Database Conference January 27-30, 2000, Washington D.C.--Do existing databases answer clinical questions about geriatric cardiovascular disease and stroke?

EXECUTIVE SUMMARY: Most randomized, controlled trials evaluating the effectiveness of pharmaceutical, surgical, and device interventions for the prevention and treatment of cardiovascular disease have excluded patients over 75 years of age. Consequently, the use of these therapies in the older population is based on extrapolation of safety and effectiveness data obtained from younger patients. However, there are many registries and observational databases that contain large amounts of data on patients 75 years of age and older, as well as on younger patients. Although conclusions from such data are limited, it is possible to define the characteristics of patients who did well and those who did poorly. The goal of this conference was to convene the principal investigators of these databases, and others in the field of geriatric cardiology, to address questions relating to the safety and effectiveness of treatment interventions for several cardiovascular conditions in the elderly. Seven committees discussed the following topics: (I) Risk Factor Modification in the Elderly; (II) Chronic Heart Failure; (III) Chronic Coronary Artery Disease: Role of Revascularization; (IV) Acute Myocardial Infarction; (V) Valve Surgery in the Elderly; (VI) Electrophysiology, Pacemaker, and Automatic Internal Cardioverter Defibrillators Databases; (VII) Carotid Endarterectomy in the Elderly. The chairs of these committees were asked to invite principal investigators of key databases in each of these areas to discuss and prepare a written statement concerning the available safety and efficacy data regarding interventions for these conditions and to identify and prioritize areas for future study. The ultimate goal is to stimulate further collaborative outcomes research in the elderly so as to place the treatment of cardiovascular disease on a more scientific basis.

Upregulation of the nitric oxide-cGMP pathway in aged myocardium: physiological response to l-arginine.

Cardiovascular aging is associated with decreased endothelial vasoreactivity and prolonged diastolic relaxation. As diminished NO signaling contributes to age-associated endothelial dysfunction, we tested the hypothesis that impaired NO signaling or bioactivity also contributes to slowed ventricular relaxation with age. Accordingly, we measured myocardial NO synthase (NOS) enzyme activity, protein abundance, and cGMP production in old (22 to 25 months) and young adult (4 to 7 months) male Wistar rats. Both NOS3 protein abundance and calcium-dependent NOS activity were elevated in old compared with young adult hearts (7.2+/-1.1 versus 4.2+/-0.6 pmol/mg protein, respectively, P=0.03). However, NOS activity and protein abundance were similar in isolated myocytes, indicating that endothelial NOS likely explains the age difference. Cardiac effluent cGMP (enzyme immunoassay) was 4.8-fold higher (1794+/-373 fmol/min per mg heart tissue) in older versus younger hearts (P=0.003). To assess NO pathway responsiveness, we administered the NOS substrate l-arginine (100 micrometer) to isolated perfused rat hearts. Baseline isovolumic relaxation (tau) was prolonged in old (42.9+/-2.5 ms, n=16) versus young hearts (36.0+/-1.9 ms, n=11, P=0.03). l-Arginine decreased tau (P<0.001) and left ventricular end-diastolic pressure in both old and young hearts. Supporting an NO/cGMP-mediating mechanism, the NO donor sodium nitroprusside reduced tau (maximal effect, -14+/-2%, n=5, P<0.001), and this lusitropic effect was attenuated by the soluble guanylyl cyclase inhibitor 1H:-[1,2,4]oxadiazolo-[4,3,-a]quinoxalin-1-one (n=7, P<0.001). Thus, the NO-cGMP pathway is upregulated in the endothelial cells of aged hearts. l-Arginine, the NOS precursor, enhances ventricular relaxation in old and young hearts, indicating that the NOS pathway may be exploited to modulate diastolic function in aged myocardium.

Spot urinary albumin-creatinine ratio predicts left ventricular hypertrophy in young hypertensive African-American men.

