Left Ventricular Cardiac Function Research Articles

Monitoring of cardiac function during doxorubicin therapy in metastasized breast cancer. Measuring systolic time interval

Assessment of systolic time interval represents an uncomplicated, sufficiently precise and cheap possibility in clinical practice of cardiac monitoring during treatment with doxorubicin (adriamycin) if the ratio between pre-ejection period interval (PEPI) and left ventricular ejection time interval (LVETI) ("Weissler index") for evaluation of left ventricular cardiac function is used. In an investigation of 352 female patients with metastatic carcinoma of the breast statistically ascertained dose-response relationships could be established as regards electrocardiographic disorders of repolarisation and the systolic time interval (P less than 0.001). Pre-irradiated patients showed more ECG changes (P less than 0.001) and higher PEPI : LVETI values (P less than 0.001) than patients without prior irradiation. There was no general influence of cytostatic treatment on systolic and diastolic blood pressure values. The upper limit of a therapeutic risk in evaluation of the systolic time interval for cardiac monitoring of doxorubicin treatment should be 0.45-0.50 for PEPI : LVETI. Above this borderline value precise cardiac evaluation including invasive methods should be attempted if continuation of treatment is indicated. This regime could help prevent the occurrence of life-threatening cardiac crises during treatment with doxorubicin.

Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice

Molecule-targeted therapies like those against the epidermal growth factor receptor (EGFR) are becoming widely used in the oncology clinic. With improvements in treatment efficacy, many cancers are being treated as chronic diseases, with patients having prolonged exposure to several therapies that were previously only given acutely. The consequence of chronic suppression of EGFR activity may lead to unexpected toxicities like altered cardiac physiology, a common organ site for adverse drug effects. To explore this possibility, we treated C57BL/6J (B6) mice with two EGFR small molecule tyrosine kinase inhibitors (TKIs), irreversible EKB-569 and reversible AG-1478, orally for 3 months. In B6 female mice, chronic exposure to both TKIs depressed body weight gain and caused significant changes in left ventricular (LV) wall thickness and cardiac function. No significant differences were observed in heart weight or cardiomyocyte size but histological analysis revealed an increase in fibrosis and in the numbers of TUNEL-positive cells in the hearts from treated female mice. Consistent with histological results, LV apoptotic gene expression was altered, with significant downregulation of the anti-apoptotic gene Bcl2l1. Although there were no significant differences in any of these endpoints in treated male mice, suggesting sex may influence susceptibility to TKI mediated toxicity, the LVs of treated male mice had significant upregulation of Egf, Erbb2 and Nppb over controls. Taken together, these data suggest that chronic dietary exposure to TKIs may result in pathological and physiological changes in the heart.

Fibroblast Growth Factor-2 Regulates Myocardial Infarct Repair: Effects on Cell Proliferation, Scar Contraction, and Ventricular Function

Fibroblast growth factor-2 (FGF2, bFGF) has been proposed to regulate wound healing and angiogenesis, but skin wound healing in FGF2-knockout (FGF2-KO) animals is only slightly delayed. To determine the role of FGF2 in myocardial infarct repair, we studied the evolution of left ventricular geometry, cell proliferation, matrix content, and cardiac function in mice lacking or overexpressing (FGF2-Tg) FGF2. Despite having no effect on initial infarct size, deletion of FGF2 resulted in reduced fibroblast proliferation and interstitial collagen deposition, decreased endothelial proliferation and vascular density, and decreased cardiomyocyte hypertrophy. Furthermore, FGF2-KO mice demonstrated a complete absence of scar contraction, resulting in increased final infarct size and marked increases in chamber size and infarct expansion. These deficits ultimately impaired left ventricular dP/dt compared with wild-type infarcted mice. Conversely, overexpression of FGF2 increased fibroblast proliferation and collagen deposition, accelerated endothelial proliferation, and enhanced cardiomyocyte hypertrophy after infarction. These changes curbed infarct expansion and preserved left ventricular function. Thus, FGF2 is an important regulator of cell proliferation, angiogenesis, collagen synthesis, myocyte hypertrophy, scar contraction, and, ultimately, left ventricular contractile function during infarct repair. FGF2 may be more important in healing of infarcts compared with skin wounds because of the mechanical stress under which infarcts heal.

