The left atrium: from the research laboratory to the clinic.

Studies of left atrial (LA) function, until the latter part of the 20th century, were mostly limited to experimental animal models and to studies related to clinical research in the cardiac catheterization laboratory. For this reason, LA function has received considerably less attention than left ventricular (LV) functions, even though evidence suggests that LA myopathy and failure may exist as an isolated entity, precede and/or coexist with LV myopathy. The introduction of echocardiography and Doppler echocardiography in clinical practice has contributed significantly to our understanding of LA function and its interrelationships with the LV, aorta, pulmonary artery and other parts of the cardiovascular system. In addition, LA with the secretion of atrial natriuretic peptides is playing an important role in cardiovascular and neurohumoral homeostasis. Today, it is well known that LA structural and functional abnormalities that are present in many diseases and disorders constitute a powerful prognostic indicator. As technology (echocardiography, magnetic resonance imaging, computed tomography and others) continues to evolve, it is expected that, in the near future, LA structure and function will be routinely used as LV function is used today.

Exercise-induced changes of B-type natriuretic peptide uncover the unknown coronary artery disease in patients with chest pain and normal left ventricular systolic function.

AIM: The diagnostic and prognostic utility of B-type natriuretic peptide (BNP) has been shown in patients either with heart failure or with known coronary artery disease (CAD). We aimed to investigate the utility of the exercise-induced changes of BNP in patients with chest pain, unknown CAD, and normal left ventricular systolic function. METHODS: We evaluated 100 consecutive patients (mean age 58.7 ± 9 years) (80% male) with left ventricular ejection fraction of more than 50%. Blood samples were collected and BNP was measured before exercise stress testing, at peak, and 20 min after it. All patients underwent coronary artery angiography. We used univariate and multivariate logistic regression analysis. RESULTS: An increment in BNP values of 1.3 fold (from before to peak exercise BNP values) have 11 times greater odds of having CAD [odds ratio (OR): 11.45 with 95% confidence interval (CI): 3.48­37.66, P < 0.001]. Receiver operating curve analysis revealed a sensitivity of 81.8% and a specificity of 71.8%. Multivariate analysis revealed that BNP increment from before to peak exercise remained statistically significant regardless of the presence of other risk factors for atherosclerosis (OR: 18.59 with 95% CI: 4.14­83.45, P < 0.001). Interestingly, patients showing 1.79 times increment of before to peak exercise BNP values have 19 times greater odds of having multivessel disease (OR: 19.28 with 95% CI: 4.95­75.17, P < 0.001) with a sensitivity of 81% and specificity of 81.8%. CONCLUSION: The exercise-induced changes of BNP in patients with chest pain, normal left ventricular systolic function, and unknown CAD may uncover patients with CAD and discriminate those with angiographically severe one.

Simvastatin in contrast to postconditioning reduces infarct size in hyperlipidemic rabbits: possible role of oxidative/nitrosative stress attenuation.

Postconditioning (POC) reduces lethal reperfusion injury under normal conditions, but its effectiveness under certain pathological states is in dispute. In the present study, we sought to determine the effect of chronic simvastatin treatment in hyperlipidemic animals with or without POC. Anesthetized rabbits were randomized into eight groups, as follows, and were subjected to 30-min myocardial ischemia followed by 3-h reperfusion. Normally fed animals: a Control group with no additional intervention, a Sim group treated with simvastatin for 3 weeks at a dose of 3 mg kg(-1), a POC group subjected to POC with eight cycles of 30-s ischemia/reperfusion, a Sim-POC group treated with simvastatin, and POC. Cholesterol fed (6 weeks) animals: a Chol group with no additional interventions, a Chol-Sim group treated with simvastatin for 3 weeks, a Chol-POC group subjected to POC, and a Chol-Sim-POC group treated with simvastatin and POC. Infarct size and plasma levels of malondialdehyde (MDA), nitrotyrosine (NT), NOx, total cholesterol, and LDL were evaluated. In a second series of experiments, heart tissue samples were taken for MDA, NT, and NOx assessment. Infarct size, circulating MDA, NT, NOx and cardiac MDA, NT, and NOx levels declined in POC and all Sim groups compared with Control, Chol, and Chol-POC (p < 0.05). Simvastatin also reduced total cholesterol and LDL plasma levels. In conclusion, a 3-week simvastatin treatment limits the infarct size and attenuates the oxidative and nitrosative stress both in normo- and in hyper-cholesterolemic rabbits subjected to ischemia-reperfusion irrespective of the presence of POC, while POC is effective only in normocholesterolemic animals.