Hypertensive patients with target organ damage are at increased cardiovascular risk, and should be treated most aggressively. The association between urinary albumin excretion and left ventricular hypertrophy (LVH) in prior studies is inconsistent, and has not been described using a single, random spot urine specimen. Therefore, we evaluated the association between the urinary albumin creatinine ratio (ACR) and left ventricular (LV) mass and also tested the hypothesis that a simple random, single-void urine ACR would identify high risk young, hypertensive, African-American men. We measured echocardiographic LV mass and a random spot urinary ACR in 109 untreated, hypertensive, young, inner city, African-American men. The mean age was 41 +/- 6 years and the mean blood pressure (BP) was 157 +/- 19/107 +/- 13 mm Hg. Microalbuminuria (ACR 30 to 300 mg/g) was present in 22% of subjects. The ACR is higher in the men with LVH than in the men without LVH (P < .05). Increased ACR is a predictor of increased LV mass index (P < .003) using multiple linear regression. An ACR >30 mg/g has a sensitivity of 33% and a specificity of 82% for the diagnosis of echocardiographic LVH. In conclusion, elevated random spot ACR is a marker of increased LV mass, independent of BP, in young urban African-American men with hypertension, and may help to determine the aggressiveness of antihypertensive therapy in this high-risk group.

Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years.

BACKGROUND: The benefit of intravenous thrombolytic therapy in elderly patients with myocardial infarction is uncertain. There are no randomized trials of thrombolytic efficacy or observational studies of clinical effectiveness that focus specifically on the elderly. METHODS AND RESULTS: To determine whether thrombolytic therapy for elderly patients is associated with a survival advantage in a large observational database, we conducted a retrospective cohort study of 7864 Medicare fee-for-service patients aged 65 to 86 years with the primary discharge diagnosis of acute myocardial infarction who were admitted with clinical and ECG indications for thrombolytic therapy and no absolute contraindications. The study included all US acute care nongovernment hospitals without on-site angioplasty capability. Using proportional-hazards methods, we found that in a comprehensive multivariate model, there was a significant interaction (P<0.001) between age and the effect of thrombolytic therapy on 30-day mortality rates. For patients 65 to 75 years old, thrombolytic therapy was associated with a survival benefit, consistent with randomized trials. Among patients aged 76 to 86 years, thrombolytic therapy was associated with a survival disadvantage, with a 30-day mortality hazard ratio of 1.38 (95% CI 1. 12 to 1.71, P=0.003). For these patients, there was no benefit from thrombolytic therapy in any clinical subgroup. CONCLUSIONS: In nationwide clinical practice, thrombolytic therapy for patients >75 years old is unlikely to confer survival benefit and may have a significant survival disadvantage. Reperfusion research that is focused on elderly patients is urgently needed.

Hemodynamic effects of unloading the old heart.

A reduction in upright exercise capacity with aging in healthy individuals is accompanied by acute left ventricular (LV) dilatation and impaired LV ejection. To determine whether acute vasodilator administration would improve LV ejection during exercise, sodium nitroprusside (NP) was administered to 16 healthy subjects, ages 64-84 yr, who had been screened for the absence of coronary heart disease by prior exercise thallium scintigraphy. Infusion of NP (0. 3-1.0 microgram. kg(-1). min(-1)), titrated to reduce the resting mean arterial pressure 10% (and eliminate the late augmentation of carotid arterial pressure), increased LV ejection fraction (EF) compared with placebo during upright, maximal graded cycle exercise at all work rates and permitted an equivalent stroke volume and stroke work from a smaller end-diastolic volume. The maximum increase in exercise EF in older subjects during NP infusion was equal to that in healthy, younger (22-39 yr) control subjects. The maximum cycle work rate and cardiac index were unchanged compared with placebo. Thus combined preload and afterload reduction with NP in older individuals improves overall LV ejection phase function: exercise LV stroke work is reduced, EF is increased, and stroke volume is maintained in the setting of a reduced ventricular size. These findings suggest that at least some of the age-associated decline in cardiac function during maximal aerobic exercise may be secondary to adverse loading conditions.

Neurogenic ST depression in stroke.

