phosphocreatine and Ventricular-Dysfunction--Left

To investigate the therapeutic effects of phosphocreatine in elderly patients with chronic congestive heart failure (CHF) and its effects on plasma brain natriuretic peptide (BNP).. Forty elderly patients with chronic CHF were randomly divided into two groups to receive basic treatment (control group) and additional phosphocreatine treatment (treatment group) with a treatment course of 8 weeks. The patients were evaluated for improvement in New York Heart Association (NYHA) functional class, symptoms, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), and left ventricular ejection fraction (LVEF) and the levels of BNP before and after treatment.. After 8 weeks of treatment, the overall efficacy rate was significantly higher in treatment group than in the control group, and LVESD, LVEDD, LVEF and BNP level of the treatment group were significantly lowered in comparison with those of the control group (P<0.05).. Phosphocreatine in addition to the basic treatment can reduce the BNP level and improve the cardiac systolic and diastolic function in elderly patients with chronic CHF.

Topics: Aged; Aged, 80 and over; Cardiotonic Agents; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Phosphocreatine; Ventricular Dysfunction, Left

Cardiac disease is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Pioglitazone has been associated with improved cardiac outcome but also with an elevated risk of heart failure. We determined the effects of pioglitazone on myocardial function in relation to cardiac high-energy phosphate, glucose, and fatty acid metabolism and triglyceride content in T2DM patients.. Seventy-eight T2DM men without structural heart disease or inducible ischemia as assessed by dobutamine stress echocardiography were assigned to pioglitazone (30 mg/d) or metformin (2000 mg/d) and matching placebo for 24 weeks. The primary end point was change in cardiac diastolic function from baseline relative to myocardial metabolic changes, measured by magnetic resonance imaging, proton and phosphorus magnetic resonance spectroscopy, and [(18)F]-2-fluoro-2-deoxy-D-glucose and [(11)C]palmitate positron emission tomography. No patient developed heart failure. Both therapies similarly improved glycemic control, whole-body insulin sensitivity, and blood pressure. Pioglitazone versus metformin improved the early peak flow rate (P=0.047) and left ventricular compliance. Pioglitazone versus metformin increased myocardial glucose uptake (P<0.001), but pioglitazone-related diastolic improvement was not associated with changes in myocardial substrate metabolism. Metformin did not affect myocardial function but decreased cardiac work relative to pioglitazone (P=0.006), a change that was paralleled by a reduced myocardial glucose uptake and fatty acid oxidation. Neither treatment affected cardiac high-energy phosphate metabolism or triglyceride content. Only pioglitazone reduced hepatic triglyceride content (P<0.001).. In T2DM patients, pioglitazone was associated with improvement in some measures of left ventricular diastolic function, myocardial glucose uptake, and whole-body insulin sensitivity. The functional changes, however, were not associated with myocardial substrate and high-energy phosphate metabolism.

Topics: Adenosine Triphosphate; Aged; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fatty Acids; Glycated Hemoglobin; Heart; Humans; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Metabolic Syndrome; Metformin; Middle Aged; Myocardium; Phosphocreatine; Pioglitazone; PPAR alpha; Radionuclide Imaging; Stroke Volume; Sulfonylurea Compounds; Thiazolidinediones; Triglycerides; Ventricular Dysfunction, Left; Ventricular Remodeling

The addition of trimetazidine to standard treatment has been shown to improve left ventricular (LV) function in patients with heart failure. The aim of this study is to non-invasively assess, by means of in vivo 31P-magnetic resonance spectroscopy (31P-MRS), the effects of trimetazidine on LV cardiac phosphocreatine and adenosine triphosphate (PCr/ATP) ratio in patients with heart failure.. Twelve heart failure patients were randomized in a double-blind, cross-over study to placebo or trimetazidine (20 mg t.i.d.) for two periods of 90 days. At the end of each period, all patients underwent exercise testing, 2D echocardiography, and MRS. New York Heart Association (NYHA) class, ejection fraction (EF), maximal rate-pressure product, and metabolic equivalent system (METS) were evaluated. Relative concentrations of PCr and ATP were determined by cardiac 31P-MRS. On trimetazidine, NYHA class decreased from 3.04+/-0.26 to 2.45+/-0.52 (P = 0.005), whereas EF (34+/-10 vs. 39+/-10%, P = 0.03) and METS (from 7.44+/-1.84 to 8.78+/-2.72, P = 0.03) increased. The mean cardiac PCr/ATP ratio was 1.35+/-0.33 with placebo, but was increased by 33% to 1.80+/-0.50 (P = 0.03) with trimetazidine.. Trimetazidine improves functional class and LV function in patients with heart failure. These effects are associated to the observed trimetazidine-induced increase in the PCr/ATP ratio, indicating preservation of the myocardial high-energy phosphate levels.

Topics: Adenosine Triphosphate; Aged; Cross-Over Studies; Double-Blind Method; Echocardiography; Female; Heart Failure; Hemodynamics; Humans; Magnetic Resonance Angiography; Male; Phosphocreatine; Prospective Studies; Trimetazidine; Vasodilator Agents; Ventricular Dysfunction, Left

To evaluate neoton therapy effects in acute myocardial infarction (MI) on systolic function of the left ventricle, arrhythmia and clinical symptoms in patients on thrombolytic therapy (TLT).. 106 males with Q-MI entered the study. 47 received treatment without TLT and neoton, 30 patients received TLT with streptokinase preparations, 29 patients were given streptokinase preparations and neoton. Left ventricular systolic function was measured by echocardiography on day 1, 3, 7, 14, 21 and 28; arrhythmia was analysed at Holter monitoring in day 1 and 2 of MI.. TLT failed to arrest progression of left ventricular dilation by the end of the hospital stay. Patients given neoton in acute period of MI had no increase in the end systolic and diastolic volumes of the left ventricle in the course of the first months after MI onset. Antiarrhythmic action of neoton manifested on MI day 2.. Neoton given to MI patients receiving TLT prevents progression of left ventricular systolic dysfunction and establishment of predictors of unfavourable outcome.