Relation of B-type natriuretic peptide to left ventricular wall stress as assessed by cardiac magnetic resonance imaging in patients with dilated cardiomyopathy

Ventricular loading conditions are crucial determinants of cardiac function and prognosis in heart failure. B-type natriuretic peptide (BNP) is mainly stored in the ventricular myocardium and is released in response to an increased ventricular filling pressure. We examined, therefore, the hypothesis that BNP serum concentrations are related to ventricular wall stress. Cardiac magnetic resonance imaging (MRI) was used to assess left ventricular (LV) mass and cardiac function of 29 patients with dilated cardiomyopathy and 5 controls. Left ventricular wall stress was calculated by using a thick-walled sphere model, and BNP was assessed by immunoassay. LV mass (r = 0.73, p < 0.001) and both LV end-diastolic (r = 0.54, p = 0.001) and end-systolic wall stress (r = 0.66, p < 0.001) were positively correlated with end-diastolic volume. LV end-systolic wall stress was negatively related to LV ejection fraction (EF), whereas end-diastolic wall stress was not related to LVEF. BNP concentration correlated positively with LV end-diastolic wall stress (r = 0.50, p = 0.002). Analysis of variance revealed LV end-diastolic wall stress as the only independent hemodynamic parameter influencing BNP (p < 0.001). The present approach using a thick-walled sphere model permits determination of mechanical wall stress in a clinical routine setting using standard cardiac MRI protocols. A correlation of BNP concentration with calculated LV stress was observed in vivo. Measurement of BNP seems to be sufficient to assess cardiac loading conditions. Other relations of BNP with various hemodynamic parameters (e.g., EF) appear to be secondary. Since an increased wall stress is associated with cardiac dilatation, early diagnosis and treatment could potentially prevent worsening of the outcome.

Fgl2deficiency causes neonatal death and cardiac dysfunction during embryonic and postnatal development in mice

We hypothesized that cardiac dysfunction was responsible for the high perinatal lethality that we previously reported in fibrinogen-like protein 2 (Fgl2) knockout (KO) mice. We therefore used ultrasound biomicroscopy to assess left ventricular (LV) cardiac structure and function during development in Fgl2 KO and wild-type (WT) mice. The only deaths observed between embryonic day (E)8.5 (onset of heart beating) and postnatal day (P)28 (weaning) were within 3 days after birth, when 33% of Fgl2 KO pups died. Histopathology and Doppler assessments suggested that death was due to acute congestive cardiac failure without evidence of valvular or other obvious cardiac structural abnormalities. Heart rates in Fgl2 KO embryos were significantly reduced at E8.5 and E17.5, and irregular heart rhythms were significantly more common in Fgl2 KO (21/26) than WT (2/21) embryos at E13.5. Indexes of systolic and/or diastolic cardiac function were also abnormal in KO mice at E13.5 and E17.5, in postnatal mice studied at P1, and in KO mice surviving to P28. M-mode analysis showed no difference in LV diastolic chamber dimension, although posterior wall thickness was thinner at P7 and P28 in Fgl2 KO mice. We conclude that Fgl2 deficiency is not associated with obvious structural cardiac defects but is associated with a high incidence of neonatal death as well as contractile dysfunction and rhythm abnormalities during embryonic and postnatal development in mice.

Reversal of diabetes‐evoked changes in mitochondrial protein expression of cardiac left ventricle by treatment with a copper(II)‐selective chelator

Cardiac disease is the commonest cause of death amongst diabetic patients. Diabetic cardiomyopathy, which has a poor prognosis, is characterized by left ventricular hypertrophy and impaired cardiac function and mitochondrial damage is said to contribute to its development. We recently showed that treatment with the Cu(II) -selective chelator, triethylenetetramine (TETA), improved cardiac structure, and function in diabetic subjects without modifying hyperglycemia. Thus, TETA has potential utility for the treatment of heart disease. To further understand the molecular mechanism by which it causes these effects, we have conducted the first study of the effect of oral TETA on protein abundance in the cardiac left ventricle of rats with severe streptozotocin-induced diabetes. Proteomic methods showed that of 211 proteins changed in diabetes, 33 recovered after treatment. Through MS, 16 proteins were identified which may constitute major targets of drug action. Remarkably, most of these were mitochondrial proteins with roles in energy metabolism. In addition to components of the mitochondrial respiratory chain and enzymes involved in fatty acid oxidation, TETA treatment normalized both myocardial expression and enzymatic activity of carnitine palmitoyltransferase 2. These findings indicate that mitochondria constitute major targets in the mechanism by which TETA restores cardiac structure and function in diabetes.

