Myocardial injection of skeletal myoblasts impairs contractility of host cardiomyocytes

BACKGROUND: Mechanisms underlying improvement of myocardial contractile function after cell therapy as well as arrhythmic side effect remain poorly understood. We hypothesised that cell therapy might affect the mechanical properties of isolated host cardiomyocytes. METHODS: Two weeks after myocardial infarction (MI), rats were treated by intramyocardial myoblast injection (SkM, n=8), intramyocardial vehicle injection (Medium, n=6), or sham operation (Sham, n=7). Cardiac function was assessed by echocardiography. Cardiomyocytes were isolated in a modified Langendorff perfusion system, their contraction was measured by video-based inter-sarcomeric analysis. Data were compared with a control-group without myocardial infarction (Control, n=5). RESULTS: Three weeks post-treatment, ejection fraction (EF) further deteriorated in vehicle-injected and non-injected rats (respectively 40.7+/-11.4% to 33+/-5.5% and 41.8+/-8% to 33.5+/-8.3%), but was stabilised in SkM group (35.9+/-6% to 36.4+/-9.7%). Significant cell hypertrophy induced by MI was maintained after cell therapy. Single cell contraction (dL/dt(max)) decreased in SkM and vehicle groups compared to non-injected group as well as cell shortening and relaxation (dL/dt(min)) in vehicle group. A significantly increased predisposition for alternation of strong and weak contractions was observed in isolated cardiomyocytes of the SkM group. CONCLUSION: Our study provides the first evidence that injection of materials into the myocardium alters host cardiomyocytes contractile function independently of the global beneficial effect of the heart function. These findings may be important in understanding possible adverse effects.

Right ventricular systolic function and cardiac resynchronization therapy

AIMS: The effect of cardiac resynchronization therapy (CRT) on right ventricular ejection fraction (RVEF) has not been well studied. Furthermore, it is unclear whether baseline RVEF influences response to CRT. To evaluate the acute and chronic effects of CRT on right ventricular systolic function, and to investigate whether baseline RVEF impacts response to CRT. METHODS AND RESULTS: Forty-four patients with a standard indication for CRT underwent radionuclide angiography at baseline and after at least 6 months' follow-up for measuring RVEF, right ventricular synchrony (using phase analysis), and left ventricular ejection fraction (LVEF). In addition, NYHA functional class and 6-min walking distance (6MWD) were evaluated. There were no significant acute changes in RVEF with CRT. After a mean follow-up of 9 +/- 5 months, RVEF was slightly improved (by 1.9 +/- 5.0% in absolute terms, P = 0.016), and to a lesser extent than LVEF (5.1 +/- 9.0%, P = 0.009 compared with RVEF). Right ventricular dyssynchrony was significantly improved at follow-up (P = 0.016). Patients with a baseline RVEF < or = 0.35 (n = 19) were less likely to improve in NYHA class (P = 0.016), and also tended to improve less in 6MWD and LVEF (P < 0.06). CONCLUSION: Cardiac resynchronization therapy has no acute effect on RVEF, and only slightly improves RVEF at follow-up. Patients with reduced RVEF at baseline were less likely to respond to CRT, indicating that right ventricular systolic dysfunction may play a role in patient selection.

[Myocardial dysfunction in sepsis]

Myocardial dysfunction appears in 25% of patients with severe sepsis and in 50% of patients with septic shock, even in the presence of hyper dynamic states. It is characterized by a reduction in left ventricle ejection fraction, that reverts at the seventh to tenth day of evolution. Right ventricular dysfunction and diastolic left ventricular dysfunction can also appear. There is no consensus if an increase in end diastolic volume is part of the syndrome. High troponin or brain natriuretic peptide levels are associated with myocardial dysfunction and a higher mortality. The pathogenesis of myocardial dysfunction is related to micro and macro circulatory changes, inflammatory response, oxidative stress, intracellular calcium management disturbances, metabolic changes, autonomic dysfunction, activation of apoptosis, mitochondrial abnormalities and a derangement in catecholaminergic stimulation. Since there is no specific treatment for myocardial dysfunction, its management requires an adequate multi systemic support to maintain perfusion pressures and systemic flows sufficient for the regional and global demands.