Topics: Adult; Aged; Arrhythmias, Cardiac; Drug Therapy, Combination; Humans; Male; Middle Aged; Myocardial Infarction; Phosphocreatine; Streptokinase; Systole; Thrombolytic Therapy; Ventricular Dysfunction, Left

The aim of the study was comparison of contractile function of isolated hearts of rats with doxorubicin-induced myocardial injury which were tentatively divided according to the level of ejection fraction determined by echocardiography in vivo. After 4 weeks of doxorubicin administration (2 mg/kg subcutaneously once a week) about half of animals had normal (86±1%) and the other half reduced (61±4%) ejection fraction. The first group was defined as diastolic heart failure (DHF) and the other as systolic (SHF). The maximal pressure developed by the isolated heart in isovolumic mode was reduced in DHF by 13%, and in SHF by 34%. The relaxation index in both groups was lowed by 22-24%. Both groups were characterized by a decline in the ability to raise developed pressure while increasing coronary perfusion pressure, as well as by the loss of the ability of coronary vessels to maintain a stable flow rate while increasing perfusion pressure. The hearts of control animals were able to raise the cardiac work index (the product of developed pressure and heart rate) during prolonged high frequency (7-9 Hz) stimulation, while the two groups treated with doxorubicin reduced the level of this index. The content of basic energy metabolites (ATP, phosphocreatine, creatine) in both groups was reduced by 20-38%. The results showed that the hearts in DHF and SHF groups showed approximately the same level of reduction of the contractile function and energy metabolism, and hence their difference in vivo was probably due to varying degrees of mobilization of compensatory mechanisms.

Topics: Animals; Heart; Myocardial Contraction; Myocardium; Phosphocreatine; Rats; Stroke Volume; Systole; Ventricular Dysfunction, Left

Higher levels of physical activity are associated with reduced cardiovascular mortality but its effect on age-related changes in cardiac structure and function is unknown. The present study defines the effect of daily physical activity on age-related changes in cardiac structure, function, metabolism, and performance in healthy women.. Sixty-three healthy women were grouped according to age (young, 20-30 years, n=21; middle, 40-50 years, n=22; and older, 65-81 years, n=20) and daily physical activity level (low active<7500 and high active>12,500 steps/d). Participants underwent cardiac MRI including tissue tagging and 31P spectroscopy and exercise testing with noninvasive central hemodynamic measurements. Aging was associated with increased concentric remodeling (P<0.01) and left ventricular torsion (P<0.01), and a decline in diastolic function (P<0.01), cardiac phosphocreatine:ATP ratio (P<0.01), peak exercise cardiac power output (P<0.01), and O2 consumption (P<0.01). Older high-active women demonstrated a phosphocreatine:ATP ratio and relative peak O2 consumption similar to young low-active women, and 23% and 26% higher than older low-active women (phosphocreatine:ATP ratio, 1.9±0.2 versus 1.4±0.1; P<0.05 and O2 consumption, 24.1±3.8 versus 17.8±2.0 mL/[kg·min]; P<0.01). In older women, physical activity had no effect on eccentricity ratio (0.9±0.2 versus 0.8±0.1 g/mL; P=0.19), E/A ratio (1.3±0.5 versus 1.4±0.5; P=0.66), torsion (7.6±1.7 versus 8.0°±2.1°; P=0.20), and peak cardiac power output (3.4±0.7 versus 3.4±0.8 W; P=0.91).. A higher level of daily physical activity preserves cardiac metabolism and exercise capacity with aging but has limited effect on age-related changes in concentric remodeling, diastolic function, and cardiac performance.

Topics: Adenosine Triphosphate; Adult; Age Factors; Aged; Aged, 80 and over; Aging; Cardiac Output; Diastole; Energy Metabolism; Exercise Test; Exercise Tolerance; Female; Health Status; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Middle Aged; Motor Activity; Myocardium; Oxygen Consumption; Phosphocreatine; Predictive Value of Tests; Sex Factors; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling; Young Adult

Hypertrophic cardiomyopathy (HCM) is the commonest cause of sudden cardiac death in the young, with an excess of exercise-related deaths. The HCM sarcomere mutations increase the energy cost of contraction and impaired resting cardiac energetics has been documented by measurement of phosphocreatine/ATP (PCr/ATP) using (31)Phosphorus MR Spectroscopy ((31)P MRS). We hypothesized that cardiac energetics are further impaired acutely during exercise in HCM and that this would have important functional consequences.. (31)P MRS was performed in 35 HCM patients and 20 age- and gender-matched normal volunteers at rest and during leg exercise with 2.5 kg ankle weights. Peak left-ventricular filling rates (PFRs) and myocardial perfusion reserve (MPRI) were calculated during adenosine stress. Resting PCr/ATP was significantly reduced in HCM (HCM: 1.71 ± 0.35, normal 2.14 ± 0.35 P < 0.0001). During exercise, there was a further reduction in PCr/ATP in HCM (1.56 ± 0.29, P = 0.02 compared with rest) but not in normals (2.16 ± 0.26, P = 0.98 compared with rest). There was no correlation between PCr/ATP reduction and cardiac mass, wall thickness, MPRI, or late-gadolinium enhancement. PFR and PCr/ATP were significantly correlated at rest (r = 0.48, P = 0.02) and stress (r = 0.53, P = 0.01).. During exercise, the pre-existing energetic deficit in HCM is further exacerbated independent of hypertrophy, perfusion reserve, or degree of fibrosis. This is in keeping with the change at the myofilament level. We offer a potential explanation for exercise-related diastolic dysfunction in HCM.

