). Patients suffering from DCM show a strong and lasting increase of OSM expression and signaling. OSM treatment induces dedifferentiation of cardiomyocytes and upregulation of stem cell markers and improves cardiac function after MI. Conversely, inhibition of OSM signaling suppresses cardiomyocyte remodeling after MI and in a mouse model of DCM, resulting in deterioration of heart function after MI but improvement of cardiac performance in DCM. We postulate that dedifferentiation of cardiomyocytes initially protects stressed hearts but fails to support cardiac structure and function upon continued activation. Manipulation of OSM signaling provides a means to control the differentiation state of cardiomyocytes and cellular plasticity.

Fibrosis in endstage human heart failure: severe changes in collagen metabolism and MMP/TIMP profiles.

OBJECTIVES: We studied fibrosis, collagen metabolism, MMPs/TIMPs and cytokine expression in various forms of human heart failure (HF) by quantitative immunofluorescent microscopy, Western blot, zymography, RT-PCR and in situ hybridization. In explanted human hearts with HF due to either dilated (DCM, n=6) or ischemic (ICM-BZ-borderzone, ICM-RZ-remote zone, n=7) or inflammatory (myocarditis, MYO, n=6) cardiomyopathy and 8 controls MMP2, 8, 9, 19, and TIMP1, 2, 3, 4 as well as procollagens I and III (PINP, PIIINP), mature collagen III (IIINTP) and the cross-linked collagen I degradation product (ICTP) were measured. RESULTS: In comparison with controls, MMPs and TIMPs were significantly upregulated ranging (from highest to lowest) from ICM-BZ, DCM, ICM-RZ, MYO for all MMPs with the exception of MMP9 (highest in DCM), and for TIMPs from ICM-BZ, ICM-RZ, DCM and MYO. MMP2 and 9 were activated in all groups. The TIMP/MMP ratio was 1.3 for control, 1.9 in ICM-BZ (TIMP>MMP) and lowered to 1.0 in the other groups. Collagen I/collagen III ratio correlated significantly with the decrease in LVEDP. PINP was higher than ICTP in all groups. PIIINP elevation was present in DCM and ICM-RZ and IIINTP was up to 4-fold augmented in all groups. Fibrosin mRNA was upregulated in ICM-BZ, activin A in MYO but FGF1 and FGF2 remained unchanged. ANP mRNA was increased in all groups. CONCLUSIONS: Although different degrees of severity of collagen metabolism, MMP/TIMP imbalance and cytokine expression in diverse forms of HF are present, the end product is collagen deposition. These findings suggest multiple mechanisms acting alone or in concert in fibrosis development in HF.

Deposition of nonsarcomeric alpha-actinin in cardiomyocytes from patients with dilated cardiomyopathy or chronic pressure overload.

Nonsarcomeric alpha-actinin (ACTN-1)-positive clusters have been detected in human myocardium structurally jeopardized by dilated cardiomyopathy, hypertrophy due to aortic stenosis, or chronic hibernation, but have never been detected in normal tissue. To systematically investigate these clusters, immunohistochemistry, electron microscopy, Northern blot and Western blot were performed in human myocardium, isolated rat cardiomyocytes and rabbit smooth muscle cells. ACTN-1-positive clusters were localized in the perinuclear area of cardiomyocytes surrounded by rough endoplasmic reticulum. Quantification of structures containing ACTN-1 showed that it was present in up to 10% of all myocytes in 60% of aortic stenosis patients with severely reduced ejection fraction and in 70% of patients with dilated cardiomyopathy, exclusively in myocytes from hearts with structural degeneration and reduced function. Ultrastructurally, clusters of medium electron density corresponding to the confocal microscopic accumulations were observed in the same tissue samples. The messenger RNA of ACTN-1 was unchanged compared with controls, but a Western blot revealed that the protein was significantly elevated in failing hearts. Because membranes of the endoplasmic reticulum surround the clusters, it was concluded that in the presence of undisturbed transcription, a post-translational malfunction of ACTN-1 glycosylation might lead to storage of this protein. Autophagic and ischemic cell death were observed, but a possible toxic effect of this storage product was excluded because markers of cell death rarely colocalized with ACTN-1. The occurrence of ACTN-1-positive clusters, however, appears to be a useful marker for structural degeneration in failing myocardium.