Two-dimensional strain analysis in patients with hypertrophic cardiomyopathy and normal systolic function: a 12-month follow-up study.

BACKGROUND: Although left ventricular (LV) and left atrial (LA) echo indices may reliably reflect loading conditions in patients with hypertrophic cardiomyopathy (HCM), little is known about 2-dimensional strain imaging. We evaluated LV and LA 2-dimensional strain imaging in relation to long-term outcome in patients with HCM. METHODS: Fifty consecutive patients (58% men, aged 51 +/- 18 years) with familial HCM and normal LV ejection fraction underwent 2-dimensional LV and LA strain imaging; total LA strain was defined as the sum of maximum positive and maximum negative atrial strain. Patients were followed up for 12 months for cardiovascular events, defined as death or hospitalization for cardiovascular causes. RESULTS: Twenty patients (40%) experienced an event after a median time of 98 days: 2 (4%) died and 18 (36%) were hospitalized. In multivariate analysis, total LA strain was the strongest predictor of 12-month outcome (odds ratio 0.858, 95% CI 0.771-0.954, P = .005); a cutoff of 21% predicted events with 90% sensitivity and 86% specificity. Total LA strain was also an independent predictor of atrial fibrillation requiring hospitalization (odds ratio 0.853, 95% CI 0.748-0.972, P = .017). CONCLUSIONS: In patients with HCM and normal systolic function, total LA strain predicts 12-month outcome in terms of death and/or hospitalization.

Self-assessment of health status is associated with inflammatory activation and predicts long-term outcomes in chronic heart failure.

AIMS: Clinicians lack a generally accepted means for health status assessment in chronic heart failure (CHF). We investigated the correlation between health status and inflammation burden as well as its long-term prognostic value in CHF outpatients. METHODS AND RESULTS: Kansas City Cardiomyopathy Questionnaires (KCCQ) were completed by 137 CHF outpatients (aged 64+/-12 years, mean ejection fraction 27+/-7%). Inflammatory markers [interleukin (IL)-6, IL-10, TNF-alpha, soluble Fas, Fas ligand, ICAM-1, VCAM-1], plasma B-type natriuretic peptide (BNP), 6 min walk test (6MWT), Zung self-rating depression scale, and Beck Depression Inventory were also assessed. Patients were followed for major cardiovascular events (death or hospitalization for disease progression) for up to 250 days. Patients with worse KCCQ-summary (KCCQ-s<50) score had lower 6MWT (P<0.05), and higher BNP (P<0.05) and pro-inflammatory markers (P<0.05) than those with KCCQ-s>or=50. Worse health status was also associated with shorter event-free survival (115+/-12 days for KCCQ-s<50 vs. 214+/-15 days for KCCQ-s>or=50, P=0.0179). Separating patients according KCCQ-functional score (KCCQ-f, cut-off 50) showed similar results. In multivariate Cox regression analysis, only LVEF (HR=0.637, 95% CI 0.450-0.900, P=0.011) and KCCQ-f (HR=0.035, 95% CI 0.002-0.824, P=0.037) were independent predictors of event-free survival at 250 days. CONCLUSION: KCCQ-s reflects neurohormonal and inflammatory burden in CHF. Among studied questionnaires, only KCCQ-f is an independent predictor of long-term event-free survival in CHF.

The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy.