Topics: Adenosine Triphosphate; Adult; Blood Pressure; Cardiomyopathy, Hypertrophic; Case-Control Studies; Diastole; Energy Metabolism; Exercise; Female; Heart Rate; Humans; Magnetic Resonance Angiography; Magnetic Resonance Imaging, Cine; Magnetic Resonance Spectroscopy; Male; Phosphocreatine; Prospective Studies; Stroke Volume; Ventricular Dysfunction, Left

Left ventricular (LV) hypertrophy (LVH) and congestive heart failure are accompanied by changes in myocardial ATP metabolism. However, the rate of ATP hydrolysis cannot be measured in the in vivo heart with the conventional techniques. Here, we used a double-saturation phosphorous-31 magnetic resonance spectroscopy-magnetization saturation transfer protocol to monitor ATP hydrolysis rate in swine hearts as the hearts became hypertrophic in response to aortic banding (AOB). Animals that underwent AOB (n = 22) were compared with animals that underwent sham surgery (n = 8). AOB induced severe LVH (cardiac MRI). LV function (ejection fraction and systolic thickening fraction) declined significantly, accompanied by deferent levels of pericardial effusion, and wall stress increased in aorta banded animals at week 1 after AOB, suggesting acute heart failure, which recovered by week 8 when concentric LVH restored LV wall stresses. Severe LV dysfunction was accompanied by corresponding declines in myocardial bioenergetics (phosphocreatine-to-ATP ratio) and in the rate of ATP production via creatine kinase at week 1. For the first time, the same linear relationships of the rate increase of the constants of the ATP hydrolysis rate (kATP→Pi) vs. the LV rate-pressure product increase during catecholamine stimulation were observed in vivo in both normal and LVH hearts. Collectively, these observations demonstrate that the double-saturation, phosphorous-31 magnetic resonance spectroscopy-magnetization saturation transfer protocol can accurately monitor myocardial ATP hydrolysis rate in the hearts of living animals. The severe reduction of LV chamber function during the acute phase of AOB is accompanied by the decrease of myocardial bioenergetic efficiency, which recovers as the compensated LVH restores the LV wall stresses.

Topics: Adenosine Triphosphate; Animals; Creatine Kinase; Female; Hydrolysis; Hypertrophy, Left Ventricular; Magnetic Resonance Spectroscopy; Phosphocreatine; Swine; Ventricular Dysfunction, Left

(31)P MRS provides a unique non-invasive window into myocardial energy homeostasis. Mouse models of cardiac disease are widely used in preclinical studies, but the application of (31)P MRS in the in vivo mouse heart has been limited. The small-sized, fast-beating mouse heart imposes challenges regarding localized signal acquisition devoid of contamination with signal originating from surrounding tissues. Here, we report the implementation and validation of three-dimensional image-selected in vivo spectroscopy (3D ISIS) for localized (31)P MRS of the in vivo mouse heart at 9.4 T. Cardiac (31)P MR spectra were acquired in vivo in healthy mice (n = 9) and in transverse aortic constricted (TAC) mice (n = 8) using respiratory-gated, cardiac-triggered 3D ISIS. Localization and potential signal contamination were assessed with (31)P MRS experiments in the anterior myocardial wall, liver, skeletal muscle and blood. For healthy hearts, results were validated against ex vivo biochemical assays. Effects of isoflurane anesthesia were assessed by measuring in vivo hemodynamics and blood gases. The myocardial energy status, assessed via the phosphocreatine (PCr) to adenosine 5'-triphosphate (ATP) ratio, was approximately 25% lower in TAC mice compared with controls (0.76 ± 0.13 versus 1.00 ± 0.15; P < 0.01). Localization with one-dimensional (1D) ISIS resulted in two-fold higher PCr/ATP ratios than measured with 3D ISIS, because of the high PCr levels of chest skeletal muscle that contaminate the 1D ISIS measurements. Ex vivo determinations of the myocardial PCr/ATP ratio (0.94 ± 0.24; n = 8) confirmed the in vivo observations in control mice. Heart rate (497 ± 76 beats/min), mean arterial pressure (90 ± 3.3 mmHg) and blood oxygen saturation (96.2 ± 0.6%) during the experimental conditions of in vivo (31)P MRS were within the normal physiological range. Our results show that respiratory-gated, cardiac-triggered 3D ISIS allows for non-invasive assessments of in vivo mouse myocardial energy homeostasis with (31)P MRS under physiological conditions.

Topics: Adenosine Triphosphate; Anesthesia, Inhalation; Anesthetics, Inhalation; Animals; Aorta; Energy Metabolism; Hemodynamics; Homeostasis; Imaging, Three-Dimensional; Isoflurane; Ligation; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C57BL; Myocardium; Oxygen; Phosphocreatine; Phosphorus Isotopes; Ventricular Dysfunction, Left

Left ventricular (LV) hypertrophy in aortic stenosis (AS) is characterized by reduced myocardial perfusion reserve due to coronary microvascular dysfunction. However, whether this hypoperfusion leads to tissue deoxygenation is unknown. We aimed to assess myocardial oxygenation in severe AS without obstructive coronary artery disease, and to investigate its association with myocardial energetics and function.. Twenty-eight patients with isolated severe AS and 15 controls underwent cardiovascular magnetic resonance (CMR) for assessment of perfusion (myocardial perfusion reserve index-MPRI) and oxygenation (blood-oxygen level dependent-BOLD signal intensity-SI change) during adenosine stress. LV circumferential strain and phosphocreatine/adenosine triphosphate (PCr/ATP) ratios were assessed using tagging CMR and 31P MR spectroscopy, respectively.. AS patients had reduced MPRI (1.1 ± 0.3 vs. controls 1.7 ± 0.3, p < 0.001) and BOLD SI change during stress (5.1 ± 8.9% vs. controls 18.2 ± 10.1%, p = 0.001), as well as reduced PCr/ATP (1.45 ± 0.21 vs. 2.00 ± 0.25, p < 0.001) and LV strain (-16.4 ± 2.7% vs. controls -21.3 ± 1.9%, p < 0.001). Both perfusion reserve and oxygenation showed positive correlations with energetics and LV strain. Furthermore, impaired energetics correlated with reduced strain. Eight months post aortic valve replacement (AVR) (n = 14), perfusion (MPRI 1.6 ± 0.5), oxygenation (BOLD SI change 15.6 ± 7.0%), energetics (PCr/ATP 1.86 ± 0.48) and circumferential strain (-19.4 ± 2.5%) improved significantly.. Severe AS is characterized by impaired perfusion reserve and oxygenation which are related to the degree of derangement in energetics and associated LV dysfunction. These changes are reversible on relief of pressure overload and hypertrophy regression. Strategies aimed at improving oxygen demand-supply balance to preserve myocardial energetics and LV function are promising future therapies.