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.

Right ventricular systolic function assessment: rank of echocardiographic methods vs. cardiac magnetic resonance imaging

Right ventricular (RV) systolic function is prognostically important, but its assessment by echocardiography remains challenging, in part because of the multitude of available measurement methods. The purpose of this prospective study was to rank these methods against the reference of RV ejection fraction (EF) as obtained in a broad clinical population by magnetic resonance imaging (MRI).

Chronotropic incompetence predicts impaired response to exercise training in heart failure patients in sinus rhythm

Background: In most patients with chronic heart failure (CHF), endurance training improves exercise capacity. However, some patients do not respond favourably. The purpose of this study was to explore the reasons of non-response and to determine their predictive value.Methods: We studied a cohort of 120 consecutive CHF patients with sinus rhythm (mean age 57 ± 12 years, ejection fraction 29.3 ± 9.9%, peak VO2 17.3 ± 5.1 ml/min/kg), participating in a 3-month outpatient cardiac rehabilitation programme. Responders were defined as subjects who improved peak VO2 by more than 5%, work load by more than 10%, or VE/VCO2 slope by more than 5%. Subjects who did not fulfil at least one of the above criteria were characterized as non-responders. Multivariate regression analyses were performed to identify parameters that were predictive for a response. Receiver operating characteristic (ROC) analyses were performed for predictive parameters to identify thresholds for response or non-response.Results: Multivariate regression analyses revealed heart rate (HR) reserve, HR recovery at 1 min, and peak HR as significant predictors for a positive training response. ROC curves revealed the optimal thresholds separating responders from non-responders at less than 30 bpm for HR reserve, less than 6 bpm for HR recovery and less than 101 bpm for peak HR.Conclusions: The presence of impaired chronotropic competence is a major predictor of poor training response in CHF patients with sinus rhythm.

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.

Diastolic dysfunction in human cardiac allografts is related with reduced SERCA2a gene expression

Previous studies demonstrated that impaired left ventricular (LV) relaxation in cardiac allografts limits exercise tolerance post-transplant despite preserved systolic ejection fraction (EF). This study tested in human cardiac allografts whether the isovolumic relaxation time (IVRT), which provides the basis for most of diastolic LV filling, relates with gene expression of regulatory proteins of calcium homeostasis or cardiac matrix proteins. Gene expression was studied in 31 heart transplant recipients (25 male, 6 female) 13-83 months post-transplant with LVEF >50%, LV end-diastolic pressure <20 mmHg, normal LV mass index and without allograft rejection or significant cardiac pathology. IVRT related with the other diastolic parameters e-wave velocity (r = -0.46; p = 0.01), e/a-wave ratio (r = -0.5; p < 0.01) but not with heart frequency (r = -0.16; p = 0.4). No relation of IVRT was observed for immunosuppression, mean rejection grade or other medication. IVRT was not related with gene expression of desmin, collagen I, phospholamban, the Na+-Ca2+ exchanger, the ryanodine receptor or interstitial fibrosis but correlated inversely with SERCA2a (r = -0.48; p = 0.02). Prolonged IVRT is associated with decreased SERCA2a expression in cardiac allografts without significant other pathology. Similar observations in non-transplanted patients with diastolic failure suggest that decreased SERCA2a expression is an important common pathomechanism.

Safety and exercise tolerance of acute high altitude exposure (3454 m) among patients with coronary artery disease

