Activation of common signaling pathways during remodeling of the heart and the bladder

The heart and the urinary bladder are hollow muscular organs, which can be afflicted by pressure overload injury due to pathological conditions such as hypertension and bladder outlet obstruction. This increased outflow resistance induces hypertrophy, marked by dramatic changes in the organs' phenotype and function. The end result in both the heart and the bladder can be acute organ failure due to advanced fibrosis and the subsequent loss of contractility. There is emerging evidence that microRNAs (miRNAs) play an important role in the pathogenesis of heart failure and bladder dysfunction. MiRNAs are endogenous non-coding single-stranded RNAs, which regulate gene expression and control adaptive and maladaptive organ remodeling processes. This Review summarizes the current knowledge of molecular alterations in the heart and the bladder and highlights common signaling pathways and regulatory events. The miRNA expression analysis and experimental target validation done in the heart provide a valuable source of information for investigators working on the bladder and other organs undergoing the process of fibrotic remodeling. Aberrantly expressed miRNA are amendable to pharmacological manipulation, offering an opportunity for development of new therapies for cardiac and bladder hypertrophy and failure.

Connexin 43 expression in human hypertrophied heart due to pressure and volume overload

Left ventricular hypertrophy (LVH) is due to pressure overload or mechanical stretch and is thought to be associated with remodeling of gap-junctions. We investigated whether the expression of connexin 43 (Cx43) is altered in humans in response to different degrees of LVH. The expression of Cx43 was analyzed by quantitative polymerase chain reaction, Western blot analysis and immunohistochemistry on left ventricular biopsies from patients undergoing aortic or mitral valve replacement. Three groups were analyzed: patients with aortic stenosis with severe LVH (n=9) versus only mild LVH (n=7), and patients with LVH caused by mitral regurgitation (n=5). Cx43 mRNA expression and protein expression were similar in the three groups studied. Furthermore, immunohistochemistry revealed no change in Cx43 distribution. We can conclude that when compared with mild LVH or with LVH due to volume overload, severe LVH due to chronic pressure overload is not accompanied by detectable changes of Cx43 expression or spatial distribution.

Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with congenital heart disease: complex congenital cardiac lesions

With advances in pediatric cardiology and cardiac surgery, the population of adults with congenital heart disease (CHD) has increased. In the current era, there are more adults with CHD than children. This population has many unique issues and needs. They have distinctive forms of heart failure and their cardiac disease can be associated with pulmonary hypertension, thromboemboli, complex arrhythmias and sudden death. Medical aspects that need to be considered relate to the long-term and multisystemic effects of single ventricle physiology, cyanosis, systemic right ventricles, complex intracardiac baffles and failing subpulmonary right ventricles. Since the 2001 Canadian Cardiovascular Society Consensus Conference report on the management of adults with CHD, there have been significant advances in the field of adult CHD. Therefore, new clinical guidelines have been written by Canadian adult CHD physicians in collaboration with an international panel of experts in the field. Part III of the guidelines includes recommendations for the care of patients with complete transposition of the great arteries, congenitally corrected transposition of the great arteries, Fontan operations and single ventricles, Eisenmenger's syndrome, and cyanotic heart disease. Topics addressed include genetics, clinical outcomes, recommended diagnostic workup, surgical and interventional options, treatment of arrhythmias, assessment of pregnancy risk and follow-up requirements. The complete document consists of four manuscripts, which are published online in the present issue of The Canadian Journal of Cardiology. The complete document and references can also be found at www.ccs.ca or www.cachnet.org.

Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with congenital heart disease: executive summary

With advances in pediatric cardiology and cardiac surgery, the population of adults with congenital heart disease (CHD) has increased. In the current era, there are more adults with CHD than children. This population has many unique issues and needs. They have distinctive forms of heart failure, and their cardiac disease can be associated with pulmonary hypertension, thromboemboli, complex arrhythmias and sudden death.Medical aspects that need to be considered relate to the long-term and multisystemic effects of single-ventricle physiology, cyanosis, systemic right ventricles, complex intracardiac baffles and failing subpulmonary right ventricles. Since the 2001 Canadian Cardiovascular Society Consensus Conference report on the management of adults with CHD, there have been significant advances in the understanding of the late outcomes, genetics, medical therapy and interventional approaches in the field of adult CHD. Therefore, new clinical guidelines have been written by Canadian adult CHD physicians in collaboration with an international panel of experts in the field. The present executive summary is a brief overview of the new guidelines and includes the recommendations for interventions. The complete document consists of four manuscripts that are published online in the present issue of The Canadian Journal of Cardiology, including sections on genetics, clinical outcomes, recommended diagnostic workup, surgical and interventional options, treatment of arrhythmias, assessment of pregnancy and contraception risks, and follow-up requirements. The complete document and references can also be found at www.ccs.ca or www.cachnet.org.

