Counseling families with chromosome 22q11 deletions: the catch in CATCH-22.
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Aorta, Thoracic↗
Biomedical subjects
J D Bristow
Publications and source records attributed to J D Bristow.
Metabolic adaptation to a gradual reduction in myocardial blood flow.
BACKGROUND: Studies during 20% to 50% reductions in regional coronary blood flow have revealed a number of metabolic and functional adaptations that suggest the heart downregulates energy requirements and contractility in response to ischemia. In contrast to prior studies of sudden changes in coronary blood flow, we tested whether the heart could reduce ATP consumption commensurate with a gradual decrease in coronary blood flow or whether transient metabolic abnormalities are a necessary trigger in this process. METHODS AND RESULTS: From 0 to 35 minutes, mean left anterior descending coronary artery blood flow was reduced by approximately 1% per minute in 10 acutely anesthetized and instrumented swine. Coronary blood flow then was held constant between 35 and 60 minutes at the resulting 35% net blood flow reduction. Although systemic hemodynamics remained stable, a significant decrease in regional left ventricular systolic wall thickening developed (from control value of 45 +/- 11% to 18 +/- 11% at 60 minutes, P < .001) without a sustained decrease in the phosphorylation potential (as assessed by a < 2% decrease in either the transmural or subendocardial phosphocreatine-to-ATP ratio) and with minimal myocardial lactate production (4 +/- 44 mumol.min-1 x 100 g-1). CONCLUSIONS: Metabolic markers of ischemia such as ratio of phosphocreatine to ATP, ATP content, lactate content, and lactate production were blunted during this protocol of gradually worsening ischemia. Thus, contractile abnormalities of mild ischemia can develop with minimal metabolic evidence of ischemia. The downregulation of myocardial energy requirements can almost keep pace with the gradual decline in coronary blood flow.
Adaptation, Physiological↗
Expression of neuronal nitric oxide synthase corresponds to regions of selective vulnerability to hypoxia-ischaemia in the developing rat brain.
Nitric oxide (NO) has been implicated in the pathogenesis of brain injury from hypoxia-ischaemia. In the brain, the enzyme responsible for NO synthesis is neuronal nitric oxide synthase (nNOS). Using in situ hybridization, immunohistochemistry and NADPH diaphorase histochemistry, we examined the spatial and temporal expression of nNOS during development of the rat brain to determine whether the expression of nNOS delineates the areas of the brain that are selectively vulnerable to hypoxic-ischaemia injury. The expression of nNOS was localized to discrete areas of the brain. nNOS could be detected in the developing forebrain in the 10-day-old embryo (E10). From E14 to E18, the highest level of expression was in the cortical plate, where the majority of neurons were positive. However, this expression diminished with time; in the adult there were only a few nNOS-positive neurones in the deep layers of the cortex. Expression of nNOS was not detected prenatally in the basal ganglia. There was transient high-level expression during the first postnatal week. Thereafter, the basal ganglia exhibited the adult pattern of expression. Expression of nNOS could be detected in the hippocampus at E16. This expression remained constant with regional localization in layers CA1 and CA3 in the adult. Similarly, nNOS expression in the developing cerebellum was observed only after birth. From the first day after birth (P1) to P6, expression was limited to the molecular cell layer. As the cerebellum matured, nNOS expression could be detected in the inner granular layer. By P21, the adult distribution of nNOS expression was observed. All regions expressing nNOS mRNA also demonstrated nNOS protein expression and NADPH diaphorase catalytic activity. Our results demonstrate that nNOS expression in the developing brain correlates with regions of selective vulnerability to hypoxic-ischaemic injury, and, therefore, supports a role for NO in hypoxic-ischaemic injury in the developing brain.
Animals↗
Metabolic aspects of hibernating myocardium.
Myocardial hibernation describes the clinical entity of a dysfunctional region of myocardium with reduced flow that shows improvement in function after flow is restored. It is postulated that despite the reduced flow, metabolic activity is sufficient to prevent tissue necrosis. Experimental work in animals supports this. A moderate reduction in flow to a region of the left ventricle in pigs initially results in the typical metabolic picture of ischemia: ATP and PCr fall and anaerobic metabolism is present. However, over the next hour, a hypometabolic response occurs that eliminates almost all metabolic findings of ischemia despite ongoing flow reductions. This appears to be an actively and tightly regulated response. The reduction in systolic function is an important part of the hypometabolic state, but cannot fully account for the downregulation of energy use.
Adenosine Triphosphate↗
Nitric oxide synthesized by gonadotropin-releasing hormone neurons is a mediator of N-methyl-D-aspartate (NMDA)-induced GnRH secretion.