Topics: Adenosine; Adenosine Triphosphate; Aged; Aortic Valve Stenosis; Biomarkers; Case-Control Studies; Coronary Circulation; Energy Metabolism; Female; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging, Cine; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myocardial Perfusion Imaging; Myocardium; Oxygen Consumption; Phosphocreatine; Predictive Value of Tests; Severity of Illness Index; Vasodilator Agents; Ventricular Dysfunction, Left; Ventricular Function, Left

Impaired energy metabolism has been implicated in the pathogenesis of heart failure. Hyperpolarized (13)C magnetic resonance (MR), in which (13)C-labelled metabolites are followed using MR imaging (MRI) or spectroscopy (MRS), has enabled non-invasive assessment of pyruvate metabolism. We investigated the hypothesis that if we serially examined a model of heart failure using non-invasive hyperpolarized [(13)C]pyruvate with MR, the profile of in vivo pyruvate oxidation would change throughout the course of the disease.. Dilated cardiomyopathy (DCM) was induced in pigs (n = 5) by rapid pacing. Pigs were examined using MR at weekly time points: cine-MRI assessed cardiac structure and function; hyperpolarized [2-(13)C]pyruvate was administered intravenously, and (13)C MRS monitored [(13)C]glutamate production; (31)P MRS assessed cardiac energetics [phosphocreatine (PCr)/ATP]; and hyperpolarized [1-(13)C]pyruvate was administered for MRI of pyruvate dehydrogenase complex (PDC)-mediated pyruvate oxidation via [(13)C]bicarbonate production. Early in pacing, the cardiac index decreased by 25%, PCr/ATP decreased by 26%, and [(13)C]glutamate production decreased by 51%. After clinical features of DCM appeared, end-diastolic volume increased by 40% and [(13)C]bicarbonate production decreased by 67%. Pyruvate dehydrogenase kinase 4 protein increased by two-fold, and phosphorylated Akt decreased by half. Peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1 gene expression decreased by a half and a third, respectively.. Despite early changes associated with cardiac energetics and (13)C incorporation into the Krebs cycle, pyruvate oxidation was maintained until DCM developed, when the heart's capacity to oxidize both pyruvate and fats was reduced. Hyperpolarized (13)C MR may be important to characterize metabolic changes that occur during heart failure progression.

Topics: Adenosine Triphosphate; Animals; Bicarbonates; Carbon Isotopes; Cardiac Pacing, Artificial; Cardiac Volume; Cardiomyopathy, Dilated; Carnitine O-Palmitoyltransferase; Citric Acid Cycle; Disease Models, Animal; Energy Metabolism; Gene Expression; Glutamic Acid; Glycolysis; Heart Failure; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Membrane Transport Proteins; Phosphocreatine; PPAR alpha; Protein Kinases; Pyruvate Dehydrogenase Complex; Pyruvic Acid; Swine; Ventricular Dysfunction, Left

Adriamycin (ADR) is an established, life-saving antineoplastic agent, the use of which is often limited by cardiotoxicity. ADR-induced cardiomyopathy is often accompanied by depressed myocardial high-energy phosphate (HEP) metabolism. Impaired HEP metabolism has been suggested as a potential mechanism of ADR cardiomyopathy, in which case the bioenergetic decline should precede left ventricular (LV) dysfunction. We tested the hypothesis that murine cardiac energetics decrease before LV dysfunction following ADR (5 mg/kg ip, weekly, 5 injections) in the mouse. As a result, the mean myocardial phosphocreatine-to-ATP ratio (PCr/ATP) by spatially localized (31)P magnetic resonance spectroscopy decreased at 6 wk after first ADR injection (1.79 + or - 0.18 vs. 1.39 + or - 0.30, means + or - SD, control vs. ADR, respectively, P < 0.05) when indices of systolic and diastolic function by magnetic resonance imaging were unchanged from control values. At 8 wk, lower PCr/ATP was accompanied by a reduction in ejection fraction (67.3 + or - 3.9 vs. 55.9 + or - 4.2%, control vs. ADR, respectively, P < 0.002) and peak filling rate (0.56 + or - 0.12 vs. 0.30 + or - 0.13 microl/ms, control vs. ADR, respectively, P < 0.01). PCr/ATP correlated with peak filling rate and ejection fraction, suggesting a relationship between cardiac energetics and both LV systolic and diastolic dysfunction. In conclusion, myocardial in vivo HEP metabolism is impaired following ADR administration, occurring before systolic or diastolic abnormalities and in proportion to the extent of eventual contractile abnormalities. These observations are consistent with the hypothesis that impaired HEP metabolism contributes to ADR-induced myocardial dysfunction.