AIMS: To investigate whether genetic variants of the histidine-rich calcium (HRC)-binding protein are associated with idiopathic dilated cardiomyopathy (DCM) and its progression. METHODS AND RESULTS: We screened 123 idiopathic DCM patients and 96 healthy individuals by single-strand conformation polymorphism analysis and direct sequencing for genetic variants in HRC. Six polymorphisms were detected: Leu35Leu (A/G), Ser43Asn (G/A), Ser96Ala (T/G), Glu202_Glu203insGlu (-/GAG), Asp261del (GAT/-), and an in-frame insertion of 51 amino acids at His321. The analysis of their frequencies did not reveal any significant correlation with DCM development. However, the Ser96Ala polymorphism exhibited a statistically significant correlation with the occurrence of life-threatening ventricular arrhythmias. During a follow-up of 4.02 +/- 2.4 years, the risk for ventricular arrhythmias was higher (HR, 9.620; 95% CI, 2.183-42.394; P = 0.003) in the Ala/Ala patients, compared with Ser/Ser homozygous patients. On multivariable Cox regression analysis, the Ser96Ala polymorphism was the only significant genetic arrythmogenesis predictor in DCM patients (HR, 4.191; 95% CI, 0.838-20.967; P = 0.018). CONCLUSION: The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of DCM.

Opposite relations of epicardial adipose tissue to left atrial size in paroxysmal and permanent atrial fibrillation.

OBJECTIVES: Atrial fibrillation has been associated with obesity in epidemiological studies. Epicardial adipose tissue is an ectopic fat depot in the proximity of atria, with endocrine and inflammatory properties that is implicated in the pathophysiology of atrial fibrillation. Inflammation also has a role in atrial arrhythmogenesis. The aim of this study was to investigate the potential relations of epicardial adipose tissue to left atrial size and to adiponectin and the pro-inflammatory mediators, high-sensitivity C-reactive protein, and interleukin-6 in paroxysmal and permanent atrial fibrillation. METHODS: This was a cross-sectional study of 103 atrial fibrillation patients, divided into two subgroups of paroxysmal and permanent atrial fibrillation, and 81 controls, in sinus rhythm. Echocardiography was used for estimation of epicardial adipose tissue and left atrial size and high-sensitivity C-reactive protein, interleukin-6 and adiponectin were measured in all subjects. RESULTS: Atrial fibrillation patients had significantly larger epicardial adipose tissue compared with controls (0.43 ± 0.17 vs 0.34 ± 0.17 cm, p = 0.002). Atrial fibrillation presence was independently related to epicardial adipose tissue thickness (b = 0.09, p = 0.002). Opposite associations of epicardial adipose tissue with left atrial volume existed in atrial fibrillation subgroups; in the paroxysmal subgroup, epicardial adipose tissue was directly related to left atrial volume (R = 0.3, p = 0.03), but in the permanent one the relation was inverse (R = -0.7, p < 0.0001). Adiponectin, high-sensitivity C-reactive protein and interleukin-6 were elevated in both atrial fibrillation groups. Only interleukin-6 was related to epicardial adipose tissue size. CONCLUSION: Opposite associations of epicardial adipose tissue with left atrial size in paroxysmal and permanent Atrial fibrillation and elevated inflammatory markers, suggest a role of epicardial adipose tissue and inflammation in the fibrotic and remodeling process.

Ventricular long-axis contraction as an earlier predictor of outcome in asymptomatic aortic regurgitation.

The long-term prognostic significance of left ventricular (LV) long-axis contraction was investigated prospectively in 65 consecutive patients aged 58+/-15 years with asymptomatic aortic regurgitation, normal LV ejection fraction at rest, and no coronary artery or aortic root disease. A complete transthoracic echocardiographic study was performed at baseline and 12 months later. In 24 of 65 patients with peak systolic wave velocity at the lateral mitral annulus (LatS)<9 cm/s, LV diameter (p<0.01), volume (por=9 cm/s, none of these parameters was significantly affected during follow-up. Aortic valve replacement was performed in 6 of 24 patients (25%) with peak systolic wave velocity at the lateral mitral annulus<9 cm/s and none with peak systolic wave velocity at the lateral mitral annulus>or=9 cm/s. In patients with peak systolic wave velocity at the lateral mitral annulus<9 cm/s, a cut-off value of 6.25 cm/s predicted aortic valve replacement within the next year with 97% sensitivity and 83% specificity. In conclusion, ventricular long-axis contraction seems to be a reliable indicator for outcome prediction in patients with asymptomatic aortic regurgitation.