N-Methyl-D-aspartate (NMDA) directly stimulates gonadotropin-releasing hormone (GnRH) neurons to secrete GnRH. It is not known if this stimulatory effect of NMDA is mediated by NO. Northern blot analysis of the immortalized hypothalamic GnRH neuronal cells (GT1-1) mRNA with a neuronal NOS cDNA revealed this clonal cell line expressed neuronal NOS transcripts as a single 10.5-kb band. Immunoblot analysis of GT1-1 proteins with anti-neuronal NOS serum showed that the GT1-1 cells contain neuronal NOS. GT1-1 cells were used to study the effects of NO and NMDA on GnRH release. L-Arginine (10(-2) M), a precursor of NO enhances basal GnRH secretion. Both oxyhemoglobin (Hb)(10(-6)-10(-4) M), a NO scavenger and N omega-nitro-L-arginine (NNA)(10(-3),10(-2) M), a NOS inhibitor and inactivator block basal as well as NMDA-induced GnRH release. Sodium nitroprusside (SNP) (10(-4), 10(-3) M), a NO donor stimulates GnRH release, an effect inhibited by Hb. Incubation of GT1-1 cells in Ca(2+)-free medium abolished the stimulatory effect of NMDA on GnRH release. In contrast, incubation in medium with increasing concentrations of Ca2+ enhances basal GnRH release as well as augments NMDA-mediated GnRH release. The results demonstrate that L-arginine-NO pathway is functional in the GT1-1 cells and an increase in intracellular Ca2+ [Ca2+]i following NMDA receptor activation activates NOS to generate NO. We conclude that endogenous NO mediates, at least in part, basal as well as NMDA-stimulated GnRH release and may play a role as an intercellular messenger in synchronizing pulsatile GnRH release.
Amino Acid Oxidoreductases↗
Data monitoring in the cardiac arrhythmia suppression trial.
OBJECTIVE: This report discusses practical aspects of data monitoring in a clinical trial which stopped ahead of schedule due to adverse findings. DESIGN: A review of the considerations and decisions made by the data-monitoring committee of the Cardiac Arrhythmia Suppression Trial (CAST), a randomized, double-blind clinical trial. PATIENTS: CAST consisted of men and women with a recent myocardial infarction, asymptomatic or minimally symptomatic ventricular arrhythmias, and reduced left ventricular ejection fraction. INTERVENTIONS: In CAST, 3 antiarrhythmic agents, encainide, flecainide, and moricizine, were compared against placebo. MAIN OUTCOME MEASURES: The main outcome measures in CAST were arrhythmic death and total mortality. RESULTS: CAST found the 3 agents to be harmful. Encainide and flecainide were stopped first. Subsequently, moricizine was discontinued ahead of schedule. CONCLUSIONS: The complexity of the study design and a midcourse protocol modification raise several data-monitoring issues not previously discussed. These include how to handle apparently dramatic yet unexpected results, the need for flexibility in modifying study design and goals, and the conflict between existing study data and both conventional wisdom and medical practice.
Anti-Arrhythmia Agents↗
Prevalence and etiology of idiopathic dilated cardiomyopathy (summary of a National Heart, Lung, and Blood Institute workshop.
Idiopathic dilated cardiomyopathy (IDC) is the primary indication for cardiac transplantation, with associated costs of approximately $177 million per year. Recognizing the economic implications of IDC, the increasing incidence, and the limited information on pathogenesis and prognosis, the National Heart, Lung, and Blood Institute convened a workshop on the Prevalence and Etiology of Idiopathic Dilated Cardiomyopathy on June 13 to 14, 1991. The difficulties of studying the disease were reviewed, including its relatively low prevalence, its potentially pluricausal nature, and the fact that it is often a diagnosis of exclusion. Still, it presents significant challenges to the cardiovascular scientific community, since the mechanism of myocardial damage and related etiologic and prognostic factors are virtually unknown. The development of more reliable measures of immune-mediated damage and noninvasive measures of impaired cardiac function present new research opportunities in this disorder. Standardized diagnostic criteria for use in observational and interventional trials were developed, and priorities for future research were proposed. Population-based registries and nested case-control studies, where feasible, are appropriate study designs for tracking incidence and prevalence, and for identifying risk factors, respectively. Interventional studies should focus on secondary prevention, through modifying immune-mediated damage in clinically evident dilated cardiomyopathy, and through prevention of sudden death in patients with the disorder. Primary prevention trials must await the identification of modifiable risk factors and of appropriate and effective interventions.