Atrial fibrillation in congestive heart failure

Atrial fibrillation (AF) and heart failure (HF) are common and interrelated conditions, each promoting the other, and both associated with increased mortality. HF leads to structural and electrical atrial remodeling, thus creating the basis for the development and perpetuation of AF; and AF may lead to hemodynamic deterioration and the development of tachycardia-mediated cardiomyopathy. Stroke prevention by antithrombotic therapy is crucial in patients with AF and HF. Of the 2 principal therapeutic strategies to treat AF, rate control and rhythm control, neither has been shown to be superior to the other in terms of survival, despite better survival in patients with sinus rhythm compared with those in AF. Antiarrhythmic drug toxicity and poor efficacy are concerns. Catheter ablation of AF can establish sinus rhythm without the risks of antiarrhythmic drug therapy, but has important procedural risks, and data from randomized trials showing a survival benefit of this treatment strategy are still lacking. In intractable cases, ablation of the atrioventricular junction and placement of a permanent pacemaker is a treatment alternative; and biventricular pacing may prevent or reduce the negative consequences of chronic right ventricular pacing.

Cell-based therapy for myocardial repair in patients with acute myocardial infarction: rationale and study design of the SWiss multicenter Intracoronary Stem cells Study in Acute Myocardial Infarction (SWISS-AMI)

Recent studies report that intracoronary administration of autologous bone marrow mononucleated cells (BM-MNCs) may improve remodeling of the left ventricle after acute myocardial infarction (AMI). Subgroup analysis suggest that early treatment between days 4 and 7 after AMI is probably most effective; however, the optimal time point of intracoronary cell administration has never been addressed in clinical trials. Furthermore, reliable clinical predictors are lacking for identifying patients who are thought to have most benefit from cellular therapy.

A protective antiarrhythmic role of ursodeoxycholic acid in an in vitro rat model of the cholestatic fetal heart

Intrahepatic cholestasis of pregnancy may be complicated by fetal arrhythmia, fetal hypoxia, preterm labor, and, in severe cases, intrauterine death. The precise etiology of fetal death is not known. However, taurocholate has been demonstrated to cause arrhythmia and abnormal calcium dynamics in cardiomyocytes. To identify the underlying reason for increased susceptibility of fetal cardiomyocytes to arrhythmia, we studied myofibroblasts (MFBs), which appear during structural remodeling of the adult diseased heart. In vitro, they depolarize rat cardiomyocytes via heterocellular gap junctional coupling. Recently, it has been hypothesized that ventricular MFBs might appear in the developing human heart, triggered by physiological fetal hypoxia. However, their presence in the fetal heart (FH) and their proarrhythmogenic effects have not been systematically characterized. Immunohistochemistry demonstrated that ventricular MFBs transiently appear in the human FH during gestation. We established two in vitro models of the maternal heart (MH) and FH, both exposed to increasing doses of taurocholate. The MH model consisted of confluent strands of rat cardiomyocytes, whereas for the FH model, we added cardiac MFBs on top of cardiomyocytes. Taurocholate in the FH model, but not in the MH model, slowed conduction velocity from 19 to 9 cm/s, induced early after depolarizations, and resulted in sustained re-entrant arrhythmias. These arrhythmic events were prevented by ursodeoxycholic acid, which hyperpolarized MFB membrane potential by modulating potassium conductance. CONCLUSION: These results illustrate that the appearance of MFBs in the FH may contribute to arrhythmias. The above-described mechanism represents a new therapeutic approach for cardiac arrhythmias at the level of MFB.

Gender differences of atrial and ventricular remodeling and autonomic tone in nonelite athletes