Multidimensional contractile reserve predicts adverse outcome in patients with severe systolic heart failure: a 4-year follow-up study.

AIMS: Left ventricular contractile reserve is a prognostic indicator for adverse outcome in patients with severe chronic heart failure with reduced ejection fraction (HFrEF). We investigated the dobutamine-induced changes of LV multidimensional deformation and their predictive value for cardiac mortality of patients with severe chronic HFrEF. METHODS AND RESULTS: In this prospective study, out of 130 patients with severe HFrEF who underwent a low-dose dobutamine stress echocardiography (LDSE) study using speckle tracking imaging, 100 patients were followed up for the occurrence of cardiac death over a period of 4 years. Compared with survivors, non-survivors (n = 32) had lower radial strain (RS) and strain rate (RSR) (10.7 ± 5.9 vs. 20.1 ± 8% and 0.5 ± 0.2 vs. 0.8 ± 0.3 L/s, P < 0.001), a smaller increase of global longitudinal strain (GLS) and strain rate after LDSE (0.9 ± 1.5 vs. -3.3 ± 3.5% and -0.1 ± 0.1 vs. -0.3 ± 0.3 L/s, P < 0.001), and a lack of change in the circumferential and radial deformation. The dobutamine-induced changes of all speckle tracking indices predicted cardiac mortality, while, among resting echocardiographic parameters, only RS and RSR predicted survival, after adjusting for age, sex, cardiomyopathy aetiology, NYHA class, AF, BNP levels, resting LVED, and LV outflow tract velocity-time integral, and their respective changes produced by dobutamine (P < 0.05). The dobutamine-induced change of GLS and resting RS were the best additive predictors of mortality with a net reclassification improvement of 0.518 (P = 0.022) CONCLUSION: In severe chronic HFrEF, resting RS and the dobutamine-induced change of GLS are independent predictors of cardiac mortality.

Deformation Analysis of Myocardial Layers Detects Early Cardiac Dysfunction after Chemotherapy in Bone Marrow Transplantation Patients: A Continuous and Additive Cardiotoxicity Process.

BACKGROUND: Chemotherapy-induced cardiotoxicity has not been extensively validated in bone marrow transplantation (BMT) patients. Speckle-tracking echocardiography is a sensitive method for the detection of subclinical cardiac dysfunction. METHODS: Cardiac function was prospectively assessed in 80 patients (44 men; mean age, 45 ± 11 years) after BMT for non-Hodgkin's lymphoma and acute or chronic myeloid leukemia by means of various echocardiographic techniques. Before chemotherapy for BMT, 89% of the patients had previously been treated with anthracyclines. Patients had normal left ventricular ejection fraction (LVEF). Left ventricular (LV) global longitudinal strain (GLS), subendocardial and subepicardial longitudinal strain, circumferential strain, LV twist, and right ventricular GLS were measured by speckle-tracking, and (2) three-dimensionally derived LVEF and right ventricular ejection fraction were also assessed. Abnormal LVEF was defined as <53%. Studies were performed before (baseline) and 1, 3, 6, and 12 months after chemotherapy conditioning followed by BMT. RESULTS: Impaired LV GLS values were observed at 1 month after chemotherapy and at 3, 6, and 12 months compared with baseline (-20 ± 2.2% at baseline, -18.4 ± 2.1% at 1 month, -17.3 ± 2.2% at 3 months, -17.1 ± 2.1% at 6 months, and -17.1 ± 2.2% at 12 months; P = .001). Early LV GLS changes were driven mostly by changes in subendocardial longitudinal strain (-22.5 ± 2.4% at baseline, -20.5 ± 2.3% at 1 month, -19.2 ± 2.3% at 3 months, -19.2 ± 2.4% at 6 months, and -19.1 ± 2.4 at 12 months; P = .001), whereas significant subepicardial strain changes were observed at 3 months after BMT. Compared with baseline, right ventricular GLS was also impaired early after chemotherapy. Compared with baseline, LVEF was slightly reduced (P = .02) at the end of the follow-up. Among echocardiographic markers, LV GLS at 1 month had the strongest predictive value for abnormal LVEF (<53%) at 12 months (area under the curve 0.86; 95% CI, 0.76-0.96). A cutoff LV GLS value of -18.4% had sensitivity of 84.6% and specificity of 71.9% for the identification of abnormal LVEF at the end of follow-up. CONCLUSIONS: In BMT patients, myocardial deformation analysis detected early and progressive subclinical cardiac dysfunction. Impaired LV GLS had predictive value for the detection of abnormal LVEF at 12-month follow-up. Thus, myocardial deformation study should be applied early after BMT to prevent irreversible cardiac dysfunction by appropriate treatment.

