Effects of walking and strength training on resting and exercise cardiovascular responses in patients with intermittent claudication.

BACKGROUND: Exercise training is recommended as the first-line therapy for intermittent claudication patients. However, the effects of exercise therapy on cardiovascular function of these patients have been poorly studied. The aim of this study is to compare the effects of walking and strength training on cardiovascular responses assessed at rest and during exercise in patients with intermittent claudication. PATIENTS AND METHODS: Thirty-four patients with stable symptoms of intermittent claudication were randomized into two groups: strength training (ST) consisting of eight exercises, three sets of 10 repetitions, intensity of 11 - 13 on 15-grade Borg scale, 2-min interval between sets; and walking training (WT) consisting of walking on a treadmill, 15 bouts of 2-min, intensity of 11 - 13 on 15-grade Borg scale, with a 2-min interval between bouts. Before and after 12 weeks, blood pressure, heart rate and rate pressure product were measured at rest and during a progressive treadmill test until maximal claudication pain. RESULTS: Fifteen patients in each group completed the training program. After the training programs, resting systolic blood pressure (ST:-6 ± 13 mmHg and WT:-3 ± 18 mmHg, P = .04), heart rate (ST: -6 ± 10 bpm and WT:-2 ± 9 bpm, P = .03), and rate pressure product (ST:-1485 ± 1442 mmHg*bpm and WT:- 605 ± 2145 mmHg*bpm, P = .01) decreased significantly and similarly in both groups. Submaximal systolic blood pressure (ST: -14 ± 23 mmHg and WT:-6 ± 23 mmHg, P = .02), and rate pressure product (ST:-1579 ± 3444 mmHg*bpm and WT: -1264 ± 3005 mmHg*bpm, P = .04) decreased significantly and similarly in both groups. There were no changes in submaximal heart rate after ST and WT. Maximal systolic blood pressure, heart rate, and rate pressure product did not change in either group, although maximal exercise time increased similarly in the ST and WT groups (+31 ± 19 %, and +31 ± 32 %, respectively, P < .01). CONCLUSIONS: Strength and walking trainings promoted similar increases in walking capacity and decreases in resting and submaximal exercise cardiovascular load.

The Impact of Frailty on the Relationship between Life-Space Mobility and Quality of Life in Older Adults during the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic has led to abrupt restrictions of life-space mobility. The impact of shelter-in-place orders on older adults' health and well-being is still unclear. OBJECTIVE: To investigate the relationship between life-space mobility and quality of life (QoL) in older adults with and without frailty during the COVID-19 pandemic. DESIGN: Multicenter prospective cohort study based on structured telephone interviews. SETTING: Four geriatric outpatient clinics in the metropolitan area of Sao Paulo, Brazil. PARTICIPANTS: 557 community-dwelling adults aged 60 years and older. MEASUREMENTS: The Life-Space Assessment was used to measure community mobility before and during the COVID-19 pandemic, and a previously validated decrease of ≥ 5 points defined restricted life-space mobility. Frailty was assessed through the FRAIL (fatigue, resistance, ambulation, illnesses, and loss of weight) scale. The impact of shelter-in-place orders on QoL was evaluated with the question «How is the COVID-19 pandemic affecting your QoL?¼, to which participants could respond «not at all¼, «to some extent¼, or «to a great extent¼. We used ordinal logistic regressions to investigate the relationship between restricted life-space mobility and impact on QoL, adjusting our analyses for demographics, frailty, comorbidities, cognition, functionality, loneliness, depression, and anxiety. We explored whether frailty modified the association between life-space mobility and impact on QoL. RESULTS: Participants were on average 80±8 years old, 65% were women, and 33% were frail. The COVID-19 quarantine led to a restriction of community mobility in 79% of participants and affected the QoL for 77% of participants. We found that restricted life-space mobility was associated with impact on QoL in older adults during the pandemic, although frailty modified the magnitude of the association (P-value for interaction=0.03). Frail participants who experienced restricted life-space mobility had twice the odds of reporting an impact on QoL when compared with non-frail individuals, with respective adjusted odds ratios of 4.20 (95% CI=2.36-7.50) and 2.18 (95% CI=1.33-3.58). CONCLUSION: Older adults experienced substantial decreases in life-space mobility during the COVID-19 pandemic, and this unexpected change impacted their QoL. Providers should be particularly watchful for the consequences of abrupt life-space restrictions on frail individuals.