Gender and Strain Variations in Left Ventricular Cardiac Function and Mass Determined With Magnetic Resonance Imaging at 7 Tesla in Adult Mice

We sought to assess with magnetic resonance imaging (MRI) the influence of strain type and gender on left ventricular (LV) global function and mass in 3 inbred mouse strains with a normal cardiac phenotype. A total of 30 mice from 3 inbred strains (C57BL/6, 29S2/SvPasCrl, and C3HFeJ) were studied on a 7.05-T MR scanner using ECG-triggered cine sequences. LV mass and volumes were calculated with inclusion and exclusion of papillary muscles (PMs) in the LV wall. Significant differences were found with strain and gender (P < 0.001), with strain-effect but no gender-effect for ejection fraction (EF), end-diastolic volume (EDV), and end-systolic volume (ESV). There were no differences in LV mass between strains but lower values in female mice except in the C3H strain. The exclusion of PMs led to the relative underestimation of EF (-6.1%) and of LV mass (-6.4 mg) and the relative overestimation of EDV (6.3 microL) and ESV (5.3 microL). Inter- and intraobserver reproducibility was better when PMs were included. The use of MRI demonstrates cardiac interstrain and gender-related phenotypic diversities that are essential factors to consider when building genomic databases and designing studies.

Predicting prognosis based on the shape of the left ventricular cavity in dilated cardiomyopathy: analysis using rate of improvement in the circle index.

To elucidate the relation between a quantitative measure of the shape of the left ventricular cavity, cardiac function, and prognosis in patients with dilated cardiomyopathy (DCM). The hearts of 20 healthy individuals and 18 patients with DCM were evaluated. Participants were aged 48.5 ± 5.0 years. On the basis of end-systolic four-chamber view echocardiograms, the endocardium of the left ventricle was traced and the resulting curve was segmented using 100 points. A line tangential to the curve was then drawn at each point, and the angle between two adjacent tangential lines was calculated. The deviation of these angles was designated as the circle index. The circle index and hemodynamic findings in patients with DCM were compared, and the rate of improvement in the circle index in these cases of DCM was determined. These patients were then placed into one of two groups: group R (11 patients), those with improvement rates of 10% or higher at time of discharge; and group NR (seven patients), those with rates less than 10%. Diuretic (furosemide) use, New York Heart Association (NYHA) classification, and readmission rate for the two groups were compared 2 years after discharge. The circle index was 2.7 ± 0.9 in the DCM group and 17.5 ± 4.2 in the healthy group (P < 0.01). The circle index in the DCM group was correlated with pulmonary capillary wedge pressure (r(2) = 0.42). Use of furosemide was unchanged in group R 2 years after discharge, but had increased for all patients in group NR. All cases in group R were classified as NYHA I 2 years after discharge. In group NR, in contrast, although all cases were classified as NYHA I at discharge, five of seven cases had deteriorated to NYHA III-IV 2 years later and were readmitted to hospital. There appears to be a quantifiable correlation between the circularity of the left ventricular cavity and the circle index. This suggests that rate of improvement after treatment for heart failure could predict prognosis in patients with DCM.

Impact of Enzyme Replacement Therapy on Cardiac Morphology and Function and Late Enhancement in Fabry’s Cardiomyopathy

The present study evaluated the evolution of cardiac morphology, function, and late enhancement as a noninvasive marker of myocardial fibrosis, and their inter-relation during enzyme replacement therapy in patients with Fabry's disease using magnetic resonance imaging and color Doppler myocardial imaging. Late enhancement, which was present in up to 50% of patients, was associated with increased left ventricular mass, the failure of a significant regression of hypertrophy during enzyme replacement therapy, and worse segmental myocardial function. Late enhancement may predict the effect of enzyme replacement therapy on left ventricular mass and cardiac function.

Left Ventricular Cardiac Function during the Course of a One Year Multicenter Trial of the Safety and Efficacy with ICL670 5–40mg/kg/day and Deferoxamine 20–60 mg/kg/day in Beta-Thalassemia Patients with Transfusional Hemosideosis.