Acute administration of vitamin E triggers preconditioning via K(ATP) channels and cyclic-GMP without inhibiting lipid peroxidation.

Vitamin E (VitE) is considered an antioxidant agent. One or more brief periods of ischemia (isc), followed by short reperfusion (rep), increase the tolerance of the heart to a subsequent prolonged ischemia, a phenomenon known as ischemic preconditioning (PC). Mitochondrial KATP channels (mitoKATP), cyclic-GMP (cGMP), and free radicals are involved in the mechanism of PC, whereas some antioxidants abolish this benefit. The purpose of this study was to evaluate the effect of VitE on infarct size, PC, and the oxidative status in vivo. Male rabbits were divided into seven groups and were subjected to myocardial ischemia (isc) and reperfusion (rep) with the following interventions: (1) control (no intervention); (2) E150 (iv VitE at a dose of 150 mg/kg for 75 min, starting 40 min before index isc and lasting through 5 min of rep); (3) E300 (iv VitE 300 mg/kg as previously described); (4) PC (two cycles of 5 min isc and 10 min rep), (5) combined E150-PC; and (6) combined E300-PC. In the last two groups VitE was given 40 min before index ischemia. Blood samples were taken for malondialdehyde (MDA) and conjugated dienes (CDs) measurement. In a second series of experiments heart tissue samples were taken at the time of long ischemia for MDA and CD determination and for cGMP assay. In order to test whether combined treatment with VitE (as the E150 group) and the mitoKATP blocker 5-hydroxydecanoic acid (5-HD) changes the infarct size, an additional group was assessed in the first series of experiments. Tissue VitE concentration was evaluated in myocardium. VitE at both doses reduced the infarct size (19.7 +/- 2.8% for E150 and 18.8 +/- 4.9% for E300 vs 47.4 +/- 2.6% in control, P < 0.05) without attenuating the effect of PC (10.2 +/- 3.1% for E150-PC, 12.4 +/- 2.2% for E300-PC, vs 13.5 +/- 3.3% for PC). Combined VitE and 5-HD treatment abrogates this benefit (37.4 +/- 6.5%, P < 0.05 vs E150 and NS vs control). VitE increases intracellular cGMP and CDs levels (P < 0.05 vs control) to the same extent as PC (P < 0.05 vs control), with no effect on MDA (P = NS between all the groups). Peripheral markers of oxidative stress are increased during reperfusion in all groups (P < 0.05 vs baseline). Overall, VitE limits infarct size via mitoKATP and cGMP, while preserving the benefit of ischemic PC.

The effectiveness of postconditioning and preconditioning on infarct size in hypercholesterolemic and normal anesthetized rabbits.