Topics: Adenosine Triphosphate; Animals; Antibiotics, Antineoplastic; Disease Models, Animal; Down-Regulation; Doxorubicin; Energy Metabolism; Magnetic Resonance Imaging, Cine; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C57BL; Myocardial Contraction; Myocardium; Phosphocreatine; Stroke Volume; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left

To study the role of early energetic abnormalities in the subsequent development of heart failure, we performed serial in vivo combined magnetic resonance imaging (MRI) and (31)P magnetic resonance spectroscopy (MRS) studies in mice that underwent pressure-overload following transverse aorta constriction (TAC). After 3 wk of TAC, a significant increase in left ventricular (LV) mass (74 +/- 4 vs. 140 +/- 26 mg, control vs. TAC, respectively; P < 0.000005), size [end-diastolic volume (EDV): 48 +/- 3 vs. 61 +/- 8 microl; P < 0.005], and contractile dysfunction [ejection fraction (EF): 62 +/- 4 vs. 38 +/- 10%; P < 0.000005] was observed, as well as depressed cardiac energetics (PCr/ATP: 2.0 +/- 0.1 vs. 1.3 +/- 0.4, P < 0.0005) measured by combined MRI/MRS. After an additional 3 wk, LV mass (140 +/- 26 vs. 167 +/- 36 mg; P < 0.01) and cavity size (EDV: 61 +/- 8 vs. 76 +/- 8 microl; P < 0.001) increased further, but there was no additional decline in PCr/ATP or EF. Cardiac PCr/ATP correlated inversely with end-systolic volume and directly with EF at 6 wk but not at 3 wk, suggesting a role of sustained energetic abnormalities in evolving chamber dysfunction and remodeling. Indeed, reduced cardiac PCr/ATP observed at 3 wk strongly correlated with changes in EDV that developed over the ensuing 3 wk. These data suggest that abnormal energetics due to pressure overload predict subsequent LV remodeling and dysfunction.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathy, Hypertrophic; Energy Metabolism; Hypertrophy, Left Ventricular; Male; Metabolic Clearance Rate; Mice; Mice, Inbred C57BL; Myocardial Contraction; Phosphocreatine; Ventricular Dysfunction, Left; Ventricular Remodeling

The use of cardiac magnetic resonance (CMR) has emerged in the last decades. Technical innovations provide fast and high-quality imaging sequences and CMR is often proposed as a gold-standard for the in vivo evaluation of cardiac function, morphologic details and infarct size. Also the 31-phosphorous magnetic resonance spectroscopy (MRS) is a unique tool to investigate the human myocardial high-energy phosphate (HEP) metabolism in vivo. PCr/b-ATP ratio examined by MRS is mainly used as an index for cardiac energy metabolism. We have described decreased PCr/b-ATP ratios in patients with diabetes mellitus, hypercholesterolemia and hemochromatosis. The use of CMR to study the effects of ischemia time on the evolution of myocardial infarct characteristics after an acute myocardial infarction (AMI) treated with a primary angioplasty (p-PTCA) is a promising new application of this technique. Results of this study will further help to clarify the impact of ischemia time on myocardial regional functional recovery after p-PTCA.

Topics: Adenosine Triphosphate; Angioplasty, Balloon, Coronary; Contrast Media; Energy Metabolism; Heart Diseases; Humans; Magnetic Resonance Imaging; Magnetic Resonance Imaging, Cine; Magnetic Resonance Spectroscopy; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphocreatine; Prognosis; Stents; Ventricular Dysfunction, Left

To test whether left ventricular (LV) dysfunction affecting type 1 diabetic-uremic patients was associated with abnormal heart high-energy phosphates (HEPs) and to ascertain whether these alterations were also present in recipients of kidney or kidney-pancreas transplantation.. Heart failure is the major determinant of mortality in patients with diabetic uremia. Both uremia and diabetes induce alterations of cardiac HEPs metabolism.. Magnetic resonance imaging and phosphorous magnetic resonance spectroscopy of the LV were performed in the resting state by means of a 1.5-T clinical scanner. Eleven diabetic-uremic patients, 5 nondiabetic patients with uremia, 11 diabetic recipients of kidney transplantation, and 16 diabetic recipients of combined kidney-pancreas transplantation were studied in a cross-sectional fashion. Eleven nondiabetic recipients of kidney-only transplant and 13 healthy subjects served as control groups.. Uremic patients had higher LV mass, diastolic dysfunction, and lower phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio in comparison with recipients of kidney-pancreas or nondiabetic recipients of kidney transplant. In diabetic recipients of kidney transplant the PCr/ATP ratio was higher than in uremic patients but was lower than in the controls. Recipients of combined kidney-pancreas transplant had a higher ratio than uremic patients but no difference was found in comparison with controls.. Altered resting myocardial HEPs metabolism may contribute to LV dysfunction in diabetic-uremic patients. In diabetic recipients of kidney transplantation, a certain degree of LV metabolic and functional impairment was found. In combined kidney-pancreas recipients the resting LV metabolism and function were not different than in controls.

Topics: Adenosine Triphosphate; Aged; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus, Type 1; Energy Metabolism; Female; Heart Ventricles; Humans; Kidney Transplantation; Magnetic Resonance Spectroscopy; Male; Middle Aged; Pancreas Transplantation; Phosphocreatine; Phosphorus Isotopes; Uremia; Ventricular Dysfunction, Left

To investigate whether alterations in high-energy phosphates occur in the myocardium of persons with diabetes mellitus type I. Microvascular abnormalities and dysfunction via thickening of the basement membrane are known to occur in diabetic patients. Myocardial high-energy phosphates have been shown to be reduced by ischemia, and alterations of the cardiac metabolism are the primary consequence of myocardial ischemia.. The present study involved 34 male patients (mean age 35.5 +/- 10.1) with diabetes mellitus type I and 35 healthy male volunteers (mean age 36 +/- 8.6) as age-matched controls. Phosphorus-31 magnetic resonance spectroscopic imaging of the heart was performed in all subjects using a 1.5-T whole-body magnetic resonance scanner. The ratios of phosphocreatine (PCr) to beta-adenosinetriphosphate (beta-ATP) were calculated. Moreover, echocardiographic evaluation and stress tests were performed in all individuals.. The myocardium of patients with diabetes mellitus type I showed significantly decreased ratios of PCr to beta-ATP compared with healthy controls in the left ventricle (1.90 +/- 0.4 vs. 2.15 +/- 0.3, p < 0.05). We found a moderate negative correlation between the ratio of PCr to beta-ATP in the left ventricle and both, the diastolic left ventricular function (E/A; r = -0.41) and the glycohemoglobin A1c (GHbA1c; r = -0.42).. This study demonstrates for the first time a decreased ratio of PCr to beta-ATP in the myocardium of persons with diabetes mellitus type I without a known history of coronary heart disease.