Historically regularly transfused patients (pts) with Thalassemia Major (TM) have received prolonged infusions of subcutaneous deferroxamine (sc DFO) to prevent the lethal cardiac complications of transfusional hemosiderosis. Cardiac function is monitored with annual electrocardiograms (EKG) and 2 Dimensonial Doppler Echocardiogram (Echo). ICL670 (Exjade) is a newly identified oral iron chelator that has completed a one-year worldwide multicenter phase III clinical study of its safety and efficacy in comparison to sc DFO in TM. 17 TM pts in our institution participated in the Novartis ICL670-107 and 108 trials. They ranged in age from 2–36 years (yrs), the youngest being naive to chelation, five pts were previously noncompliant with the use of sc DFO, one of which developed acute heart failure more than 15 yrs prior to the study which resolved with vigorous DFO therapy and in whom all cardiac medications were discontinued 10 yrs prior to study entry. 10 TM pts ranging in age from 2–36 yrs received ICL670 at 10–30mg/kg/day and 7 TM pts ranging in age from 7–33 yrs received sc DFO at 40–60 mg/kg over 8 hour infusions 5 days per week. Each pt underwent a 2 dimensional Doppler Echo as part of their routine care prior to entry and after one year of study as well as regular EKGs before and during the study. Pre and post Liver Iron Concentration (LIC) was performed by biopsy in 15 adolescent/adult patients and 2 children had SQUID LIC. Laboratory analysis of blood counts, serum chemistries and ferritin levels were performed by a central laboratory. No clinically significant EKG changes were observed during the course of the study. Normal Ejection Fractions (EF) = 0.55 ± 0.75 ml/m2 and Shortening Fractions (SF) = >26%. One of the ten pts on ICL670 developed an abnormal EF = 47 and a SF = 24% compared to 0 of 7 pts on sc DFO. None of the pts experienced clinical cardiac decomensation. In conclusion regularly transfused TM pts receiving oral ICL670 for one year had no statistically significant mean changes or relative mean changes in EF or SF on 2 dimensional Dopler Echo in comparison to those pts receiving sc DFO.Echo ResultsMean Pre EFMean Post EFMean ChangeMean Relative ChangeICL67060.3 ± 5.558.6 ± 5.4−1.7 ± 6.9−2% ± 12%DFO63.7 ± 4.667.1 ± 4.23.4 ± 6.36% ± 11%Mean Pre SFMean Post SFMean ChangeMean Relative ChangeICL67032.4 ± 3.431.2 ± 3.3−1.2 ± 4.3−3% ± 13%DFO35.0 ± 3.137.4 ± 3.32.4 ± 4.68% ± 14%

Echocardiography Identifies Changes in Left Ventricular Cardiac Function after Low Doses of Anthracycline, Particularly in Older Patients.

Anthracyclines remain an essential component of treatment regimes for lymphoma. Increasing numbers of older patients are being offered potentially curative treatment for lymphoma and a corresponding increase in cases of cardiac toxicity might be expected. Upper limits for total doses of anthracycline are published, but there is little information on whether age predicts independently for cardiac susceptibility to anthracyclines. There is also little data on the effect of low doses of anthracycline on the heart. We have prospectively studied cardiac function in patients receiving Doxorubicin (DOX) for High Grade Non Hodgkin's Lymphoma and Hodgkin's disease. 28 patients are included: 18 male, 9 female aged 16 to 89 (median 59) years. Echocardiographic examinations were undertaken before and after patients received DOX at a median dose of 85 mg/m2 (50 mg/m2 to 150 mg/m2). The Left Ventricular (LV) Tei index was calculated in all cases as the sum of the isovolumetric contraction time and isovolumetric relaxation time divided by the ejection time. Higher values represent cardiac dysfunction and a rise post treatment was regarded as deterioration in LV function. For the group, there was a significant post treatment deterioration in LV function as measured by the Tei index: 0.400 ± 0.12 pre-treatment to 0.475 ± 0.16 post treatment (P = 0.0076). Multivariate analysis of age, pre-treatment Tei index and DOX dose (in this low range) revealed age to be the only significant predictor of deterioration in cardiac function after treatment (correlation coefficient 0.69, p < 0.0001).We conclude that measurable changes in cardiac function occur after very low doses of DOX and that these changes are more marked in older patients. Whether these changes will predict for further deterioration after higher doses of DOX and potentially predict for long term symptomatic cardiac dysfunction post therapy will require further study and follow up.