Cardiomyopathy, Dilated↗
Correlates of aortic distensibility in chronic aortic regurgitation and relation to progression to surgery.
Aortic distensibility decreases with increasing age. Patients with chronic aortic regurgitation eject a large stroke volume into the proximal aorta. A decrease in distensibility of the aorta may impose a higher afterload on the left ventricule and may contribute to deterioration of left ventricular function over time. Accordingly, aortic distensibility was measured in 33 patients aged 13 to 73 years who had chronic isolated aortic regurgitation with minimal or no symptoms. Ascending aortic diameter was measured 4 cm above the aortic valve by two-dimensional echocardiography and pulse pressure was measured simultaneously by sphygmomanometry. Aortic distensibility was calculated as (Change in aortic diameter between systole and diastole/End-diastolic diameter)/Pulse pressure. Left ventricular systolic wall stress and mass were derived from standard M-mode echocardiographic measurements. Left ventricular volumes and ejection fraction were measured by radionuclide ventriculography. Aortic distensibility decreased logarithmically with increasing age (r = -0.62, p less than 0.001) and also correlated inversely with systolic wall stress, left ventricular mass and end-diastolic volume. Patients who eventually underwent aortic valve replacement for symptoms of left ventricular dysfunction had significantly lower aortic distensibility than did those who did not yet require valve replacement: 0.09 +/- 0.08 vs. 0.22 +/- 0.19 x 1/100 (1/mm Hg) (p less than 0.05). Thus, the reduced aortic distensibility that occurs with increasing age may contribute to the gradual left ventricular dilation and dysfunction seen in patients with chronic aortic regurgitation.
Adult↗
Energy metabolism and contractile function after 15 beats of moderate myocardial ischemia.
Difficulties in studying myocardial metabolism with adequate time resolution have led to contradictory conclusions regarding the mechanisms causing contractile abnormalities during the early stages of ischemia. In acutely instrumented swine, we investigated whether abnormalities in subendocardial ATP, phosphocreatine, or lactate content develop rapidly enough during the first few heart beats after onset of partial myocardial ischemia to contribute to contractile failure. Within the first 15 beats of a 40-50% reduction in left anterior descending coronary artery blood flow, regional myocardial function was significantly reduced but continuing to deteriorate. Rapidly frozen transmural left ventricular biopsies obtained on the 15th heart beat (+/- 1.5 beats) after the onset of ischemia revealed significant decrements in subendocardial phosphocreatine and ATP levels to 77% (p less than 0.05) and 84% (p less than 0.005) of control values, respectively, but minimal change in lactate content. Metabolic effects as assessed by transmural averages took longer to become detectable; thus, there was a tendency to underestimate the importance of subendocardial metabolic effects on myocardial function. When left ventricular preload was assessed during this early time period, left ventricular end-diastolic wall thickness only decreased by 3%, and left ventricular end-diastolic pressure did not change significantly despite a large fall in coronary perfusion pressure. Thus, in an in vivo pig model with techniques optimized to detect subendocardial metabolic changes within the period of very early moderate myocardial ischemia, abnormalities in high energy phosphate compounds occurred rapidly enough to contribute to developing myocardial dysfunction, whereas preload-mediated mechanisms related to vascular distending pressure could not explain the functional deterioration under these conditions.
Adenosine Triphosphate↗
Effects of stopping long-term vasodilator therapy in patients with chronic aortic insufficiency.
We studied the effects of stopping long-term vasodilator therapy in 17 patients with chronic stable aortic insufficiency. These patients received hydralazine for 37 +/- 15 months (mean +/- SD) and, as a result, had experienced a significant decrease in left ventricular volumes. All patients were followed clinically and ten of the patients underwent serial radionuclide evaluation at baseline, while receiving drug, and at 20 +/- 7 months after stopping drug therapy. No patient showed evidence of acute clinical deterioration when drug therapy was stopped. The rate of progression to valve replacement due to onset of symptoms or left ventricular dysfunction was not significantly different from that previously reported in a population with similar characteristics. Left ventricular size, however, returned to levels similar to baseline after drug therapy was stopped. We conclude that long-term vasodilator therapy may be discontinued in patients with chronic stable aortic insufficiency without causing clinical deterioration or significant alteration in rate of progression to valve replacement.
Adult↗
Effects of long-term vasodilator therapy on electrocardiographic abnormalities in chronic aortic regurgitation.