BACKGROUND: Postconditioning with multiple very short coronary occlusions immediately after prolonged ischemia is a new endogenous mechanism for protection of the ischemic heart. We tested whether postconditioning is effective in limiting infarct size in hypercholesterolemic rabbits. METHODS: Male rabbits were fed a cholesterol-enriched diet for 6 weeks. Animals were subjected to 30 min of regional ischemia of the heart and 3h of reperfusion with the following additional interventions: Control group no additional intervention, ischemic preconditioning (IPC) group to two cycles of 5 min ischemia separated by 10 min reperfusion before the index ischemia, 6/10 IPostC group to six cycles of 10s ischemia separated by 10s reperfusion and 4/30 IPostC group to four cycles of 30s ischemia separated by 30s reperfusion immediately after the end of the index ischemia. In a second series of experiments the same interventions were applied to animals fed with a normal diet. Infarct size (I) was determined by triphenyltetrazolium chloride staining. RESULTS: The I/R in hypercholesterolemic rabbits was 55.2+/-5.9% in Control, 17.9+/-4.2% in IPC (P<0.01 versus Control), 63.4+/-4.8% in 6/10 IPostC and 55.6+/-8.2% in 4/30 IPostC (P=NS between them and the Control group). In the normal diet rabbits, the I/R was 48.2+/-4.3% in Control, 15.1+/-2.1% in IPC, 20.4+/-2.9% in 6/10 IPostC (P<0.01 versus Control) and 45.1+/-8.9% in 4/30 IPostC (P=NS versus Control). Blood cholesterol levels were increased and atheromatic lesions were present in the first series. CONCLUSION: Postconditioning is ineffective in limiting the infarct size in rabbits with hypercholesterolemia and atherosclerosis while preconditioning continued to be effective under the same conditions.

Familial origin of atrial septal aneurysm.

The familial origin of atrial septal defects has been previously reported. This is the first study describing 2 families with atrial septal aneurysm of familial origin. The present study represents both clinically manifested and silent atrial septal aneurysms. Moreover, female gender predominance is also reported. Based on the presented data it could be suggested that all first-degree relatives of affected patients should be screened by cross-sectional echocardiography, particularly if they are women. In these patients, the use of aspirin might be the first line of treatment.

Tissue Doppler imaging analysis at pre-cardioversion time predicts recurrent atrial fibrillation: a 12-month follow-up study.

INTRODUCTION: Tissue Doppler imaging (TDI) has been extensively used in several clinical settings. We aimed to investigate whether TDI can predict recurrent atrial fibrillation (AF). METHODS AND RESULTS: Seventy-four consecutive patients (aged 62.6 +/- 11.7 years) with AF (>48 hours and <6 months of duration) who underwent successful external electrical direct current cardioversion and 20 healthy individuals were enrolled. Conventional echocardiography and TDI were prospectively performed before cardioversion. Based on a cutoff point of 5.43 cm/sec for the negative systolic wave velocity (NSWV), derived by the normal controls (mean + 2 SD), patients were divided into Group I (36 patients) with a NSWV >5.43 cm/sec and Group II (38 patients) with NSWV 48 hours; all patients were in AF at 12 months. In Group II, all patients were in sinus rhythm at 12 months. However, those patients presenting with a NSWV less but near to 5 cm/sec had frequent episodes of asymptomatic paroxysmal AF lasting for <48 hours. CONCLUSION: One year after successful direct current cardioversion, TDI analysis at pre-cardioversion time may be a useful marker to identify a subgroup of patients with increased risk for AF recurrence.

Prediction of successful cardioversion and maintenance of sinus rhythm in patients with lone atrial fibrillation.

OBJECTIVE: We aimed to prospectively investigate the predictive value of echocardiographic parameters for the prediction of successful cardioversion and long-term sinus rhythm (SR) maintenance in patients who have experienced a lone episode of atrial fibrillation (AF). MEASUREMENTS AND RESULTS: Clinical and echocardiographic data, including mean left atrial appendage (LAA) peak flow velocity and mitral annulus motion, were analyzed in 78 consecutive patients (mean [+/- SD] age, 59.3 +/- 9.3 years) with AF lasting > 48 h and < 6 months. Sixty-one patients (78%) underwent successful external electrical cardioversion, while the remaining remained in AF. At the 1-year follow-up, of the 61 patients who had successfully been converted to SR, 24 (39.3%) remained in SR. For predicting the success of the cardioversion, we used a model consisting of two variables. LAA flow velocity (> 20 cm/s) and left ventricular (LV) fractional shortening (> 30%) appear to be quite strong, yielding 83.3% correct results. For predicting the maintenance of SR, we used a model consisting of two variables. The absence of the early systolic abnormal mitral annulus motion and LAA flow velocity (> 20 cm/s) appears to be quite strong, yielding 84.6% correct results. LAA flow velocity only marginally enters the model, and, if removed, little predictive value is lost (dropping to 83.3%). Removing the early systolic abnormal mitral annulus motion variable, the prediction value drops significantly to 70.5%. CONCLUSION: LAA flow velocity combined with LV fractional shortening can predict the success of the conversion of AF to SR. Additionally, LAA flow velocity, combined with the analysis of mitral annulus motion before cardioversion, can predict the long-term maintenance of SR.