Administration of Erythropoietin Fails to Improve Long-Term Healing or Cardiac Function After Myocardial Infarction in the Rat

Erythropoietin (epo), initially recognized and used clinically to increase erythropoiesis, has been shown to have beneficial effects on various other tissues in the setting of hypoxia and ischemia. Epo has been shown to reduce apoptosis after myocardial infarction, but few studies have evaluated the long-term effects of epo treatment on left ventricular (LV) remodeling, cardiac function, and blood flow after healing of a permanent coronary artery occlusion. The aim of this study was to assess the effects of epo treatment on the healed heart 6 weeks after myocardial infarction. Anesthetized rats underwent coronary artery occlusion and were treated with erythropoietin (5000 units/kg/day, n=21) or saline (n=20) the day before surgery, the day of, then for 5 days. At 6 weeks LV ventriculography to assess LV volumes and ejection fractions and histologic assessment of infarct size and LV cavity and wall dimensions were performed. Overall epo had no effect on LV remodeling or cardiac function. There were no significant differences in infarct morphology, infarct size (44+/-3% of the LV circumference versus 39+/-3%), LV cavity area, scar thickness, LV systolic volume, or ejection fraction (44+/-3% versus 39+/-3%) between the epo and saline groups, respectively. However, for any given size of myocardial infarct, LV ejection fraction was significantly higher in erythropoietin hearts and LV systolic volumes lower. Thus, in our model, treatment with epo had no long-term beneficial effect on LV remodeling after myocardial infarction but may have exerted some positive effect on LV function.

Impairment of cardiac function in hypertensive patients with Type 2 diabetes: a LIFE study

Type 2 diabetic patients with hypertension have an increased left ventricular (LV) mass and impaired cardiac function compared to hypertensive patients without diabetes. However, it is unknown if the impaired cardiac function can be explained solely by LV hypertrophy, or is independently related to diabetes. The aim of the present study was to compare LV function between diabetic and non-diabetic hypertensive patients with electrocardiographic LV hypertrophy. In 937 patients participating in the LIFE echocardiographic substudy, all echocardiograms were centrally evaluated by a core reading centre measuring LV mass, systolic and diastolic LV function. Known diabetes was present in 105 patients. Left ventricular mass was similar in diabetic and non-diabetic patients. Endocardial systolic LV function, estimated by LV ejection fraction, was reduced and indices of midwall systolic LV function were impaired in the diabetic patients. Diastolic LV filling pattern was impaired and arterial stiffness, measured by pulse pressure/stroke index, was increased in diabetic patients. Systolic and diastolic LV function in hypertensive patients with electrocardiographic LV hypertrophy and diabetes are impaired independent of LV mass, most likely reflecting the adverse effects of diabetes per se.

The role of vitamin D in left ventricular hypertrophy and cardiac function

The role of vitamin D in left ventricular hypertrophy and cardiac function. Cardiovascular disease is the leading cause of death among patients with end-stage renal disease (ESRD). Traditional cardiac risk factors, as well as other factors specific to the ESRD population such as hyperphosphatemia, elevated calcium and phosphate product, abnormal lipid metabolism, hyperhomocysteinemia, and chronic inflammation play a role in the excessive risk of cardiovascular death in this population. Left ventricular disorders are proven risk factors for cardiac mortality in hemodialysis patients. These disorders are present in incident ESRD patients at rates far above the general population. There is an accumulating body of evidence that suggests that vitamin D plays a role in cardiovascular disease. Abnormal vitamin metabolism, through deficiency of the active form of 1,25-dihydroxyvitamin D(3), and acquired vitamin D resistance through the uremic state, have been shown to be important in ESRD. Vitamin D deficiency has long been known to affect cardiac contractility, vascular tone, cardiac collagen content, and cardiac tissue maturation. Recent studies using vitamin D receptor deficient mice as a model demonstrate a crucial role of vitamin D in regulation of the renin-angiotensin system. Additionally, there is emerging evidence linking treatment with vitamin D to improved survival on hemodialysis and improvement in cardiac function. The emergence of this data is focusing attention on the previously underappreciated nonmineral homeostatic effects of vitamin D that very likely play an important role in the pathogenesis of cardiac disease in ESRD.