Electrocardiographic abnormalities develop in patients with chronic aortic regurgitation (AR). Although vasodilator drugs may reduce left ventricular (LV) volume overload, the effects of such therapy on electrocardiographic abnormalities have not been previously evaluated. Accordingly, electrocardiograms were analyzed before and after double-blind, randomized administration of either hydralazine or placebo in 54 patients with chronic AR. These patients were without limiting symptoms and had preserved ejection fraction on entry in the study. The magnitude of ST-segment depression and Romhilt-Estes point score for LV hypertrophy were assessed. Baseline ST depression and LV hypertrophy scores in the placebo and hydralazine groups were not significantly different. At follow-up, after a mean of 19 +/- 6 months, there was a significant reduction in ST depression in patients taking hydralazine (n = 28) compared with patients given placebo (n = 26): -0.023 +/- 0.044 vs 0.029 +/- 0.055 mV, respectively (p = 0.0001); and in the LV hypertrophy score (-1.1 +/- 2.2 vs 0.9 +/- 2.3 points, respectively; p = 0.002). Hydralazine-treated patients also had significant decreases in LV end-diastolic and end-systolic volume indexes, and a significant increase in ejection fraction. These results suggest that such vasodilator therapy may be beneficial in patients with chronic AR.
Adult↗
Cardiac metabolism during exercise in healthy volunteers measured by 31P magnetic resonance spectroscopy.
A technique was devised for individuals to exercise prone in a magnet during magnetic resonance spectroscopy of the heart and phosphorus-31 magnetic resonance spectra of the heart were obtained by the phase modulated rotating frame imaging technique in six healthy volunteers during steady state dynamic quadriceps exercise. During prone exercise heart rate, blood pressure, and total body oxygen consumption were measured at increasing loads and the results were compared with those during Bruce protocol treadmill exercise. During prone exercise with a 5 kg load the heart rate was similar and the systolic and diastolic blood pressures were higher than those during stage 1 of the Bruce protocol. The rate-pressure products were similar but the total body oxygen consumption was lower during prone exercise. There was no difference in the ratio of phosphocreatine to adenosine triphosphate during rest and exercise.Thus during exercise that produced a local cardiac stress equal to or greater than that during stage 1 of the Bruce protocol treadmill exercise, the energy requirements of the normal human myocardium were adequately supplied by oxidative phosphorylation.
Blood Pressure↗
Response to myocardial ischemia as a regulated process.
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Adaptation, Physiological↗
Active downregulation of myocardial energy requirements during prolonged moderate ischemia in swine.
We studied the effects of rapid atrial pacing during the final 10 minutes of a 70-minute, 31% reduction in coronary blood flow in anesthetized swine to understand the significance of apparent metabolic improvements during the initial 60 minutes of segmental ischemia. Within 5-10 minutes of ischemia, subendocardial phosphocreatine (PCr) and ATP were depleted to 47% and 63% of control, respectively; lactate accumulated within the subendocardium to 300% of control; and net arteriovenous lactate production occurred. Despite continued ischemia and no significant changes in the external determinants of myocardial oxygen consumption, by 60 minutes subendocardial PCr and lactate contents returned to near control levels and there was net arteriovenous lactate consumption. Ischemic left ventricular wall thickening and ATP levels remained depressed throughout the experiment. Atrial pacing during the final 10 minutes of ischemia again resulted in depletion of PCr and lactate production. Since the myocardium was capable of hydrolyzing PCr in response to atrial pacing at 60 minutes of ischemia, we conclude it was capable of hydrolyzing PCr during the period of constant ischemia when instead it was accumulating PCr. We propose the ischemic myocardium downregulates regional energy requirements below blood flow-limited rates of energy production during ischemia. This appears to be an active adaptation to ischemia and not a result of passive damage or cellular injury.
Adaptation, Physiological↗
Adenosine. Renewed interest in an old drug.
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Adenosine↗
Regeneration of myocardial phosphocreatine in pigs despite continued moderate ischemia.