Adult rat cardiac myocytes in culture: 'Second-floor' cells and coculture experiments.

OBJECTIVE: To compare adult rat cardiomyocytes in primary culture for up to 28 days with those in primary culture for 10 days plus up to 18 days in a coculture (CC) system. The phenomenon of 'second-floor' cells in primary cultures and the behaviour of CC myocytes were studied over varying times with regard to protein content and attachment to underlying cells. METHODS: Qualitative confocal microscopy and quantitation using the Imaris program (Bitplane, Switzerland) for the measurement of the fluorescence intensity in the confocal microscope were used. The protein content of actin, myosin, desmin, tubulin, titin, myomesin, cadherin and connexin was determined. Cell death was evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling method for apoptosis and using propidium iodide applied to unfixed cultures to detect necrosis. RESULTS: Compared with controls, second-floor cells contained only 14% of the actin and 4.9% of the tubulin at 10 days, whereas these proteins were well preserved in CC cells. All other proteins slowly declined in second-floor cells, whereas they were still present in normal amounts in CC cells. Cell death was evident in second-floor cells but absent in CC myocytes. Cellular attachment was still evident through original in vivo adherens junctions in second-floor cells but numerous newly developed cadherin- and connexin-containing junctions were visible in CC cells. It appears from the present study that second-floor cells are mummified dead cardiomyocytes, whereas CC myocytes survive and start to dedifferentiate. CONCLUSION: The absence of actin and tubulin, together with nuclear changes, are indicators of loss of cell viability despite preservation of the cells' rod shape and cross-striation, as observed in second-floor cells. In contrast, the establishment of a CC system of cardiomyocytes results in survival and organization of a three-dimensional cellular system, which may in the future be useful for tissue engineering attempts for replacement of lost tissue after myocardial infarction.

Transforming growth factor-beta1 downregulates beating frequency and remodeling of cultured rat adult cardiomyocytes.

We have observed increased levels of transforming growth factor-beta1 (TGF-beta1) in human hibernating myocardium (HM). Impaired ventricular function in HM is known to be restored to normal following revascularization implying that myocardial structure in HM is to a certain degree preserved. We have therefore tested whether TGF-beta1 can imitate features of HM by reducing the number and frequency of beating cells (chronotropism) and structural remodeling of cultured adult rat cardiomyocytes (ARC), thus saving substrate, energy, and oxygen. Parameters measured were cell size, protein synthesis, protein degradation, protein content, myofibrillogenesis, and chronotropism. ARC were stimulated for 6 days with sera from patients with coronary heart disease, as this period led to a maximum response of cells. An increase of 90% in cell surface area following such treatment was reduced to a 20% increase of the original size by TGF-beta1. Concomitantly, the rate of protein synthesis dropped from 3.6-fold to 2.4-fold, and myofibrillogenesis was reduced. TGF-beta1 downregulated both the number of contracting cells from 81% to 10% and the frequency from 52 to nine beats per minute. However, TGF-beta1 treatment did not reduce the augmentation of protein content (1.28-fold versus 1.25-fold) indicating that protein degradation was also inhibited. Similar results were obtained with serum from healthy volunteers. The effects of TGF-beta1 were reversible. We conclude that TGF-beta1 constrains protein turnover and beating activity in underperfused myocardium, thus mediating protection by adapting myocytes to shortages in blood supply.

Matrix metalloproteinases and their tissue inhibitors in pressure-overloaded human myocardium during heart failure progression.