Multiview Active Appearance Models for Simultaneous Segmentation of Cardiac 2- and 4-Chamber Long-Axis Magnetic Resonance Images

Long-axis cardiac magnetic resonance (MR) views enable a rapid, online evaluation of cardiac function from only 2 views. In this article, we aimed to evaluate a model-based method for the simultaneous detection of 2- and 4-chamber endocardial and epicardial contours in end-diastolic and end-systolic phases of MR images. We introduce multiview Active Appearance Models for the automated segmentation of long-axis cardiac MR images of the left ventricle. Two modes of initialization were used to test the accuracy of the model with minimal user interaction and the best-obtainable accuracy with this model. The segmentation was initialized by annotating 2 points in the base and one in the apex. We tested the method's performance by comparing the point-to-curve errors, ejection fractions, and biplane area-length volumes calculated with the automatically detected contours to those calculated from contours that were annotated manually by experts. Leave-one-out experiments were performed with 2- and 4-chamber long axis MR images of 59 subjects in end-diastolic and end-systolic phases. When initializing in all 4 frames, 97% of the segmentations were successful, and the standard deviation in the volume-errors with respect to the average manually identified volume was 9.0% for the end-diastolic volumes and 15% for the end-systolic volumes. When the method was initialized in the end-systolic frames only, 92% of the segmentations were successful, and the standard deviation in the errors in the volumes with respect to the average manually identified volume was 13.3% for the end-diastolic volumes and 16.7% for the end-systolic volumes. Bland-Altman plots showed that the errors were distributed randomly around 0, and by using a paired t test comparing manual and computer-determined volumes, we were able to detect that the volume differences were not significant. Simultaneous detection of the endocardial and epicardial contours in 2- and 4-chamber views and end-diastolic and end-systolic phases for one subject takes approximately 3 seconds. The accuracy of the reported method is comparable with the interobserver variability for initialization in all frames and slightly worse than the interobserver variability with initialization in the end-systolic frames only. However, in both cases the errors were not significant. Initialization in end-systolic frames only leads to a statistically insignificantly lower model accuracy; however, it requires only half the user interaction. Therefore, we can conclude that this method enables rapid analysis of the cardiac left ventricular function with little user interaction.

Left ventricular geometric patterns and cardiac function in patients with chronic renal failure undergoing hemodialysis

The aim of this study was to estimate the impact and prevalence of left ventricular geometric alterations and systolic and diastolic dysfunction in hemodialysis patients, as well as the relationship with cardiac troponin as a marker of myocardial damage. 31 patients (pts), 19 males and 12 females, age 58.1+/-16.4 (26 on hemodialysis, 5 on peritoneal dialysis) and 31 healthy normal controls were enrolled. Echocardiography measurements were carried out according to the American Society of Echocardiography recommendations. Left ventricular mass was calculated, according to the Devereux formula and indexed to height and weight 2.7. Doppler echocardiography was performed to study diastolic function by measurements of isovolumetric relaxation period (IVRT), E wave deceleretion time (DTE) and E/A ratio. Cardiac troponin was measured by a third generation electro-chemiluminescence immunoassay. Statistical analysis was performed using the t-test for between-group comparisons and the Pearson and Spearman's tests to investigate correlations; p values of <0.05 were considered statistically significant. Eccentric hypertrophy was the most frequent pattern (n=17; 55%), followed by normal cardiac geometry (n=7; 23%), and concentric hypertrophy (n=5; 16%). Only 6% of pts (n=2) showed concentric remodelling. Systolic dysfunction was present in terms of endocardial parameters in 3 pts (9%) (fractional shortening <25%, EF<50%), but in terms of midwall myocardial shortening in 51% (n=16). Diastolic dysfunction was present in 87% (n=27) with a pattern of impaired relaxation (in 5 without left ventricular hypertrophy). E/A was negatively correlated with age (r=-0.41, p=0.02); DTE was positively correlated with posterior wall thickness (r=0.36, p=0.05) and interventricular septum thickness (r=0.45, p=0.01); cardiac troponin was positively correlated with age (r=0.50, p=0.00), left ventricular mass (r=0.41, p=0.02), posterior wall thickness (r=0.41; p=0.02) and interventricular septum thickness (r=0.39, p=0.03) but not with diastolic dysfunction parameters. No significant difference was found in terms of duration of dialysis between patients with normal left ventricular geometry and those with left ventricular hypertrophy, but a significant difference in age was found (p=0.03). Pts with diastolic dysfunction had more frequent hypotensive episodes during dialysis (p<0.01). Impaired geometry and cardiac function is frequently observed in pts undergoing hemodialysis. Diastolic dysfunction is associated to a geometric pattern of left ventricular hypertrophy, although it can be an isolated initial manifestation of myocardial damage. Depressed midwall myocardial shortening can discriminate left ventricular dysfunction better than traditional endocardial systolic indexes.