Veteran endurance athletes have an increased risk of developing atrial fibrillation (AF), with a striking male predominance. We hypothesized that male athletes were more prone to atrial and ventricular remodeling and investigated the signal-averaged P wave and factors that promote the occurrence of AF. Nonelite athletes scheduled to participate in the 2010 Grand Prix of Bern, a 10-mile race, were invited. Of the 873 marathon and nonmarathon runners who were willing to participate, 68 female and 70 male athletes were randomly selected. The runners with cardiovascular disease or elevated blood pressure (>140/90 mm Hg) were excluded. Thus, 121 athletes were entered into the final analysis. Their mean age was 42 ± 7 years. No gender differences were found for age, lifetime training hours, or race time. The male athletes had a significantly longer signal-averaged P-wave duration (136 ± 12 vs 122 ± 10 ms; p <0.001). The left atrial volume was larger in the male athletes (56 ± 13 vs 49 ± 10 ml; p = 0.001), while left atrial volume index showed no differences (29 ± 7 vs 30 ± 6 ml/m²; p = 0.332). In male athletes, the left ventricular mass index (107 ± 17 vs 86 ± 16 g/m²; p <0.001) and relative wall thickness (0.44 ± 0.06 vs 0.41 ± 0.07; p = 0.004) were greater. No differences were found in the left ventricular ejection fraction (63 ± 4% vs 66 ± 6%; p = 0.112) and mitral annular tissue Doppler e' velocity (10.9 ± 1.5 vs 10.6 ± 1.5 cm/s; p = 0.187). However, the tissue Doppler a' velocity was higher (8.7 ± 1.2 vs 7.6 ± 1.3 cm/s; p < 0.001) in the male athletes. Male athletes had a higher systolic blood pressure at rest (123 ± 9 vs 110 ± 11 mm Hg; p < 0.001) and at peak exercise (180 ± 15 vs 169 ± 19 mm Hg; p = 0.001). In the frequency domain analysis of heart rate variability, the sympatho-vagal balance, represented by the low/high-frequency power ratio, was significantly greater in male athletes (5.8 ± 2.8 vs 3.9 ± 1.9; p < 0.001). Four athletes (3.3%) had at least one documented episode of paroxysmal AF, all were men (p = 0.042). In conclusion, for a comparable amount of training and performance, male athletes showed a more pronounced atrial remodeling, a concentric type of ventricular remodeling, and an altered diastolic function. A higher blood pressure at rest and during exercise and a higher sympathetic tone might be causal. The altered left atrial substrate might facilitate the occurrence of AF.

Continuous flow left ventricular assist devices: a valid option for heart failure patients

Recent outstanding clinical advances with new mechanical circulatory systems (MCS) have led to additional strategies in the treatment of end stage heart failure (HF). Heart transplantation (HTx) can be postponed and for certain patients even replaced by smaller implantable left ventricular assist devices (LVAD). Mechanical support of the failing left ventricle enables appropriate hemodynamic stabilisation and recovery of secondary organ failure, often seen in these severely ill patients. These new devices may be of great help to bridge patients until a suitable cardiac allograft is available but are also discussed as definitive treatment for patients who do not qualify for transplantation. Main indications for LVAD implantation are bridge to recovery, bridge to transplantation or destination therapy. LVAD may be an important tool for patients with an expected prolonged period on the waiting list, for instance those with blood group 0 or B, with a body weight over 90 kg and those with potentially reversible secondary organ failure and pulmonary artery hypertension. However, LVAD implantation means an additional heart operation with inherent peri-operative risks and complications during the waiting period. Finally, cardiac transplantation in patients with prior implantation of a LVAD represents a surgical challenge. This review summarises the current knowledge about LVAD and continuous flow devices especially since the latter have been increasingly used worldwide in the most recent years. The review is also based on the institutional experience at Berne University Hospital between 2000 and 2012. Apart from short-term devices (Impella, Cardiac Assist, Deltastream and ECMO) which were used in approximately 150 cases, 85 pulsatile long-term LVAD, RVAD or bi-VAD and 44 non-pulsatile LVAD (mainly HeartMateII and HeartWare) were implanted. After an initial learning curve, one-year mortality dropped to 10.4% in the last 58 patients.

Cardiac G-protein-coupled receptor kinase 2 ablation induces a novel Ca2+ handling phenotype resistant to adverse alterations and remodeling after myocardial infarction

G-protein-coupled receptor kinase 2 (GRK2) is a primary regulator of β-adrenergic signaling in the heart. G-protein-coupled receptor kinase 2 ablation impedes heart failure development, but elucidation of the cellular mechanisms has not been achieved, and such elucidation is the aim of this study.

Long-term cardiac remodeling and arrhythmias in nonelite marathon runners

Long-term endurance sports are associated with atrial remodeling and atrial arrhythmias. More importantly, high-level endurance training may promote right ventricular (RV) dysfunction and complex ventricular arrhythmias. We investigated the long-term consequences of marathon running on cardiac remodeling as a potential substrate for arrhythmias with a focus on the right heart. We invited runners of the 2010 Grand Prix of Bern, a 10-mile race. Of 873 marathon and nonmarathon runners who applied, 122 (61 women) entered the final analysis. Subjects were stratified according to former marathon participations: control group (nonmarathon runners, n = 34), group 1 (1 marathon to 5 marathons, mean 2.7, n = 46), and group 2 (≥6 marathons, mean 12.8, n = 42). Mean age was 42 ± 7 years. Results were adjusted for gender, age, and lifetime training hours. Right and left atrial sizes increased with marathon participations. In group 2, right and left atrial enlargements were present in 60% and 74% of athletes, respectively. RV and left ventricular (LV) dimensions showed no differences among groups, and RV or LV dilatation was present in only 2.4% or 4.3% of marathon runners, respectively. In multiple linear regression analysis, marathon participation was an independent predictor of right and left atrial sizes but had no effect on RV and LV dimensions and function. Atrial and ventricular ectopic complexes during 24-hour Holter monitoring were low and equally distributed among groups. In conclusion, in nonelite athletes, marathon running was not associated with RV enlargement, dysfunction, or ventricular ectopy. Marathon running promoted biatrial remodeling.