Topics: Adenosine Triphosphate; Adult; Biomarkers; Case-Control Studies; Data Interpretation, Statistical; Diabetes Mellitus, Type 1; Echocardiography; Exercise Test; Glycated Hemoglobin; Heart Ventricles; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myocardium; Phosphocreatine; Phosphorus Isotopes; Ventricular Dysfunction, Left

Topics: Adenosine Triphosphate; Aortic Valve Stenosis; Case-Control Studies; Heart Valve Prosthesis; Humans; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Phosphates; Phosphocreatine; Ventricular Dysfunction, Left

Hypertension is an important clinical problem and is often accompanied by left ventricular (LV) hypertrophy and dysfunction. Whether the myocardial high-energy phosphate (HEP) metabolism is altered in human hypertensive heart disease and whether this is associated with LV dysfunction is not known.. Eleven patients with hypertension and 13 age-matched healthy subjects were studied with magnetic resonance imaging at rest and with phosphorus-31 magnetic resonance spectroscopy at rest and during high-dose atropine-dobutamine stress. Hypertensive patients showed higher LV mass (98+/-28 g/m2) than healthy control subjects (73+/-13 g/m2, P<0.01). LV filling was impaired in patients, reflected by a decreased peak rate of wall thinning (PRWThn), E/A ratio, early peak filling rate, and early deceleration peak (all P<0. 05), whereas systolic function was still normal. The myocardial phosphocreatine (PCr)/ATP ratio determined in patients at rest (1. 20+/-0.18) and during stress (0.95+/-0.25) was lower than corresponding values obtained from healthy control subjects at rest (1.39+/-0.17, P<0.05) and during stress (1.16+/-0.18, P<0.05). The PCr/ATP ratio correlated significantly with PRWThn (r=-0.55, P<0.01), early deceleration peak (r=-0.56, P<0.01), and with the rate-pressure product (r=-0.53, P<0.001).. Myocardial HEP metabolism is altered in patients with hypertensive heart disease. In addition, there is an association between impaired LV diastolic function and altered myocardial HEP metabolism in humans. The level of myocardial PCr/ATP is most likely determined by the level of cardiac work load.

Topics: Adenosine Triphosphate; Adult; Aged; Diastole; Humans; Hypertension; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Phosphocreatine; Ventricular Dysfunction, Left

The cardioprotective properties of inhibition of poly (ADP-ribose) synthetase (PARS) were investigated in the isolated perfused heart of the rat. Hearts were perfused in the Langendorff mode and subjected to 23 min total global ischaemia and reperfused for 60 min. Left ventricular function was assessed by means of an intra-ventricular balloon. High energy phosphates were measured by 31P-NMR spectroscopy. Intracellular levels of NAD were measured by capillary electrophoresis of perchloric acid extracts of hearts at the end of reperfusion. Reperfusion in the presence of the PARS inhibitor 1,5 didroxyisoquinoline (ISO, 100 microM) attenuated the mechanical dysfunction observed following 1 h of reperfusion; 27+/-13 and 65+/-8% recovery of preischaemic rate pressure product for control and 100 microM ISO, respectively. This cardioprotection was accompanied by a preservation of intracellular high-energy phosphates during reperfusion; 38+/-2 vs 58+/-4% (P<0.05) of preischaemic levels of phosphocreatine (PCr) for control and 100 microM ISO respectively and 23+/-1 vs 31+/-3% (P < 0.05) of preischaemic levels of ATP for control and 100 microM ISO respectively. Cellular levels of NAD were higher in ISO treated hearts at the end of reperfusion; 2.56+/-0.45 vs 4.76+/-1.12 micromoles g(-1) dry weight (P<0.05) for control and ISO treated. These results demonstrate that the cardioprotection afforded by inhibition of PARS activity with ISO is accompanied by a preservation of high-energy phosphates and cellular NAD levels and suggest that the mechanism responsible for this cardioprotection may involve prevention of intracellular ATP depletion.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiotonic Agents; Diastole; Enzyme Inhibitors; Heart; In Vitro Techniques; Isoproterenol; Isoquinolines; Magnetic Resonance Spectroscopy; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Phosphocreatine; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Sprague-Dawley; Systole; Ventricular Dysfunction, Left

31P-NMR was used to monitor myocardial bioenergetics in compensated and failing SHHF/MCC-fa(cp) (SHF) rat hearts. The SHHF/Mcc-fa(cp) (spontaneous hypertension and heart failure) rat is a relatively new genetic model in which all individuals spontaneously develop congestive heart failure, most during the second year of life. Failing SHF rat hearts displayed a pronounced decrease in resting PCr:ATP ratios (P<0.001), which was explained by a significant (P<0. 0001) drop in total creatine (47.2+/-3.1 nmol/mg protein) v age matched controls (106+/-3 nmol/mg protein). In end stage failure, NMR determined PCr was 2.9+/-0.1 micro mol/g wet weight under basal conditions. In contrast, 6- and 20-month-old controls and compensated SHFs had PCr values of 5.3+/-0.1, and 5.1+/-0.5 and 5. 1+/-0.2 micro mol/g wet weight. Both compensated and failing SHF hearts were metabolically compromised when the rate pressure product (RPP) was increased, as evidenced by an increase in Pi and a drop in PCr. Compensated SHF hearts, however, were able to increase rate pressure products (RRP, mmHg X beats/min) from 44.5+/-1.4 to 66.6+/-3. 4 K with dobutamine infusion, whereas hearts in end-stage failure were able to increase their RPP from baseline values of 27+/-4 K to only 37+/-7 K. The data indicate that a pronounced decline in PCr and total creatine signals the transition from compensatory hypertrophy to decompensation and failure in the SHF rat model of hypertensive cardiomyopathy.