OBJECTIVES: To assess the safety and cardiopulmonary adaptation to high altitude exposure among patients with coronary artery disease. METHODS: 22 patients (20 men and 2 women), mean age 57 (SD 7) years, underwent a maximal, symptom limited exercise stress test in Bern, Switzerland (540 m) and after a rapid ascent to the Jungfraujoch (3454 m). The study population comprised 15 patients after ST elevation myocardial infarction and 7 after a non-ST elevation myocardial infarction 12 (SD 4) months after the acute event. All patients were revascularised either by percutaneous coronary angioplasty (n = 15) or by coronary artery bypass surgery (n = 7). Ejection fraction was 60 (SD 8)%. beta blocking agents were withheld for five days before exercise testing. RESULTS: At 3454 m, peak oxygen uptake decreased by 19% (p < 0.001), maximum work capacity by 15% (p < 0.001) and exercise time by 16% (p < 0.001); heart rate, ventilation and lactate were significantly higher at every level of exercise, except at maximum exertion. No ECG signs of myocardial ischaemia or significant arrhythmias were noted. CONCLUSIONS: Although oxygen demand and lactate concentrations are higher during exercise at high altitude, a rapid ascent and submaximal exercise can be considered safe at an altitude of 3454 m for low risk patients six months after revascularisation for an acute coronary event and a normal exercise stress test at low altitude.

Impact of left ventricular hypertrophy late after aortic valve replacement for aortic stenosis on cardiovascular morbidity and mortality

AIMS: The goal of this study was to assess the prevalence of left ventricular (LV) hypertrophy in patients with aortic stenosis late (>6 months) after aortic valve replacement and its impact on cardiac-related morbidity and mortality. METHODS AND RESULTS: In a single tertiary centre, echocardiographic data of LV muscle mass were collected. Detailed information of medical history and angiographic data were gathered. Ninety-nine of 213 patients (46%) had LV hypertrophy late (mean 5.8 +/- 5.4 years) after aortic valve replacement. LV hypertrophy was associated with impaired exercise capacity, higher New York Heart Association dyspnoea class, a tendency for more frequent chest pain expressed as higher Canadian Cardiovascular Society class, and more rehospitalizations. 24% of patients with normal LV mass vs. 39% of patients with LV hypertrophy reported cardiac-related morbidity (p = 0.04). In a multivariate logistic regression model, LV hypertrophy was an independent predictor of cardiac-related morbidity (odds ratio 2.31, 95% CI 1.08 to 5.41), after correction for gender, baseline ejection fraction, and coronary artery disease and its risk factors. Thirty seven deaths occurred during a total of 1959 patient years of follow-up (mean follow-up 9.6 years). Age at aortic valve replacement (hazard ratio 1.85, 95% CI 1.39 to 2.47, for every 5 years increase in age), coexisting coronary artery disease at the time of surgery (hazard ratio 3.36, 95% CI 1.31 to 8.62), and smoking (hazard ratio 4.82, 95% CI 1.72 to 13.45) were independent predictors of overall mortality late after surgery, but not LV hypertrophy. CONCLUSIONS: In patients with aortic valve replacement for isolated aortic stenosis, LV hypertrophy late after surgery is associated with increased morbidity.

Myoblast-seeded biodegradable scaffolds to prevent post-myocardial infarction evolution toward heart failure

OBJECTIVE(S): Even though the mechanism is not clearly understood, direct intramyocardial cell transplantation has demonstrated potential to treat patients with severe heart failure. We previously reported on the bioengineering of myoblast-based constructs. We investigate here the functional outcome of infarcted hearts treated by implantation of myoblast-seeded scaffolds. METHODS: Adult Lewis rats with echocardiography-confirmed postinfarction reduced ejection fraction (48.3% +/- 1.1%) were randomized to (1) implantation of myoblast-seeded polyurethane patches at the site of infarction (PU-MyoB, n = 11), (2) implantation of nonseeded polyurethane patches (PU, n = 11), (3) sham operation (Sham, n = 12), and (4) direct intramyocardial myoblast injection (MyoB, n = 11). Four weeks later, the functional assessment by echocardiography was repeated, and we additionally performed left ventricular catheterization plus histologic studies. RESULTS: The ejection fraction significantly decreased in the PU (39.1% +/- 2.3%; P = .02) and Sham (39.9% +/- 3.5%; P = .04) groups, whereas it remained stable in the PU-MyoB (48.4% +/- 3.1%) and MyoB (47.9% +/- 3.0%) groups during the observation time. Similarly, left ventricular contractility was significantly higher in groups PU-MyoB (4960 +/- 266 mm Hg/s) and MyoB (4748 +/- 304 mm Hg/s) than in groups PU (3909 +/- 248 mm Hg/s, P = .01) and Sham (4028 +/- 199 mm Hg/s, P = .01). Immunohistology identified a high density of myoblasts within the seeded scaffolds without any migration toward the host cardiac tissue and no evidence of cardiac cell differentiation. CONCLUSIONS: Myoblast-seeded polyurethane scaffolds prevent post-myocardial infarction progression toward heart failure as efficiently as direct intramyocardial injection. The immunohistologic analysis suggests that an indirect mechanism, potentially a paracrine effect, may be assumed.