OBJECTIVES: We studied the role of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in fibrosis formation in the transition from hypertrophy to heart failure (HF) as well as the cellular source of MMPs and TIMPs. BACKGROUND: Human pressure-overloaded hearts are characterized by a significant increase in cardiac fibrosis. However, the contribution of the proteolytic/antiproteolytic system in aortic stenosis (AS) during hypertrophy progression has not yet been elucidated. METHODS: Three groups of AS patients (I: EF >50%, n = 12; II: EF 50% to 30%, n = 10; III: EF <30%, n = 12) undergoing aortic valve replacement and seven controls were studied. Tissue samples were investigated by immunoconfocal microscopy, Western blotting, and zymography. RESULTS: Quantitative analysis by immunoconfocal microscopy and Western blotting showed an upregulation of MMP-1, -2, -3, -9, -13, and -14 in group I and further increases in later stages. Tissue inhibitors of metalloproteinase-1 and -2 were enhanced and TIMP-4 was decreased in comparison to control. Gelatinolytic activity of MMP-2 significantly (p < 0.05) increased 1.2-fold (group I), 1.5-fold (group II), and 1.6-fold (group III) over control. The level of collagen I was significantly upregulated in all AS groups. Immunoconfocal microscopy showed that MMPs and TIMPs are produced predominantly by fibroblasts. The number of proliferating fibroblasts was significantly elevated during the transition to HF (0.67 n/mm(2)-control, 5.03-group III, p < 0.05). CONCLUSIONS: In human hearts a continuous turnover of the extracellular matrix occurs during the progression from compensated hypertrophy to HF that is characterized by the upregulation of MMPs and inadequate inhibition by TIMPs. The altered balance between proteolysis/antiproteolysis with accompanying proliferation of fibroblasts results in fibrosis progression.

Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis.

OBJECTIVES: Gap junctions (GJ) are important determinants of conduction. In advanced heart failure alterations of the major ventricular GJ protein, connexin 43 (Cx43) are found. However, changes in Cx43 expression during the progression from compensated cardiac hypertrophy to heart failure, especially in humans, have not been studied extensively. The aim of the present study was to investigate changes in Cx43 expression and distribution in compensated and decompensated left ventricular (LV) hypertrophy in pressure-overloaded human hearts with valvular aortic stenosis (AS). METHODS: We measured Cx43 levels by Western blot and quantitative immunoconfocal microscopy of LV septum biopsies from three groups of patients with AS (group I (n=9): ejection fraction (EF)>50%; group II (n=12): EF 30-50%; group III (n=9): EF<30%). LV biopsies from six patients with mitral valve stenosis and two donor hearts served as controls. RESULTS: Only the early phase of LV hypertrophy (AS-I) was characterized by extensive Cx43 lateral staining. As compared to controls, the AS-I group showed a 44.3% increase in Cx43 protein, which was reflected in an augmented number of GJs per 100 microm(2) intercalated disc area (control: 62.5+/-6.4 vs. AS-I: 79.8+/-4, p<0.001) and an increased GJ surface density (control: 0.00547 vs. AS-I: 0.00724 microm(2)/microm(3), p<0.01). Decompensated LV hypertrophy (AS-III) was specified by reduced percentage of the Cx43 signal per myocyte area (control: 1.74% vs. AS-III: 1.31%, p<0.01) or per intercalated disc (control: 18.3% vs. AS-III: 11.3%, p<0.005). Mean GJ area and GJ number per intercalated discs in the AS-III group were decreased significantly by, respectively, 42.5% and 36.4% as compared to control. In addition, decompensated LV myocardium showed a markedly heterogeneous spatial distribution of Cx43. CONCLUSION: The quantity and spatial distribution of Cx43 differs markedly between compensated and decompensated LV hypertrophy in human patients with AS. Upregulation of Cx43 in compensated hypertrophy may represent the immediate adaptive response to increased load, whereas diminished and heterogeneous Cx43 distribution in decompensated hypertrophy may play maladaptive roles culminating in heart failure and ventricular arrhythmias.