Severe novel influenza A (H1N1) infection in cancer patients.

BACKGROUND: The natural history and consequences of severe H1N1 influenza infection among cancer patients are not yet fully characterized. We describe eight cases of H1N1 infection in cancer patients admitted to the intensive care unit of a referral cancer center. PATIENTS AND METHODS: Clinical data from all patients admitted with acute respiratory failure due to novel viral H1N1 infection were reviewed. Lung tissue was submitted for viral and bacteriological analyses by real-time RT-PCR, and autopsy was conducted on all patients who died. RESULTS: Eight patients were admitted, with ages ranging from 55 to 65 years old. There were five patients with solid organ tumors (62.5%) and three with hematological malignancies (37.5%). Five patients required mechanical ventilation and all died. Four patients had bacterial bronchopneumonia. All deaths occurred due to multiple organ failure. A milder form of lung disease was present in the three cases who survived. Lung tissue analysis was performed in all patients and showed diffuse alveolar damage in most patients. Other lung findings were necrotizing bronchiolitis or extensive hemorrhage. CONCLUSIONS: H1N1 viral infection in patients with cancer can cause severe illness, resulting in acute respiratory distress syndrome and death. More data are needed to identify predictors of unfavorable evolution in these patients.

Acute renal failure and hypercalcemia in an athletic young man.

Hypercalcemia is a life-threatening disorder and is related primarily to neoplastic diseases and primary and secondary hyperparathyroidism. The association of hypercalcemia and renal failure is frequent in the medical literature, although pathogenetic mechanisms remain to be elucidated. In this article, we present a case of hypercalcemia and acute renal failure secondary to vitamin D and vitamin A intoxication, after an over-the-counter intramuscular use by a young man starting an athletic performance program. A discussion of clinical picture, diagnosis and treatment is made, and we highlight the risk of pathological conditions triggered by inadvertent use of supplementation products and formulas available in health and fitness commercial centers.

Lipid core nanoparticles resembling low-density lipoprotein and regression of atherosclerotic lesions: effects of particle size.

Particles are usually polydispersed and size is an important feature for lipid-based drug delivery systems in order to optimize cell-particle interactions as to pharmacologic action and toxicity. Lipid nanoparticles (LDE) with composition similar to that of low-density lipoprotein carrying paclitaxel were shown to markedly reduce atherosclerosis lesions induced in rabbits by cholesterol feeding. The aim of this study was to test whether two LDE fractions, one with small (20-60 nm) and the other with large (60-100 nm) particles, had different actions on the atherosclerotic lesions. The two LDE-paclitaxel fractions, prepared by microfluidization, were separated by density gradient ultracentrifugation and injected (4 mg/body weight, intravenously once a week) into two groups of rabbits previously fed cholesterol for 4 weeks. A group of cholesterol-fed animals injected with saline solution was used as control to assess lesion reduction with treatment. After the treatment period, the animals were euthanized for analysis. After treatment, both the small and large nanoparticle preparations of LDE-paclitaxel had equally strong anti-atherosclerosis action. Both reduced lesion extension in the aorta by roughly 50%, decreased the intima width by 75% and the macrophage presence in the intima by 50%. The two preparations also showed similar toxicity profile. In conclusion, within the 20-100 nm range, size is apparently not an important feature regarding the LDE nanoparticle system and perhaps other solid lipid-based systems.

Normal high energy phosphate ratios in "stunned" human myocardium.