BACKGROUND: Stroke is occasionally associated with ECG repolarization changes including ST depression. Recent evidence suggests a neurogenic contribution to these abnormalities in stroke patients. Animal studies implicate the insular cortex in cardiovascular control. We describe a patient with a left insular infarct and without cardiac or coronary artery disease, who developed ST depression indicating a neurogenic etiology. CASE DESCRIPTION: A 48 year-old female, with no risk factors for stroke, developed sudden expressive aphasia. MRI brain showed an infarct in the left insular cortex. Twenty-four hour Holter monitoring on the third day revealed transient ST depression more than 1.5 mm, which was not reproducible on subsequent monitoring. Transesophageal echo-cardiography (TEE) was normal. She had no cardiac symptoms and serial ECGs, cardiac enzymes (CKMB) and adenosine thallium scan were normal. To-date, there had been no cardiac events like congestive heart failure or myocardial ischemia. CONCLUSION: These findings suggest neurogenic ST depression is related to the left insular infarct in view of the normal adenosine thallium scan, non-reproducibility and evanescence of the ST segment changes and lack of associated cardiac symptoms. When neurogenic ST depression is combined with underlying coronary artery disease, it may adversely influence cardiac outcome after stroke.

Verapamil acutely reduces ventricular-vascular stiffening and improves aerobic exercise performance in elderly individuals.

OBJECTIVES: We tested the hypothesis that acute intravenous verapamil acutely enhances aerobic exercise performance in healthy older individuals in association with a combined reduction of ventricular systolic and arterial vascular stiffnesses. BACKGROUND: Age-related vascular stiffening coupled with systolic ventricular stiffening may limit cardiovascular reserve and, thus, exercise performance in aged individuals. METHODS: Nineteen healthy volunteers with mean age 70 +/- 10 years underwent maximal-effort upright ergometry tests on two separate days after receiving either 0.15 mg/kg i.v. verapamil or 0.5 N saline in a double-blind, randomized, crossover study. RESULTS: Baseline vascular stiffness, indexed by arterial pulse-wave velocity (Doppler) and augmentation index (carotid tonometry) declined with verapamil (-5.9 +/- 2.1% and -31.7 +/- 12.8%, respectively, both p < 0.05). Preload-adjusted maximal ventricular power, a surrogate for ventricular end-systolic stiffness, also declined by -9.5 +/- 3.6%. Peripheral resistance and peak filling rate were unchanged. With verapamil, exercise duration prior to the anaerobic threshold (AT) increased by nearly 50% (260 +/- 129 to 387 +/- 176 s) with a corresponding 13.4 +/- 4.7% rise in oxygen consumption (VO2) at that time (both p < 0.01). Total exercise duration prolonged by +6 +/- 2.7% (p < 0.05) with no change in maximal VO2. Baseline cardiodepression from verapamil reversed by peak exercise with net increases in stroke volume and cardiac output (p < 0.05). CONCLUSIONS: Acute intravenous verapamil reduces ventriculovascular stiffening and improves aerobic exercise performance in healthy aged individuals. This highlights a role for heart-arterial coupling in modulating exertional capacity in the elderly, suggesting a potentially therapeutic target for aged individuals with exertional limitations.

High extracellular K+ during hypoxic preconditioning episodes attenuates the post-ischemic contractile and ionic benefits of preconditioning.

Hypoxic preconditioning improves contractile recovery and decreases calcium loading following ischemia and reperfusion. To test whether changing the trans-sarcolemmal K+ gradient during the preconditioning period changes preconditioning's benefits, isolated rat hearts were subjected to two, 5 min hypoxic intervals in the presence of normal K+ (5mM, NmlK-PC) or high K+ (10.3 mM, HiK-PC), separated by 5 min of normoxic reflow. Preconditioning with 5 mM K+ significantly improved developed pressure (DP) after 30 min of ischemia as compared to non-preconditioned control hearts (55.9+/-4.41% v 12.4+/-2.01% of baseline, P<0.05). DP recovery was diminished with 10.3 mM K+ (25.1+/-4.20% of baseline, P<0.05). At the end of reperfusion, cell Ca2+ trended lower in hypoxic preconditioned hearts compared with control hearts (12.9+/-1.9 v 19.4+/-2.6 micromol/g dry wt, P=0.09) and was significantly lower than high K+ hearts (22.9+/-1.4 micromol/g dry wt, P<0.006). Intracellular K+ during reperfusion was significantly higher in preconditioned compared with control hearts (P<0.02) and high K+ hearts (P<0.002) (231+/-10 v 166+/-17 v 155+/-14 micromol/g dry wt, respectively). Thus, the trans-sarcolemmal K+ gradient during the preconditioning period influences preconditioning effects; decreasing the gradient attenuates preconditioning's favorable influences on contractile recovery, cellular K+ loss, and calcium loading during reperfusion.