The effects of 1 hour of mild and moderate reductions in coronary blood flow on myocardial high-energy phosphate levels were evaluated. Thirty anesthetized pigs were instrumented with left anterior descending arterial and venous catheters, crystals for instantaneous wall thickness, and a fluid-filled occluder. Measurement of myocardial blood flow was performed with microspheres, and a series of myocardial biopsies also was performed. In 10 pigs, overall coronary blood flow was lowered by 22%, with a fall in subendocardial-to-subepicardial flow ratio from 1.11 to 0.54 and in wall thickening from 33% to 15%. Subendocardial flow fell 48%. Coronary blood flow and thickening were constant during 1 hour of ischemia. Phosphocreatine (mumol/g wet wt) in the subendocardial third of the ischemic zone fell from 7.6 to 3.8 at 5 minutes of ischemia (p less than 0.005 versus control) and returned to normal (7.9) at 60 minutes (p = NS), despite ongoing ischemia. Subendocardial ATP (mumol/g wet wt) fell slowly from 4.3 and leveled off at 2.1 at 60 minutes of ischemia (p less than 0.001 versus control). Similar regeneration of phosphocreatine was found in seven additional pigs, with a 43% transmural reduction in coronary blood flow and a 66% reduction in subendocardial flow. No significant changes in ATP and phosphocreatine were noted in two different control groups (n = 13 pigs). The regeneration of phosphocreatine despite ongoing ischemia and low ATP levels was not related to changes in myocardial oxygen demand or consumption, or in regional function during the period of ischemia. This may reflect 1) a successful downregulation of the energy needs of the ischemic myocardium to maintain cell viability, or 2) a metabolic abnormality in the ability of the cells to produce ATP primarily or by use of phosphocreatine.
Adenosine Triphosphate↗
Chronic aortic insufficiency: factors associated with progression to aortic valve replacement.
STUDY OBJECTIVE: To determine whether the initial measurement of clinical variables in patients with chronic stable aortic insufficiency is helpful in identifying patients at risk for earlier progression to aortic valve replacement. DESIGN: Prospective analysis of a cohort of patients for a median follow-up time of 44 months (range, 8 to 57). SETTING: Referral-based cardiology clinics at two university hospitals and their affiliated Veterans Administration medical centers. PATIENTS: Cohort of 50 asymptomatic or minimally symptomatic patients with chronic aortic insufficiency and left ventricular enlargement. Patients had preserved left ventricular ejection fraction at rest and no evidence of coronary artery disease or significant noncardiac illness. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Baseline evaluation included a history and physical examination, chest roentgenogram. M-mode echocardiogram, treadmill test, and radionuclide angiogram done at rest and during supine bicycle exercise. Ten patients progressed to surgery because of the onset of limiting symptoms or objective evidence of left ventricular dysfunction, or both; the overall rate was 4% +/- 3% per year. The Breslow and Mantel-Cox statistics were used to compute survival (surgery-free) dichotomized by prognostic variables. The progression to surgery was earlier in patients with left ventricular end-diastolic volume indices of 150 cc/m2 or more, end-systolic volume indices of 60 cc/m2 or more, a left ventricular ejection fraction at maximal exercise of less than 0.50, or an end-systolic wall stress of 86 dynes/cm2 or more. CONCLUSIONS: Patients at higher and lower risk for early progression to aortic valve replacement can be identified through the measurement of left ventricular size and function. This information can be used to decide the frequency and intensity of follow-up evaluation in these patients.
Actuarial Analysis↗
Measurement of transmural distribution of phosphorus metabolites in the pig heart by 31P magnetic resonance spectroscopy.
We used the phase modulated rotating frame imaging technique to measure transmural distribution of phosphorus metabolites in 10 anaesthetised ventilated pigs using a double surface coil placed on the surface of the left ventricle. Anaesthesia was maintained in five animals with halothane, barbiturate and nitrous oxide and in five others with intravenous chloralose. 31Phosphorus spectra were acquired, gated to expiration and systole. From phantom experiments the resolution of the experiment was shown to be approximately 2 mm. The anatomical limits of the myocardium were identified by the appearance of 2,3-diphosphoglycerate peaks from red blood cells. The limits of the epicardium were confirmed by obtaining images after placing a phantom containing fluorophosphate on the surface of the heart. The endocardium was identified by inserting a small balloon catheter through the centre of the coil into the left ventricular cavity, filling it with 0.5 ml of fluorophosphate and pulling it gently against the endocardium. No transmural differences in phosphocreatine to ATP ratio were identified in the normal heart. The animals anaesthetised with chloralose showed a significantly higher phosphocreatine to ATP ratio compared to those anaesthetised with halothane and barbiturate. The chloralose animals tended to have a higher blood pressure and a lower heart rate when compared to the other animals. No transmural differences, however, were identified in either group. When regional ischaemia was produced using a snare to occlude the left coronary artery, phosphocreatine fell and the signal from the inorganic phosphate + 2,3-diphosphoglycerate region increased. The inner wall tended to become more acid compared to the outer wall during ischaemia. These experiments show that the phase modulated rotating frame imaging technique can be used to study the effects of changes in workload, ischaemia, or pharmacological intervention on transmural distribution of metabolites in the heart and thus help elucidate factors responsible for subendocardial vulnerability to stress.
2,3-Diphosphoglycerate↗