OBJECTIVES: We sought to investigate whether alterations in cardiac high energy phosphates occur in postischemic "stunned" human myocardium. BACKGROUND: Transient postischemic myocardial dysfunction is a common phenomenon that occurs in a variety of clinical settings in the absence of necrosis, and its pathogenesis is still unclear. Cardiac high energy phosphates are reduced during ischemia, and persistently altered myocardial high energy phosphate metabolism has been suggested as a mechanism contributing to stunning. METHODS: We studied 29 patients with a first anterior myocardial infarction (MI) who underwent successful reperfusion within 6 h of the onset of chest pain. These patients underwent 31P magnetic resonance spectroscopy (MRS) a mean of 4 days after MI for measurement of left ventricular contractility and relative high energy phosphate metabolites. Twenty-one patients underwent a second 31P MRS study a mean of 39 days after MI. Eight volunteers served as control subjects. RESULTS: Global and infarct area wall motion scores improved significantly between the early and late studies. No difference was found between early cardiac phosphocreatine (PCr)/beta-adenosine triphosphate (beta-ATP) ratios in patients and control subjects ([mean +/- SD] 1.51 +/- 0.17 vs. 1.61 +/- 0.18, respectively, p = 0.17) or between early and late study results in patients (1.51 +/- 0.17 vs. 1.53 +/- 0.17, respectively, p = 0.6). For alpha of 0.05, the study had a 90% power to detect a 9% difference. CONCLUSIONS: The results of this study demonstrate normal myocardial PCr/ATP ratios in patients with myocardial stunning after reperfusion and suggest that relative cardiac high energy phosphates are not depleted in stunned human myocardium.

Effects of glycemic control upon serum lipids and lipid transfers to HDL in patients with type 2 diabetes mellitus: novel findings in unesterified cholesterol status.

OBJECTIVE: Investigate the relations of glycemic levels with plasma lipids and in vitro lipid transfers to HDL in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: 143 patients with type 2 diabetes not taking anti-lipidemic drugs were separated into 2 groups: group A included 62 patients with glycated hemoglobin (HbA1c)≤6.5% (48 mmol/mol) and group B 81 patients with HbA1c>6.5%. In vitro transfer of lipids was determined by 1 h incubation of a donor nanoemulsion containing radioactively labeled unesterified and esterified cholesterol, phospholipids and triglycerides with whole plasma followed by chemical precipitation and radioactive counting in the supernatant (HDL). RESULTS: LDL and HDL cholesterol were similar in Group A and B, but group B had higher triglycerides (2.31±1.30 vs. 1.58±0.61 mmol/l, P<0.0001) and total and non-HDL unesterified cholesterol (36.3±7.8 vs. 33.9±5.9 mmol/l, P<0,05; 30.6±7.9 vs. 27.6±6.2 mmol/l, P<0,05; respectively) than group A and a non-significant trend to increased apolipoprotein B (103±20 vs. 97±20 mg/dl, P=0.08). 36 patients with the highest, ≥8.0% (64 mmol/mol), HbA1c also showed non-significant trend of elevated non-esterified fatty acids (NEFA) compared to 37 with lowest, ≤6.0% (42 mmol/mol), HbA1c (P=0.08). Patients with higher NEFA had higher triglycerides than those with lower NEFA levels (P<0.01).Transfers of all lipids from nanoemulsion to HDL and lipid composition of HDL were equal in both groups. CONCLUSIONS: For the first time it was shown that in addition to triglycerides, unesterified cholesterol is also a marker of poor glycemic control. In vitro HDL lipid transfers, an important aspect of HDL metabolism, were not related with the glycemic control.

Usefulness of ST-segment depression in non-infarct-related electrocardiographic leads in predicting prognosis after thrombolytic therapy for acute myocardial infarction.

This study investigated both the in-hospital and long-term prognostic significance of ST-segment depression in non-infarct-related leads in patients who received thrombolytic therapy after acute myocardial infarction (AMI). We evaluated 221 consecutive patients who were admitted with their first AMI and underwent thrombolysis. Patients were followed for an average of 31 months and were classified into 3 groups: group 1 included 51 patients with persistent ST-segment depression, group 2 had 97 patients with transient ST-segment depression, and group 3 consisted of 73 patients without ST-segment depression (absent). Group 1 had significantly worse long-term survival during follow up by Kaplan-Meier analysis (55%) versus group 2 (81%) and group 3 (94%) (p = 0.0004) and higher event rates. This prognostic significance seemed to be maintained in both the anterior and inferior wall AMI groups. Multivariate analysis, using the Cox model, showed that Killip class, in-hospital left ventricular ejection fraction, and the persistence of ST-segment depression on the predischarge electrocardiogram (group 1) were independent predictors of survival. ST-segment depression in non-infarct-related leads on the predischarge electrocardiogram is an independent risk factor for worse long-term survival after anterior as well as inferior AMI treated with thrombolytic therapy.