Preservation of canine myocardial high-energy phosphates during low-flow ischemia with modification of hemoglobin-oxygen affinity.

Conventional approaches for the treatment of myocardial ischemia increase coronary blood flow or reduce myocardial demand. To determine whether a rightward shift in the hemoglobin-oxygen saturation curve would reduce the metabolic and contractile effects of a myocardial oxygen-supply imbalance, we studied the impact of a potent synthetic allosteric modifier of hemoglobin-oxygen affinity, a 2-[4-[[(3,5-disubstituted anilino)carbonyl]methyl] phenoxy] -2-methylproprionic acid derivative (RSR13), during low-flow ischemia. Changes in myocardial high-energy phosphate levels and pH were studied by 31P nuclear magnetic resonance (NMR) spectroscopy in 12 open-chest dogs randomized to receive RSR13 or vehicle control during a reversible reduction of left anterior descending (LAD) coronary artery blood flow. Changes in cardiac metabolites and regional ventricular function studied by pressure segment-length relations were also investigated in additional animals before and after RSR13 administration during low-flow LAD ischemia. The intravenous administration of RSR13 before ischemia resulted in a substantial increase in the mean hemoglobin p50 and attenuated the decline in cardiac creatine phosphate/adenosine triphosphate (PCr/ATP), percent PCr, and pH during ischemia without a change in regional myocardial blood flow, heart rate, or systolic blood pressure. RSR13 given after the onset of low-flow ischemia also improved cardiac PCr/ATP ratios and regional function as measured by fractional shortening and regional work. Thus, synthetic allosteric reduction in hemoglobin-oxygen affinity may be a new and important therapeutic strategy to ameliorate the metabolic and functional consequences of cardiac ischemia.

Acute effects of conjugated estrogens on coronary blood flow response to acetylcholine in men.

Estrogen therapy is associated with a 50% reduction in the clinical manifestations of coronary artery disease in postmenopausal women. Attenuation of coronary vasomotor dysfunction may contribute to estrogen's cardioprotective effects. We hypothesized that conjugated estrogens, which contain several vasoactive estrogenic compounds, may favorably influence the vasomotor response to acetylcholine in men. Twenty men, 56 +/- 5 years of age, referred for clinically indicated coronary angiography, participated in this study. Acetylcholine-induced changes in coronary flow were measured by quantitative coronary angiography and intracoronary Doppler ultrasonography before and 15 minutes after intravenous administration of conjugated estrogens (0.625 mg) in 12 men and placebo in 8 men. Initial acetylcholine infusion resulted in no significant increase in coronary blood flow. However, 15 minutes after estrogen administration repeat acetylcholine infusion caused a mean 32% increase in coronary blood flow from 41 +/- 5 to 54 +/- 8 ml/min (p = 0.02). Acetylcholine-induced change in flow after estrogen was significantly different from that before estrogen (p = 0.03). Placebo administration did not affect acetylcholine-induced changes in coronary flow. Thus, intravenous conjugated estrogens favorably modulate acetylcholine-induced changes in coronary hemodynamics in men. This suggests that novel nonfeminizing estrogenic compounds may have anti-ischemic effects in men.

Tissue magnesium levels and the arrhythmic substrate in humans.

INTRODUCTION: Magnesium deficiency has been implicated in the pathogenesis of sudden death, but the investigation of arrhythmic mechanisms has been hindered by difficulties in measuring cellular tissue magnesium stores. METHODS AND RESULTS: To see if magnesium deficiency is associated with a propensity toward triggered arrhythmias, we measured tissue magnesium levels and QT interval dispersion (as an index of repolarization dispersion) in 40 patients with arrhythmic complaints. Magnesium was measured in sublingual epithelium using X-ray dispersive analysis. QT interval dispersion was assessed on 12-lead surface ECGs in all patients, and programmed stimulation was performed in 28. The sublingual epithelial magnesium level ([Mg]1), but the not the serum level, correlated inversely with QT interval dispersion in 40 patients (r = 0.58, P < 0.005); in 12 patients undergoing repeat testing on therapy, the change in magnesium also correlated inversely with the change in QT dispersion (r = 0.61, P < 0.05). Patients with left ventricular ejection fractions > 40% had significantly higher tissue magnesium and lower QT dispersion (34.5 +/- 0.5 mEq/L, 81 +/- 8 msec) than those with left ventricular ejection fractions < 40% (32.7 +/- 0.5 mEq/L, P < 0.01, and 114 +/- 9 msec, P < 0.05). There was no difference in either [Mg]1 or QT dispersion in the 16 patients with inducible monomorphic ventricular tachycardia versus the 12 noninducible patients. CONCLUSION: Reduced tissue magnesium stores may represent a significant risk factor for arrhythmias associated with abnormal repolarization, particularly in patients with poor left ventricular systolic function, but may not represent a risk for excitable gap arrhythmias associated with a fixed anatomic substrate (e.g., monomorphic ventricular tachycardia).