Anti-inflammatory and anti-apoptotic effects of levosimendan in decompensated heart failure: a novel mechanism of drug-induced improvement in contractile performance of the failing heart.

Recent experimental and clinical observations indicate that over-expression of pro-inflammatory cytokines is actively implicated to chronic heart failure progression through their cytotoxic and negative inotropic effects. Calcium-sensitizing agents, such as levosimendan, promotes inotropy by stabilizing troponin C in a configuration that enhances the calcium sensitivity of cardiac myofilaments, preserving also diastolic relaxation. Levosimendan also opens ATP-dependent potassium channels in peripheral vessels, leading to vasodilatation. Large scale randomized clinical trials have shown that levosimendan administration in patients with severe heart failure due to left ventricular systolic dysfunction results in favorable hemodynamic changes, symptomatic benefit, and a reduction in short-term morbidity and mortality. This review describes current knowledge about novel cellular mechanisms associated with beneficial effects of levosimendan on cardiac contractile performance, focusing mainly on its immunomodulatory and anti-apoptotic properties. Levosimendan-induced improvement in contractile reserve and clinical status of severe heart failure patients, seems to be related with the reduction of major pro-inflammatory cytokines (TNF-alpha, IL-6) and soluble apoptosis signaling molecules Fas/Fas Ligand. Modulation of pro-inflammatory and pro-apoptotic pathways into the failing heart by levosimendan may be an additional pathophysiologic mechanism that prevents further clinical and hemodynamic consequences of abnormal immune responses in decompensated heart failure and beneficially affects the progression of the syndrome.

Repeated exercise stress testing identifies early and late preconditioning.

BACKGROUND: The warm-up phenomenon has been considered to trigger preconditioning. We investigated whether repeated exercise treadmill tests in humans are capable of inducing adaptation to ischemia by triggering both the early and late phase of preconditioning. METHODS: In 25 consecutive patients with stable coronary artery disease, four repeated treadmill tests were performed. Thirty minutes following the first test (T1) a second one was performed (T2), followed 6 h later by a third test (T3). Twenty-four hours later all patients were subjected to a fourth exercise test (T4). In every fifth patient, simultaneous echocardiographic examination was performed at the time of the exercise tests in an attempt to reveal ischemic abnormalities. RESULTS: At baseline there was no difference between the variables. At ST segment depression >1.5 mm, the rate-pressure product (RPP) was higher in T2 and T4 (231.3+/-17.9 and 232.6+/-15.8 mm Hg s 10(2)) than in T1 and T3 (210+/-17 and 210.2+/-16.7 mm Hg s 10(2)), p<0.001. Additionally, time to the onset of chest pain was longer in T2 and T4 (430.8+/-60.5 and 438+/-47 s) than in T1 and T3 (345.6+/-69 and 345.6+/-58 s), p<0.001. At peak exercise, the RPP was higher in T2 and T4 (278.6+/-21.6 and 278.3+/-19.6 mm Hg s 10(2)) than in T1 and T3 (255.6+/-23.1 and 256.6+/-23 mm Hg s 10(2)), p<0.001. The wall motion score index was higher in T1 and T3 (1.65+/-0.17 and 1.53+/-0.16) than in T2 and T4 (1.3+/-0.07 and 1.37+/-0.1), p<0.001. CONCLUSION: By using repeated exercise treadmill tests both the early and late phase of protection can be obtained.

Doppler-derived left ventricular end-diastolic pressure prediction model using the combined analysis of mitral and pulmonary A waves in patients with coronary artery disease and preserved left ventricular systolic function.