Echocardiogram versus cardiac magnetic resonance imaging for assessing systolic function of subaortic right ventricle in adults with complete transposition of great arteries and previous atrial switch operation

In adults with congenital heart disease and a systemic right ventricle, subaortic ventricular systolic dysfunction is common. Echocardiographic assessment of systolic right ventricular (RV) function in these patients is important but challenging. The aim of the present study was to assess the reliability of conventional echocardiographic RV functional parameters to quantify the systolic performance of a subaortic right ventricle. We compared 56 contemporary echocardiograms and cardiac magnetic resonance studies in 37 adults, aged 26.9 ± 7.4 years, with complete transposition and a subaortic right ventricle. The fractional area change (FAC), lateral tricuspid annular plane systolic excursion, lateral RV systolic motion velocities by tissue Doppler, RV myocardial performance index, and the rate of systolic RV pressure increase (dp/dt) measured across the tricuspid regurgitant jet were assessed by echocardiography and correlated with the cardiac magnetic resonance-derived RV ejection fraction (EF). The mean RVEF was 48.0 ± 7.8%. FAC (r(2) = 0.206, p = 0.001) and dp/dt (r(2) = 0.173, p = 0.009) significantly correlated with RVEF, and the other nongeometric echocardiographic parameters failed to show a significant correlation with RVEF by linear regression analysis. FAC <33% and dp/dt <1,000 mm Hg/s identified a RVEF of <50% with a sensitivity of 77% and 69% and a specificity of 58% and 87%, respectively. In conclusion, in patients with a systemic right ventricle, routine nongeometric echocardiographic parameters of RV function correlated weakly with cardiac magnetic resonance-derived EF. RV FAC and the measurement of the rate of systolic RV pressure increase (dp/dt) should be preferentially used to assess systemic systolic function in adult patients with a subaortic right ventricle.

Energy harvesting from the beating heart by a mass imbalance oscillation generator

Energy-harvesting devices attract wide interest as power supplies of today's medical implants. Their long lifetime will spare patients from repeated surgical interventions. They also offer the opportunity to further miniaturize existing implants such as pacemakers, defibrillators or recorders of bio signals. A mass imbalance oscillation generator, which consists of a clockwork from a commercially available automatic wrist watch, was used as energy harvesting device to convert the kinetic energy from the cardiac wall motion to electrical energy. An MRI-based motion analysis of the left ventricle revealed basal regions to be energetically most favorable for the rotating unbalance of our harvester. A mathematical model was developed as a tool for optimizing the device's configuration. The model was validated by an in vitro experiment where an arm robot accelerated the harvesting device by reproducing the cardiac motion. Furthermore, in an in vivo experiment, the device was affixed onto a sheep heart for 1 h. The generated power in both experiments-in vitro (30 μW) and in vivo (16.7 μW)-is sufficient to power modern pacemakers.

Do women have impaired regional systolic function in hypertensive heart disease? A 3-dimensional echocardiography study

AIMS: In pressure overload left ventricular (LV) hypertrophy, gender-related differences in global LV systolic function have been previously reported. The goal of this study was to determine regional systolic function of the left ventricle in male and female patients with hypertensive heart disease. METHODS AND RESULTS: Regional LV function was analyzed from multiplane transesophageal echocardiography with three-dimensional (3D) reconstruction of the left ventricle. In 24 patients (13 males and 11 females), four parallel (2 basal and 2 apical) equidistant short axis cross-sections from base to apex were obtained from the reconstructed LV. In each short axis 24 wall-thickness measurements were carried out at 15 degrees intervals at end-diastole and end-systole. Thus, a total of 192 measurements were obtained in each patient. Wall thickening was calculated as difference of end-diastolic and end-systolic wall thickness, and fractional thickening as thickening divided by end-diastolic thickness. Fractional thickening and wall stress were inversely related to end-diastolic wall thickness in both, males and females. Females showed less LV systolic function when compared to males (p<0.001). However, when corrected for wall stress, which was higher in females, there was no gender difference in systolic function. CONCLUSION: There are regional differences in LV systolic function in females and males which are directly related to differences in wall stress. Thus, gender-related differences in LV regional function are load-dependent and not due to structural differences.