Role of preischemic glycogen depletion in the improvement of postischemic metabolic and contractile recovery of ischemia-preconditioned rat hearts.

BACKGROUND: Ischemic preconditioning (IPC) attenuates acidosis during prolonged ischemia and improves contractile and metabolic parameters during subsequent reperfusion. Glycogen depletion induced by IPC is proposed as a potential mechanism. METHODS AND RESULTS: We studied the influence of manipulations of preischemic glycogen levels (Pre-G, micromol glucose/g wet wt) on contractile and metabolic (via 31P-nuclear magnetic resonance) parameters during 30 minutes of ischemia and recovery in four groups of isovolumic rat hearts: First, control (Con, n=18, mean Pre-G, 21.5+/-0.8); second, after two 5-minute IPC periods (IPC, n=12, Pre-G, 11.3+/-0.7); third, a control group in which Pre-G was depleted by glucose-free, acetate perfusion (Con-LowG, n=9, Pre-G, 7.9+/-1.2); and fourth, an IPC group in which Pre-G was raised by glucose and lactate perfusion such that Pre-G was similar to Con (IPC-HiG, n=11, Pre-G, 20+/-1.4). Manipulation of Pre-G significantly altered the pH fall during 30 minutes of ischemia (Con, 5.76+/-.03, Con-LowG, 6.26+/-.07; IPC-HiG, 5.91+/-.02, IPC, 6.05+/-.09). IPC-HiG hearts had significantly worse metabolic recovery (PCr, 70+/-7 versus 91+/-3% initial; IPC-HiG versus IPC, P<.05) and contractile recovery (end-diastolic pressure, 52+/-5 versus 29+/-5 mm Hg, P<.05) than IPC hearts but better recovery than Con (%PCr, 56+/-6% and end-diastolic pressure, 72+/-6 mm Hg). An ischemic rise in intracellular magnesium occurred and was atttenuated in preconditioned hearts. CONCLUSIONS: Pre-G levels before ischemia influence but are not the sole determinants of the extent of acidosis during prolonged ischemia and of metabolic and contractile recovery during reperfusion in control and preconditioned hearts.

Long-term estrogen therapy abolishes acute estrogen-induced coronary flow augmentation in postmenopausal women.

Postmenopausal estrogen replacement therapy (ERT) may reduce the clinical manifestations of coronary heart disease by favorably modulating coronary vasoreactivity. Intravenous ethinyl estradiol acutely increases coronary flow in postmenopausal women not receiving ERT. Because several vasoactive agents induce vasomotor tolerance when administered on a long-term basis, we hypothesized that long-term ERT attenuates the acute coronary vasomotor effects of intravenous ethinyl estradiol. To test this hypothesis, coronary hemodynamics were determined before and 15 minutes after intravenous ethinyl estradiol (35 micrograms) in 10 postmenopausal women who were receiving long-term conjugated ERT (group 1) and 10 who had never received ERT (group 2). Estradiol administration in group 1 was not associated with significant changes in coronary flow or resistance. However, women in group 2 exhibited a 28.6% +/- 6.5% (p < 0.001) increase in coronary flow and a 19.9% +/- 3.5% (p = 0.008) decrease in resistance. These results demonstrate that long-term ERT significantly attenuates the response of coronary arteries to the acute vasomotor effects of a high dose of estradiol. This response may be caused by long-term estrogen-induced coronary flow augmentation or to the development of vasomotor tolerance to estrogen.