Prostaglandin E1 testing in heart failure-associated pulmonary hypertension enables transplantation: the PROPHET study

BACKGROUND: Elevated pulmonary vascular resistance (PVR) is relevant to prognosis of congestive heart failure and heart transplantation. Proof of reversibility by pharmacologic testing in potential transplantation candidates is important because it indicates a reduced probability of right ventricular failure or death in the early post-transplant period. This study aimed to clarify the possible extent of acute reversibility of elevated PVR in a large, consecutive cohort of heart transplant candidates. METHODS: This study included 208 consecutive patients (age 52 +/- 10 years, 89% men and 11% women, ejection fraction 21 +/- 9%, Vo2max 12.6 +/- 4.2 ml/kg/min) being evaluated for heart transplantation in 7 transplant centers in Germany and Switzerland. Testing was performed with increasing intravenous doses of prostaglandin E1 (PGE1; average maximum dose 173 +/- 115 ng/kg/min for at least 10 minutes) in 92 patients exhibiting a baseline PVR of > 2.5 Wood units (WU) and/or a transpulmonary gradient (TPG) of > 12 mm Hg. RESULTS: PGE1 testing lowered PVR from 4.1 +/- 2.0 to 2.1 +/- 1.1 WU (p < 0.01), increased cardiac output from 3.8 +/- 1.0 to 5.0 +/- 1.5 liters/min (p < 0.01), and decreased TPG from 14 +/- 4 to 10 +/- 3 mm Hg (p < 0.01), mean pulmonary artery pressure (PAM) from 39 +/- 9 to 29 +/- 9 mm Hg (p < 0.01) and mean pulmonary capillary wedge pressure (PCWP) from 24 +/- 7 to 19 +/- 9 mm Hg (p < 0.01). Mean aortic pressure (MAP) decreased to 85% and systemic vascular resistance (SVR) to 65% of baseline values (p < 0.01). Symptomatic systemic hypotension was not observed. For the whole population the percentage of patients with PVR > 2.5 WU was reduced from 44.2% to 10.5% with PGE1. PVR decreased in each patient; only 2 patients (1%) remained ineligible for listing because of a final PVR of > 4.0 WU. TPG, ejection fraction and male gender were independent predictors of reversibility of PVR. CONCLUSIONS: Elevated PVR in heart transplant candidates is highly reversible and can be normalized during acute pharmacologic testing with PGE1.

Effects of percutaneous coronary interventions in silent ischemia after myocardial infarction: the SWISSI II randomized controlled trial