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Creatine; Disease Models, Animal; Energy Metabolism; Heart Failure; In Vitro Techniques; Magnetic Resonance Spectroscopy; Male; Myocardium; Perfusion; Phosphocreatine; Phosphorus Isotopes; Rats; Rats, Inbred F344; Rats, Mutant Strains; Rats, Sprague-Dawley; Ventricular Dysfunction, Left

Hemodynamic deterioration resulting from brain death-induced myocardial left ventricular dysfunction may preclude heart donation. A reduced myocardial high-energy phosphate content, assessed by biopsy specimens, has been suggested to be responsible for this phenomenon. By applying phosphorus 31 magnetic resonance spectroscopy, in vivo myocardial high-energy phosphate metabolism can be studied continuously.. Twelve cats were sedated, intubated, ventilated, and studied for 240 minutes. Heart rate, arterial blood pressure, and arterial blood gases were monitored. Central venous pressure was kept constant. Myocardial work was expressed as rate-pressure product (RPP=heart rate x systolic arterial blood pressure). After sternotomy a radio frequency surface coil was positioned onto the left ventricle. A parietal trephine hole was drilled, and an inflatable balloon was inserted. The animal was placed into a 4.7 T horizontal 40 cm bore magnet interfaced to a spectrometer. Brain death (n=6) was induced by rapid inflation of the balloon; the six other cats served as a sham-operated control group. 31P spectra were obtained in 30 seconds, with ventilation and arterial blood pressure curve triggering. The phosphocreatine/to/adenosine triphosphate ratio, as an estimator of energy metabolism, was calculated.. Brain death was established within 30 seconds after inflation of the balloon. Changes in RPP were characterized by a triphasic profile with a maximum increase from 19.3+/-1.4 x 10(3) to 87.5+/-8.1 x 10(3) mm Hg x min(-1) (p < .0001 vs control group) at 2 minutes after inflation of the balloon. Subsequently, RPP decreased and was normalized at 15 minutes after inflation. The third phase was characterized by hemodynamic deterioration, which became significant at 180 minutes and resulted in mean arterial pressure of 71+/-12 mm Hg (p < .05 vs control group) at the end of the experimental period. RPP deteriorated to 14.6+/-2.0 x 10(3) mm Hg x min(-1) (p < .05 vs control group) at 240 minutes. Because the heart rate remained constant during the third phase, the decrease in RPP was caused by a decrease in systolic arterial blood pressure. The initial phosphocreatine/adenosine triphosphate ratio of 1.65+/-0.16 varied to 1.52+/-0.06 at 2 minutes, and to 1.73 +/-0.17 (all values NS vs control group and vs initial ratio) at 240 minutes.. The energy status of the heart is not affected by brain death. Therefore brain death-induced hemodynamic deterioration is not caused by impaired myocardial high-energy phosphate metabolism.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Brain Death; Cats; Energy Metabolism; Heart Rate; Hemodynamics; Magnetic Resonance Spectroscopy; Male; Myocardial Contraction; Phosphocreatine; Ventricular Dysfunction, Left; Ventricular Function, Left

The novel blocker of voltage-gated Na+ channels KC 12291 (1-(5-phenyl-1,2,4-thiadiazol-3-yl-oxypropyl)-3-[N-methyl-N- [2-(3,4-dimethoxyphenyl)ethyl] amino] propane hydrochloride) delays myocardial Na+ overload in ischemia. To test whether KC 12291 displays cardioprotective properties in the intact heart, cardiac function, energy status and intracellular pH (31P NMR) as well as ion homeostasis (23Na NMR) were investigated during low-flow ischemia (100 microl/min for 36 min) followed by reperfusion. In the well-oxygenated, isolated perfused guinea pig heart, KC 12291 (1 microM) had no effect on left ventricular developed pressure (LVDP; 54+/-19 mmHg). KC 12291 delayed the onset and decreased the extent of ischemic contracture and markedly improved the recovery of LVDP in reperfusion [39+/-14 mmHg (n=4) vs 2+/-2 mmHg in controls (n=5)]. KC 12291 did not influence the rapid drop in phosphocreatine (PCr) following onset of ischemia but attenuated the decline in ATP. It also diminished the ischemia-induced fall in intracellular pH [6.39+/-0.2 (n=6) vs 6.18+/-0.20 in controls (n=6)]. In reperfusion, KC 12291 remarkably enhanced the recovery of PCr (84.8+/-9.6% vs 51.1+/-8.8% of baseline) and ATP (38.2+/-12.9% vs 23.7+/-9.3% of baseline). It also accelerated the recovery of intracellular pH. KC 12291 not only reduced the extent of ischemia-induced Na+ overload, but also enhanced Na+ recovery. It is concluded that KC 12291 delays contracture and reduces ATP depletion and acidosis in ischemia, and markedly improves the functional, energetic and ionic recovery in reperfusion. Blocking voltage-gated Na+ channels in ischemia to delay Na+ overload may thus constitute a promising therapeutic approach for cardioprotection.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiovascular Agents; Energy Metabolism; Guinea Pigs; Heart; Hydrogen-Ion Concentration; In Vitro Techniques; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Phosphocreatine; Sodium; Thiadiazoles; Ventricular Dysfunction, Left; Ventricular Function, Left