Magnetic resonance imaging in Chagas' heart disease.

Many important aspects of Chagas' heart disease can be successfully assessed using magnetic resonance imaging of the heart. It is possible to obtain with great detail the anatomic characterization of the cardiac as well as important information of the functional or metabolic status of the heart. Magnetic resonance imaging after gadolinium infusion seems also a promising technique to obtain a better regional characterization of myocardial tissue, and may be important in the non-invasive diagnosis of active myocarditis in patients with Chagas' heart disease.

[Role of circumflex coronary artery involvement in non-Q wave myocardial infarction]. / Papel do acometimento da artéria coronária circunflexa no infarto do miocárdio sem onda Q.

PURPOSE: To determine the patency and incidence rates of left circumflex coronary artery (LCX) as the infarct related artery (IRA) in Q-wave and non-Q wave acute myocardial infarction (AMI). METHODS: Two-hundreds and twenty one patients (172 men) with AMI were stratified in Q and non-Q waves groups. All patients were submitted to cinecoronary angiography 72 hours after the beginning of symptoms and the IRA and its patency were evaluated. RESULTS: In non-Q wave AMI, the LCX was considered to be the IRA in 35% of the patients. In Q wave AMI, this incidence was 8% (p < 0.001). Occlusion of LCX was seen in all non-Q wave AMI patients when it was the IRA. CONCLUSION: The incidence of LCX as IRA was significantly higher in non-Q wave AMI patients. This group did not have the previously expected greater patency rates, what could result in different clinical and evolutive characteristics.

[Early revascularization of the arteries not related to infarction improves regional and global function of the left ventricle after acute myocardial infarction]. / A revascularização precoce das artérias não relacionadas ao infarto melhora a função regional e global do ventrículo esquerdo após o infarto agudo do miocárdio.

PURPOSE: To evaluate if early interventions which increase flow in the non-infarct related arteries (NRA) could improve long-term ventricular function in the non-infarct (NI) area after an acute myocardial infarction (MI). METHODS: We studied regional wall motion analyzed by the center-line method in two groups of patients with significant stenoses (> or = 70%) in the NRA after successful coronary reperfusion (chemical or mechanical thrombolysis). Group I (GI) consisted of 21 patients that were submitted to early (mean 14 days) complete surgical revascularization of both NRA and infarct related artery (IRA); the 12 group II (GII) patients underwent successful revascularization of the IRA only, with percutaneous transluminal coronary angioplasty (mean 6 days). Paired ventriculograms were obtained within 48 hours of the infarction and a mean of 17 months later. RESULTS: NI area contractility in GI patients improved from -0.35 +/- 2.16 to +0.62 +/- 1.6sd/chord (p < 0.05), whereas in GII decreased from +0.54 +/- 1.78 to -0.66 +/- 1.72 sd/chord (p < 0.05), p < 0.05 between the groups at follow-up. Mean infarct area wall motion did not differ between the two groups: from -3.04 +/- 2.43 to 2.61 +/- 2.49 sd/chord in GI (p = NS), and from -2.68 +/- 2.54 to -2.93 +/- 2.35 sd/chord in GII (p = NS). Mean global left ventricular (LV) ejection fraction did not change in GII patients (0.72 +/- 0.09 and 0.67 +/- 0.12, p = NS), but significantly increased from 0.63 +/- 0.12 to 0.72 +/- 0.11 in GI patients (p < 0.01). CONCLUSION: These data suggest that early revascularization of NRA with significant stenoses can improve not only the NI area regional contractility, but also the global LV function in the long-term follow-up of post MI patients treated with thrombolytic therapy.

[Evaluation of chronic morphological changes in the latissimus dorsi, after cardiomyoplasty, with magnetic resonance]. / Avaliação das alterações morfológicas crônicas do músculo grande dorsal, após cardiomioplastia, através da ressonância magnética.