CONTEXT: The effect of a percutaneous coronary intervention (PCI) on the long-term prognosis of patients with silent ischemia after a myocardial infarction (MI) is not known. OBJECTIVE: To determine whether PCI compared with drug therapy improves long-term outcome of asymptomatic patients with silent ischemia after an MI. DESIGN, SETTING, AND PARTICIPANTS: Randomized, unblinded, controlled trial (Swiss Interventional Study on Silent Ischemia Type II [SWISSI II]) conducted from May 2, 1991, to February 25, 1997, at 3 public hospitals in Switzerland of 201 patients with a recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease. Follow-up ended on May 23, 2006. INTERVENTIONS: Percutaneous coronary intervention aimed at full revascularization (n = 96) or intensive anti-ischemic drug therapy (n = 105). All patients received 100 mg/d of aspirin and a statin. MAIN OUTCOME MEASURES: Survival free of major adverse cardiac events defined as cardiac death, nonfatal MI, and/or symptom-driven revascularization. Secondary measures included exercise-induced ischemia and resting left ventricular ejection fraction during follow-up. RESULTS: During a mean (SD) follow-up of 10.2 (2.6) years, 27 major adverse cardiac events occurred in the PCI group and 67 events occurred in the anti-ischemic drug therapy group (adjusted hazard ratio, 0.33; 95% confidence interval, 0.20-0.55; P<.001), which corresponds to an absolute event reduction of 6.3% per year (95% confidence interval, 3.7%-8.9%; P<.001). Patients in the PCI group had lower rates of ischemia (11.6% vs 28.9% in patients in the drug therapy group at final follow-up; P = .03) despite fewer drugs. Left ventricular ejection fraction remained preserved in PCI patients (mean [SD] of 53.9% [9.9%] at baseline to 55.6% [8.1%] at final follow-up) and decreased significantly (P<.001) in drug therapy patients (mean [SD] of 59.7% [11.8%] at baseline to 48.8% [7.9%] at final follow-up). CONCLUSION: Among patients with recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease, PCI compared with anti-ischemic drug therapy reduced the long-term risk of major cardiac events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00387231.

Outcome of elderly patients undergoing primary percutaneous coronary intervention for acute ST-elevation myocardial infarction

AIM: To investigate the outcome of primary percutaneous coronary interventions (PCI) in elderly patients (>/=>/=75 years) with ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Between 1995 and 2003, a total of 319 consecutive patients with acute ST-elevation myocardial infarction presenting within 6-12 hr after onset of symptoms were prospectively enrolled in a registry. Of 296 patients undergoing primary PCI, 40 patients were >/=>/=75 years old (group A) and 256 patients younger than 75 years (group B). Elderly patients presented with a lower ejection fraction (49 +/- 14% vs. 53 +/- 13%, P = 0.046) and a higher number of cardiovascular risk factors. PCI success was achieved in 80% (group A) and 91% (group B, P = 0.031), respectively with comparable door-to-balloon times (87 +/- 49 and 95 +/- 79 min, P = ns). Periprocedural complications in both groups were low and major adverse cardiac events (death, myocardial infarction, target vessel revascularization and cardiac rehospitalization) after 6 months amounted to 23% (group A) and 20% (group B, P = ns), respectively. CONCLUSIONS: Clinical outcome of elderly patients (>/=>/=75 years) with acute STEMI is favorable and comparable with the middle-aged population. However, procedural success was significantly lower in elderly (80%) compared to younger patients (90%). Acute percutaneous coronary intervention appears to be safe and not associated with higher periprocedural complications, in elderly patients.

Admission glycaemia and outcome in patients with acute coronary syndrome

Some studies of patients with acute myocardial infarction have reported that hyperglycaemia at admission may be associated with a worse outcome. This study sought to evaluate the association of blood glucose at admission with the outcome of unselected patients with acute coronary syndrome (ACS). Using the Acute Myocardial Infarction and unstable angina in Switzerland (AMIS Plus) registry, ACS patients were stratified according to their blood glucose on admission: group 1: 2.80-6.99 mmol/L, group 2: 7.00-11.09 mmol/L and group 3: > 11.10 mmol/L. Odds ratios for in-hospital mortality were calculated using logistic regression models. Of 2,786 patients, 73% were male and 21% were known to have diabetes. In-hospital mortality increased from 3% in group 1 to 7% in group 2 and to 15% in group 3. Higher glucose levels were associated with larger enzymatic infarct sizes (p<0.001) and had a weak negative correlation with angiographic or echographic left ventricular ejection fraction. High admission glycaemia in ACS patients remains a significant independent predictor of in-hospital mortality (adjusted OR 1.08; 95% confidence intervals [CI] 1.05-1.14, p<0.001) per mmol/L. The OR for in-hospital mortality was 1.04 (95% CI 0.99-1.1; p=0.140) per mmol/L for patients with diabetes but 1.21 (95% CI 112-1.30; p<0.001) per mmol/L for non-diabetic patients. In conclusion, elevated glucose level in ACS patients on admission is a significant independent predictor of in-hospital mortality and is even more important for patients who do not have known diabetes.