Amiodarone Improves Cardiac Sympathetic Nerve Function to Hold Norepinephrine in the Heart, Prevents Left Ventricular Remodeling, and Improves Cardiac Function in Rat Dilated Cardiomyopathy

It is unclear how amiodarone therapy exerts its effects on left ventricular remodeling and cardiac sympathetic nerve function in chronic heart failure. We investigated long-term effects of amiodarone on rat dilated cardiomyopathy after healing of cardiac myosin-induced autoimmune myocarditis. Rats were treated with oral amiodarone or vehicle for 6 weeks. We determined cardiac function, left ventricular remodeling, and cardiac sympathetic nerve function with iodine-125-labeled metaiodobenzylguanidine ([I125]MIBG). Amiodarone treatment improved left ventricular pressure, central venous pressure, and rate of isovolumetric contraction and decreased ventricular weight (P<0.005). Expression of cytokine mRNA was unchanged; expression of atrial natriuretic peptide, collagen III, and transforming growth factor-beta1 mRNA was decreased in amiodarone-treated rats (P<0.05). Phenotype of myosin heavy chain was moved toward that of normal rats by amiodarone. Initial myocardial uptake of MIBG decreased by 67% (P<0.001) and washout rate accelerated by 221% in rats with chronic heart failure compared with normal rats. Whereas amiodarone decreased the initial uptake by 71% in normal rats, amiodarone decelerated the early washout and the late washout and improved the late myocardial distribution of MIBG in rats with chronic heart failure (257% compared with vehicle-treated rats with chronic heart failure; P<0.01). In proportion to MIBG distributions, cardiac tissue catecholamines were increased by amiodarone treatment. Long-term amiodarone treatment prevented left ventricular remodeling and improved cardiac function in rat dilated cardiomyopathy. Long-term amiodarone treatment also restored cardiac sympathetic tone to hold norepinephrine in the heart.

Intensification of Chelating-Therapy in Patients with Thalassemia major

With the introduction of "hypertransfusion" regimens the extent of disease- and therapy-related hemosiderosis has become the survival limiting factor for patients with beta-thalassemia major as iron transferred with transfusions cannot be excreted by physiological means. Subsequent introduction of deferoxamine therapy for iron elimination and prophylaxis of hemosiderosis has improved prognosis and life quality of these patients considerably. We report our experience with seven adolescent patients with beta-thalassemia and ineffective subcutaneous therapy and severe hemosiderosis-related organ complications. For that reason they received i. v. intensified chelate therapy. The patients were given 70 to 120 mg/kg DFO 7 days a week continuously via a Port-a-cath or Hickman central venous line. Under high-dose i. v. DFO therapy, serum ferritin levels significantly decreased in all patients. Target serum ferritin levels of 3 000 ng/ml were reached after 12 to 20 months of treatment. In 3 of the 5 patients that were treated for longer than 43 months serum ferritin levels even dropped below 2 000 ng/ml. Serum ferritin levels also correlated well with SQUID examinations. Therefore, monitoring of serum ferritin may be useful to monitor patient's compliance and control intensified DFO therapy. Continuous administration of the intensified DFO therapy induced normalization of liver function and left ventricular cardiac function in all patients who are still alive. Two patients died due to cardiac decompensation. In five patients 19 episodes of central catheter-related infections were observed (1.5 infections per 1 000 catheter days). No DFO-associated allergic reactions nor irreversible organ dysfunction were observed. Our results indicate that intensified i. v. DFO therapy is an effective and safe method for treatment of severe organ dysfunction in patients with thalassemia major. The most severe problems are catheter-related infections and inconsistent long-term compliance.