PURPOSE: Long term clinical and hemodynamic benefits of dynamic cardiomyoplasty (DC) have been reported. However, no information is available about long-term morphological changes in the wrapped latissimus dorsi (LD) muscle in humans. METHODS: The latissimus dorsi muscle flap was evaluated by magnetic resonance imaging (MRI) in 5 patients submitted to DC for treatment of severe dilated cardiomyopathy. All patients were studied from 24 to 52 months after the surgical procedure at the time of the cardiomyostimulator replacement. In the interim, LD was stimulated with burst of 6 pulses (burst duration 185 msec, burst freq 30Hz) synchronized to every cardiac contraction with a maximum of 100 LD contractions/min. Images were acquired on a GE Sigma 1.5 T system (TE = 25ms, TR = R- Rx2, slice thickness 8mm). RESULTS: The thickness of was 7.6 +/- 0.8mm. In addition, the signal intensity of the LD was compared with that of thoracic skeletal muscle and was found to be increased (2.19 +/- 0.42). The signal intensity was similar to that of subcutaneous fat in those images. CONCLUSION: Morphologic changes in the wrapped LD muscle consistent with fatty degeneration occur after DC and can be detected by MRI. Further studies will be necessary to demonstrate the clinical significance of such LD muscle flap changes.

[Hospital outcome of patients with right ventricular infarction and the importance of right coronary artery patency]. / Evolução hospitalar de pacientes com infarto de ventrículo direito e a importância da perviabilidade da artéria coronária direita.

PURPOSE: To evaluate the importance of the right coronary artery (RCA) patency in patients with right ventricular infarction. METHODS: Fifty-two patients with inferior wall myocardial infarction and right ventricular involvement were studied and divided in two groups: group A (GA) included 35 patients in whom the RCA was patent at coronary angiography, and group B (GB), 17 who had an occluded RCA. They were prospectively evaluated for electrical and hemodynamic complications, as well as in-hospital mortality. RESULTS: The mortality in GA was 11% and 29% in GB, p = 0.13; electrical complications were 11% in GA and 35% in GB, p = 0.06; hemodynamic complications were 8% in GA and 41% in GB, p = 0.009. CONCLUSION: These findings suggest a trend towards reduction in mortality and electrical complications, and significant reduction of hemodynamic complications in patients with inferior wall myocardial infarction with involvement of the right ventricle who have the RCA patent. Thus, RCA patency appears to be important in determining in-hospital outcomes of these patients.

[Significance of the nuclear magnetic resonance in the detection of coronary artery patency after thrombolysis]. / Valor da ressonância nuclear magnética na detecção da perviabilidade da artéria coronária após trombólise.

PURPOSE: To determine the value of magnetic resonance imaging (MRI) in the noninvasive detection of infarct related coronary artery patency after thrombolysis. METHODS: We studied 26 patients with acute myocardial infarction submitted to thrombolysis underwent MRI studies before and after 0.1mmol/kg gadolinium-DTPA injection within the first 48 h of MI. Signal intensity was assessed by circumferential profile analysis techniques. RESULTS: The average ratio of signal intensity of infarcted tissue over normal myocardium (I/N) was significantly higher in patients with patent arteries (1.3 +/- 0.13 vs 1.12 +/- 0.07, p < 0.02). Compared to coronariography MRI, sensitivity of 81% and specificity of 100% for the diagnosis of coronary patency. CONCLUSION: Gadolinium infusion increased infarcted and normal myocardium differentiation. The study of gadolinium kinetics at MRI is a promising technique for noninvasive diagnosis of coronary patency.

Lipid core nanoparticles resembling low-density lipoprotein and regression of atherosclerotic lesions: effects of particle size