The aim of this study was to analyze the components of mitral and pulmonary A waves and to construct a Doppler-derived left ventricular (LV) end-diastolic pressure (EDP) prediction model based on the combined analysis of transmitral and pulmonary venous flow velocity curves. Combined analysis of transmitral and pulmonary venous flow velocity curves at atrial contraction is a reliable predictor of increased LV filling pressure. The duration of pulmonary and mitral A waves is determined by the sum of respective acceleration and deceleration time. Mitral flow and left upper pulmonary vein flow velocity curves were recorded simultaneously with LVEDP in 40 consecutive patients (aged 59 +/- 8 years) with coronary artery disease and preserved LV systolic function. Differences in all parameters represent values of pulmonary minus those of mitral A wave curve. The difference in deceleration time was the strongest candidate, being included in all models. After redundancy evaluation, we reached the following model: LVEDP = 20.61 + 0.229 x difference in deceleration time (r(2) = 0.80, p <0.001). In the entire study group, the difference in duration and in deceleration time of the A wave was highly correlated with LVEDP (r = 0.79, p <0.001, and r = 0.88, p <0.001, respectively). The entire study group was further divided according to whether LVEDP was above (group I, 20 patients) or below (group II, 20 patients) the median value (15.5 mm Hg). In group I, the difference in duration and in deceleration time correlated well (r = 0.62, p = 0.01, and r = 0.75, p = 0.001, respectively) with LVEDP, whereas in group II only the difference in deceleration time correlated well (r = 0.68, p = 0.005). In patients with coronary artery disease and preserved LV systolic function, the combined analysis of mitral and pulmonary A waves can predict LVEDP. The difference in deceleration time between pulmonary and mitral A waves can reliably evaluate high and normal LVEDP.

Prognostic usefulness of echocardiographic dobutamine in younger (14 to 25 years) and older (40 to 55 years) patients with idiopathic dilated cardiomyopathy.

We studied 16 younger patients (<25 years old) and 16 older patients (>40 years old) to investigate the prognostic value of echocardiographic dobutamine-induced changes. The results of this study showed that although the percent achieved of predicted oxygen consumption was lower in the younger group, no prognostic information was given regarding the outcome of this particular group. In contrast, echocardiographic dobutamine-induced changes can distinguish high-risk younger patients.

Left atrial functional reserve in patients with nonischemic dilated cardiomyopathy: an echocardiographic dobutamine study.

OBJECTIVE: To evaluate left atrial functional reserve in patients with chronic heart failure and nonischemic dilated cardiomyopathy (DCM). BACKGROUND: Left ventricular functional status has been investigated using echocardiographic dobutamine. METHODS: In 35 consecutive patients (29 men and 6 women; mean +/- SD age, 42.37 +/- 13.5 years), peak oxygen consumption (O(2)max) was measured; the day after, a low-dose dobutamine (5 to 10 micro g/kg/min, of 5 min each step) study was performed. Left atrial volumes at mitral valve opening, onset of left atrial systole, and mitral valve closure were measured by using two-dimensional echocardiography. Left atrial active emptying volume (LAEV) [volume at onset of atrial systole - minimal volume] was calculated, as was left atrial active emptying fraction (LAEF): [(volume at onset of atrial systole - minimal volume)/volume at onset of atrial systole] x 100. The changes (values obtained after inotropic stimulation minus those obtained at baseline) of the above-mentioned echocardiographic variables were considered as left atrial functional reserve. RESULTS: In the entire study group after dobutamine infusion, increases in LAEV (3.34 +/- 7.54 mL, p = 0.01) and LAEF (6 +/- 13.2%, p = 0.01) were observed. The changes in the above-mentioned parameters were correlated with O(2)max values (r = 0.73 and r = 0.71, respectively; p < 0.001). After inotropic stimulation, LAEV and LAEF were increased in patients with O(2)max values > 14 mL/kg/min (5.62 +/- 7.28 mL and 10.04 +/- 13.13%, respectively) and decreased in patients with O(2)max values < 14 mL/kg/min (- 1.08 +/- 6.13 mL and - 1.6 +/- 9.9%, respectively; p = 0.01 for both). CONCLUSION: Echocardiographic dobutamine can evaluate left atrial functional reserve in patients with nonischemic DCM.