Hepatocyte growth factor prevents ventricular remodeling and dysfunction in mice via Akt pathway and angiogenesis

This study determines the effect of hepatocyte growth factor (HGF) on post-infarction left ventricular (LV) remodeling and cardiac function. In mice, on day 1 after myocardial infarction (MI), HGF (0.45 mg/kg per day) was injected into the tail vein for 7 days ( n = 12). In the control mice ( n = 12), 0.9% sodium chloride was injected instead of HGF. Hemodynamic data were obtained in vehicle treated control and HGF-treated hearts 4 weeks after the onset of MI. In the HGF-treated group, cardiac function was well preserved as indicated by LV pressure–volume relationship. These mice exhibited better LV systolic and diastolic function. The infarcted LV wall in HGF-treated heart was thicker as compared to vehicle treated group. Fibrosis and infarct size of the ventricular wall was significantly reduced in the HGF-treated hearts. 5-Bromo-2′-deoxy-uridine (BrdU) and Ki67 positive cardiomyocytes were observed in the border area of the HGF-treated infarcted hearts. c-Met and c-kit positive cardiomyocytes were observed in the border area and epicardium. Angiogenesis was significantly enhanced in HGF-treated hearts as determined by vessel density per unit area. A significant reduction in apoptosis in the HGF-treated hearts was observed compared with control hearts, and was strongly associated with increased Akt activation. Treatment with HGF improved heart function through angiogenesis, ventricular wall thickening, and hypertrophy of cardiomyocytes. The antiapoptotic effect of HGF was mediated by activation of PI3-kinase/Akt pathway.

Monocyte Chemoattractant Protein 1-Induced Monocyte Infiltration Produces Angiogenesis but Not Arteriogenesis in Chronically Infarcted Myocardium

Monocyte chemoattractant protein 1 (MCP-1) stimulates the invasion of monocytes into ischemic tissue with concomitant adhesion to endothelial cells. Monocyte stimulation has been shown to be involved in the induction of arteriogenesis, which is the development of functional arterioles resulting in improvement of perfusion. However, angiogenesis (newly developed capillaries contribute to improved tissue perfusion) in several models has not resulted in any improvement in blood flow. The effects of MCP-1 on potential angiogenesis and arteriogenesis as well as changes in left ventricular function were tested in a chronic infarct model in rat hearts. Anesthetized rats were subjected to open-chest ligation of the left coronary artery with subsequent myocardial infarction. After 6 weeks, animals were randomized to receive either MCP-1 (3 microL in 0.15 mL NaCl, group 1, n = 9) or saline (0.15 mL, group 2, n = 9), which was injected into the myocardium at the border zones of the infarcts. For assessment of left ventricular dimensions and global cardiac function, transthoracic two-dimensional echocardiography was performed at baseline, 6 weeks after myocardial infarction, and 4 weeks after MCP-1 or saline injection, by use of a 12-MHz pediatric transducer. For light microscopic analysis, myocardial tissue was stained with Elastica-van-Giesson and von Willebrand factor for blood vessels and endothelial cells, respectively. In a subset of animals, hearts were excised 24 hours after MCP-1 administration (n = 4) or saline administration (n = 4) for assessment of monocyte infiltration by immunohistologic staining of the CD31 antigen. Left ventricular dimensions and ejection fraction changed after coronary occlusion (from 60.4% +/- 2.85% to 24.8% +/- 5.01% ejection fraction in group 1, and from 58.4% +/-2.06% to 26.3% +/- 4.3% ejection fraction in group 2 at 6 weeks, P < .005) without any further change 4 weeks after treatment (ejection fraction in group 1, 26.3% +/- 2.7%, ejection fraction in group 2, 25.0% +/- 5.18%). The MCP-1 group resulted in 390.6 +/- 10.36 endothelial cells compared with 285.2 +/- 13.56 in group 2 (P < .005) at the injection site. Monocyte infiltration was observed at the MCP-1 injection site with an increase in capillary growth (angiogenesis). However, there was no difference in the number of arteriolar structures between animals treated with MCP-1 and saline animals (group 1, 19.0 +/- 1.52 vs group 2, 16.4 +/- 0.68, P > .05). A single intramyocardial injection of MCP-1 into the infarct border zone resulted in neo-angiogenesis and monocyte infiltration but not arteriogenesis in the rat heart. There was no functional change of chronically infarcted myocardium in the present model.