Particles are usually polydispersed and size is an important feature for lipid-based drug delivery systems in order to optimize cell-particle interactions as to pharmacologic action and toxicity. Lipid nanoparticles (LDE) with composition similar to that of low-density lipoprotein carrying paclitaxel were shown to markedly reduce atherosclerosis lesions induced in rabbits by cholesterol feeding. The aim of this study was to test whether two LDE fractions, one with small (20-60 nm) and the other with large (60-100 nm) particles, had different actions on the atherosclerotic lesions. The two LDE-paclitaxel fractions, prepared by microfluidization, were separated by density gradient ultracentrifugation and injected (4 mg/body weight, intravenously once a week) into two groups of rabbits previously fed cholesterol for 4 weeks. A group of cholesterol-fed animals injected with saline solution was used as control to assess lesion reduction with treatment. After the treatment period, the animals were euthanized for analysis. After treatment, both the small and large nanoparticle preparations of LDE-paclitaxel had equally strong anti-atherosclerosis action. Both reduced lesion extension in the aorta by roughly 50%, decreased the intima width by 75% and the macrophage presence in the intima by 50%. The two preparations also showed similar toxicity profile. In conclusion, within the 20-100 nm range, size is apparently not an important feature regarding the LDE nanoparticle system and perhaps other solid lipid-based systems.

Oxygen consumption is less in rat hearts arrested by low calcium than by high potassium at fixed flow.

The purpose of the present study was to determine whether myocardial oxygen consumption (MVO2) differs when the heart is arrested by hyperkalemic arresting solution (ASK) or by hypocalcemic arresting solution (ASCa) when coronary flow is maintained constant. MVO2 was measured in 12 isolated, Langendorff-perfused rat hearts alternately perfused with ASK (20 mM K+ and 1.5 mM Ca2+) and ASCa (5 mM K+ and 0.08 mM Ca2+). Six of the hearts were perfused with ASK for 10 min, ASCa for 5 min, ASK for a second 5 min, and finally ASCa for 5 min; ASCa and ASK were opposite in this sequence for the other six hearts. Measurements of MVO2 during ASK and ASCa arrest, taken at the end of each perfusion period, were analyzed to distinguish the independent influences of time and perfusate composition on MVO2 in the arrested hearts (analysis of covariance). Consistent with previous findings, MVO2 decreased with time after the onset of cardiac arrest with both solutions. The average per minute fall was 0.0003 ml O2.min-1.g-1 (P less than 0.01). However, at any given time after arrest, MVO2 averaged 0.004 ml.min-1.g-1 less during ASCa arrest than during ASK arrest (P less than 0.01), which amounted to a 15% reduction in MVO2. To test whether the increased MVO2 during hyperkalemic arrest was dependent on calcium in the perfusion medium, a third series of six hearts was studied in which MVO2 values measured during ASCa and ASK arrest were compared with those measured during arrest by hyperkalemic-hypocalcemic solution (ASK,Ca: 20 mM K+, 0.08 mM Ca2+).(ABSTRACT TRUNCATED AT 250 WORDS)

Cryptogenic mycotic aneurysm of the right coronary artery.

A 61-year-old man with chest pain and fever was referred to our hospital. The physical examination and electrocardiogram were unrevealing. Laboratory tests showed leukocytosis, and echocardiography showed mild pericardial effusion. The patient died soon after hospital admission. Necropsy revealed ruptured mycotic aneurysm of the right coronary artery in the absence of infective endocarditis. Thus, mycotic aneurysm of the coronary artery may occur without infective endocarditis and may be clinically manifested as pericarditis and leukocytosis.

Regulation of myocardial glycogenolysis during post-ischemic reperfusion.

Myocardial glycogen and the factors which primarily regulate its metabolism were studied during post-ischemic reperfusion. Myocardial [13C]glycogen was continuously monitored by 13C-NMR spectroscopy in beating rat hearts perfused with oxygenated solutions containing [1-13C]glucose (5 mM) and insulin, during normal flow at 15 ml/min (n = 5), and during reperfusion after 30 min of 1 ml/min (n = 5), or 0 ml/min (n = 4) ischemia. Mean myocardial [13C]glycogen fell during reperfusion from 1.1 +/- 0.6 at the end of zero-flow ischemia to 0.4 +/- 0.4 mumol of [13C]glucosyl units/g wet wt (P less than 0.02) over the first 7 min of reperfusion; it also fell during reflow following 1 ml/min ischemia, from 2.3 +/- 1.4 to 1.7 +/- 1.0 mumol (P less than 0.03) over the same interval. In parallel experiments, glycogen phosphorylase % a (GPA%) content was higher at the end of 30 min of 0 ml/min (37.3 +/- 7.3%, P less than 0.01), and trended higher after 1 ml/min flow (30.8 +/- 12.1%, P = 0.18) than under baseline conditions (20.1 +/- 7.4%). However GPA% returned to baseline values within 1 min of reflow after both 0 and 1 ml/min ischemic periods (20.6 +/- 3.0% and 19.0 +/- 8.0%, respectively). Inorganic phosphate, as determined by simultaneous 31P-NMR, remained elevated during early reperfusion relative to baseline, and significantly correlated with the extent of decline in [13C]glycogen during reperfusion (r = 0.79, P less than 0.01). Thus, glycogen breakdown continues to occur during early post-ischemic reperfusion, but the mechanism is not related to elevated GPA%, and may be due to persistently increased inorganic phosphate at that time.