We tested whether angiotensin-converting enzyme (ACE) inhibitor therapy with quinapril prevents the deterioration of mechanical function and high-energy phosphate metabolism that occurs in chronically infarcted heart. Rats were subjected to ligation of the left anterior descending coronary artery (LAD) or sham operation. Four groups were studied: sham-operated rats (n = 10), rats with myocardial infarction (MI, n = 9), sham-operated quinapril-treated rats (n = 8), and infarcted quinapril-treated (n = 13) rats. Treated rats received 6 mg/kg/day of the ACE inhibitor quinapril orally, initiated 1 h after MI or sham operation. Eight weeks after LAD ligation or sham operation, hearts were isolated and buffer-perfused isovolumically. High-energy phosphate metabolism and intracellular pH were continuously recorded with 31P-nuclear magnetic resonance (NMR) spectroscopy. Hearts were subjected to 15-min control, 30-min hypoxia (95% N2/5% CO2, and 30-min reoxygenation. Left ventricular developed pressure (LVDP) was reduced in infarcted hearts (58 +/- 10 vs. 98 +/- 9 mm Hg in sham, p < 0.05), and this reduction was partially prevented by quinapril (78 +/- 8 mm Hg). ATP content of residual intact myocardium after sham operation or MI was unchanged. Creatine phosphate was reduced in infarcted hearts (107 +/- 10 vs. 138 +/- 5% of control ATP, p < 0.05), and quinapril prevented this decrease (131 +/- 8%). Therefore, quinapril preserved both function and high-energy phosphate metabolism in the chronically infarcted heart. However, when hearts were subjected to acute hypoxia, susceptibility to acute metabolic stress was substantially increased in both quinapril-treated groups: ATP content at end-hypoxia was reduced to 31 +/- 7 and 37 +/- 6% in sham and infarcted quinapril-treated groups, whereas ATP in untreated sham and infarcted hearts was 66 +/- 6 and 66 +/- 3% of baseline values (p < 0.05 untreated vs. quinapril treated). Likewise, recovery of LVDP during reoxygenation was impaired by quinapril treatment (15 +/- 7 and 15 +/- 4 mm Hg in quinapril-treated sham and MI vs. 73 +/- 9 and 46 +/- 9 mm Hg in untreated sham and MI groups, p < 0.05 untreated vs. quinapril treated). The most likely explanation for the unexpected finding of increased susceptibility to acute metabolic stress in the quinapril-treated groups is reduced wall thickness leading to increased wall stress. The preservation of high-energy phosphate content in residual intact hearts after MI may contribute to

Topics: Adenosine Triphosphate; Angiotensin-Converting Enzyme Inhibitors; Animals; Energy Metabolism; Hypoxia; Isoquinolines; Magnetic Resonance Spectroscopy; Myocardial Infarction; Phosphates; Phosphocreatine; Quinapril; Rats; Rats, Wistar; Tetrahydroisoquinolines; Ventricular Dysfunction, Left

Cardiac failure remains an important problem after heart transplantation and may be associated with events that occur during brain death (BD) before transplantation. In this study, cardiac function is studied after BD, and biochemical evaluation of myocardial high-energy phosphates and the beta-adrenergic receptor system is presented.. The hearts of 17 mongrel dogs (23 to 31 kg) were instrumented with flow probes, micromanometers, and ultrasonic dimension transducers to measure ventricular pressure and volume relationships. In a validated canine BD model, systolic right and left ventricular (RV/LV) function was analyzed by load-insensitive measurements during caval occlusion (preload-recruitable stroke work, PRSW). The beta-adrenergic receptor (BAR) density, adenylate cyclase (AC) activity, and myocardial ATP and creatine phosphate (CP) were measured before and 6 to 7 hours after BD. Results are expressed as mean +/- SEM (*P < .05 versus baseline, paired two-tailed Student's t test). Myocardial function deteriorated significantly from baseline PRSW (RV, 22 +/- 1 erg x 10(3); LV, 75 +/- 4 erg x 10(3)) by 37 +/- 10% for the RV (P < .001) and 22 +/- 7% for the LV (P < .001). BAR density increased from 282 +/- 42 to 568 +/- 173 fmol/mg for the RV and from 291 +/- 64 to 353 +/- 56 fmol/mg for the LV. Isoproterenol-stimulated AC activity was also significantly enhanced after BD. ATP and CP, however, remained unchanged after BD compared with baseline values before BD.. BD causes significant systolic biventricular dysfunction. The loss of ventricular function after BD was more prominent in the right ventricle and may contribute to early postoperative RV failure in the recipient. These injuries occurred despite BAR system upregulation after BD. Global myocardial ischemia is unlikely, since ATP and CP remained normal before and after BD.

Topics: Adenosine Triphosphate; Animals; Brain Death; Dogs; Energy Metabolism; Heart; Hemodynamics; Male; Myocardium; Phosphocreatine; Receptors, Adrenergic, beta; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right; Ventricular Function

The aim of the present experimental study in the rat heart was to assess cardiac performance and metabolism in mild diabetes of 2 months' duration (postprandial blood sugar levels of 307 +/- 101 mg/dl and nearly normal fasting blood glucose of 102 +/- 40 mg/dl) using the working rat heart model at physiological workload with a perfusion time of 60 min. We also compared the effect of two forms of therapy for diabetes, islet transplantation and insulin therapy (s.c.), after 2 months. A 36% reduction in glucose utilization is metabolically characteristic for the diabetic heart, mainly caused by a 55% reduced glucose uptake (P < 0.001), but also by a nearly twofold increased lactate and pyruvate production (P < 0.001). This reduced carbohydrate metabolism is accompanied by a 37% reduction of oxygen uptake (P < 0.001) as well as a significant reduction in myocardial ATP and CP levels (P < 0.001), resulting in a significantly reduced cardiac output (P < 0.001). Moreover, the balance of energy reveals that the diabetic heart obtains 46% of its energy requirements for 1 h from endogenous glycogen, whereas the control heart obtains 91% of its energy needs (i.e. preferentially) from exogenous glucose (only 9% from endogenous glycogen). Both investigated therapeutic interventions led to a complete reversibility of the hemodynamic and metabolic alterations, indicating that the cause of diabetic cardiomyopathy in this model of mild and short-term diabetes is due to a defect in cardiac carbohydrate metabolism, which is correctable by insulin administration.

Topics: Adenosine Triphosphate; Analysis of Variance; Animals; Cardiac Output; Cardiomyopathies; Diabetes Mellitus, Experimental; Energy Metabolism; Glucose; Glycogen; In Vitro Techniques; Insulin; Islets of Langerhans Transplantation; Lactates; Male; Myocardium; Oxygen Consumption; Phosphocreatine; Pyruvates; Rats; Rats, Inbred Lew; Triglycerides; Ventricular Dysfunction, Left

Topics: Adenosine Triphosphate; Animals; Cardiotonic Agents; Carnitine; Humans; Myocardium; Phosphocreatine; Ventricular Dysfunction, Left