Indexing tricarboxylic acid cycle flux in intact hearts by carbon-13 nuclear magnetic resonance.

Although the tricarboxylic acid (TCA) cycle is the prime means of carbon metabolism for energy generation in normal myocardium, the noninvasive quantification of TCA cycle flux in intact cardiac tissues is difficult. A novel approach for estimating citric acid cycle flux using 13C nuclear magnetic resonance (NMR) is presented and evaluated experimentally by comparison with measured myocardial oxygen consumption over a wide range of cardiac contractile function in intact, beating rat hearts. Continuous series of 13C NMR spectra, obtained after the introduction of [2-13C]acetate as substrate, quantified the time course of 13C appearance in the carbon positions of myocardial glutamate, which are sequentially enriched via citric acid cycle metabolism. A TCA cycle flux parameter was calculated using the premise that TCA cycle flux is inversely proportional to the time difference between 13C appearance in the C-4 and C-2 positions of glutamate (glutamate delta t50 [minutes]), which are enriched in subsequent "turns" of the TCA cycle. This TCA cycle flux parameter, termed KT, correlated strongly with myocardial oxygen consumption over a range of developed pressures in hearts perfused with 5 mM acetate (r = 0.98, p less than 0.001), as well as in separate studies in hearts perfused with 5 mM glucose and 0.5-0.8 mM acetate (r = 0.94, p less than 0.001). Results of numerical modeling of 13C glutamate kinetics suggest that this TCA cycle flux parameter, KT, is relatively insensitive to changes in metabolite pool sizes that could occur during metabolism of other substrates or during conditions of altered oxygen availability. Additional studies in separate hearts indicated that the time course of 13C appearance in citrate, which is predominantly mitochondrial in the rat heart, is similar to that in glutamate, further supporting the premise that the described 13C NMR parameters reflect mitochondrial citric acid cycle activity in intact cardiac tissues.

Influence of metabolic substrate on rat heart function and metabolism at different coronary flows.

The influence of metabolic substrate on contractile strength, myocardial oxygen consumption (MVO2), high- and low-energy phosphate levels, and intracellular pH were determined in isovolumically contracting isolated rat hearts perfused with solutions containing either glucose or hexanoate at both high and low coronary perfusion pressures (CPP). Contractile strength was not significantly influenced by substrate at a CPP of 80 mmHg. As coronary flow was decreased, developed pressure measured at a fixed left ventricular volume (LVV) was lower during hexanoate than glucose perfusion. The relationship between MVO2 and mechanical work determined at a CPP of 80 mmHg over a range of LVVs was shifted upward in a parallel manner when substrate was switched from glucose to hexanoate. The MVO2-work relationship measured at a fixed LVV but over a range of coronary flows (7-20 ml/min) was also parallel shifted upward on switching from glucose to hexanoate. Basal MVO2 was greater during hexanoate than glucose perfusion by an amount that accounted for two-thirds the total increase in MVO2 observed between the substrates under unloaded beating conditions. The remainder of the difference was attributed to increased energy requirements for excitation-contraction coupling. Inorganic phosphate concentrations increased more and phosphocreatine concentrations decreased more during low-flow conditions (3 ml/min) when hearts were perfused with hexanoate compared with glucose. Thus hexanoate decreases myocardial efficiency compared with glucose in large part by increasing non-work-related oxygen demands. This inefficiency impacts adversely on contractile strength and high-energy phosphate concentrations at low coronary flows.