Role of aging on electrical, mechanical, and coronary modification induced by ouabain and epinine in isolated rat heart.

OBJECTIVE: The contractile response to digitalis and beta adrenoceptor agonists is lower in the senescent than in the adult myocardium, while the development of ventricular arrhythmias is increased. The aim of this study was to examine the effects of aging on cardiac response to digitalis and an adrenergic agonist used clinically. METHODS: The electrical and mechanical responses were tested in isolated and perfused hearts from 3-24 month old rats receiving 15 min infusion of digitalis drug (ouabain, 6 x 10(-5) M) alone, and after 5 min of beta adrenoceptor agonist drug (epinine, 1.5 x 10(-7) M). RESULTS: Ouabain action was associated with a rise in left ventricular end diastolic pressure (p < 0.01) which increased progressively with aging, and with an elevation of left ventricular developed pressure (p < 0.01) which decreased progressively with aging. Epinine induced a reduction of left ventricular end diastolic pressure (p < 0.01) and a rise in left ventricular developed pressure (p < 0.01) but both effects decreased progressively with aging. Ouabain reduced coronary flow and this decrease was more pronounced with aging (p < 0.01), while epinine caused an increase (p < 0.01) that diminished in older hearts. Ouabain given after epinine resulted in a greater increase in left ventricular end diastolic pressure than epinine (p < 0.01) but lower than that caused by ouabain alone (p < 0.01), a greater increase in left ventricular developed pressure than epinine and ouabain (p < 0.01), and a smaller reduction of coronary flow rate than ouabain alone (p < 0.01). All these effects, however, diminished progressively with aging. Arrhythmia scores were higher during ouabain than in control (p < 0.01) and in epinine treated hearts (p < 0.01); pretreatment with epinine did not modify arrhythmia score during ouabain administration. The number and severity of arrhythmias, however, increased with aging in all groups. CONCLUSIONS: Aging has a negative effect on both the positive inotropic and the arrhythmogenic effects of ouabain and epinine, although these phenomena are more pronounced during ouabain administration. However, when the two drugs are given simultaneously, epinine does not modify the arrhythmogenic effect of ouabain but reduces some of its deleterious haemodynamic effects.

Dipyridamole echocardiography as a useful and safe test in the assessment of coronary artery disease in the elderly.

We prospectively studied the sensitivity, specificity, feasibility, and safety of high-dose dipyridamole echocardiography, compared to exercise electrocardiography in 130 subjects (67 younger and 63 elderly patients) referred for angiographic evaluation of suspected or proven coronary artery disease. Sensitivity, specificity, and feasibility of dipyridamole echocardiography were respectively 75.5%, 100%, and 88.0% in younger patients and 82.9%, 100%, and 79.4% in elderly patients (P = NS). The sensitivity of exercise electrocardiography was 72.7% in young and 66.6% in elderly patients (P = NS); specificity 66.0% vs 60.0% (P = NS); feasibility 83.6 vs 63.5 (P = 0.05). Forty-nine younger and 38 elderly patients performed both tests. Sensitivity of dipyridamole echocardiography compared to exercise electrocardiography was 76.2% vs 73.8% in young patients and 83.3% vs 70% in the older group (P = NS). The feasibility of the two tests was significantly different in the elderly group only (dipyridamole echocardiography 79.4% vs exercise electrocardiography 63.5%; P less than 0.01). The incidence of side effects during dipyridamole echocardiography was similar in the two groups, except for dyspnea which was observed in 20% of older and 5% of younger patients (P less than 0.05). Our data demonstrate that the dipyridamole test combined with echocardiographic monitoring of regional myocardial contractility may be considered a valid non-invasive method for evaluating coronary artery disease in the elderly and that this test is a satisfactory alternative to the exercise stress test.

Safety of echo-dipyridamole test in elderly patients with coronary artery disease.

The authors prospectively studied the feasibility and safety of high-dose dipyridamole echocardiography in 166 patients (77 younger and 89 elderly patients) referred for clinical evaluation of coronary artery disease. Echocardiographic examinations were adequate for analysis of parameters considered in 135 of the 166 patients (81.3%; 73 elderly, 62 younger patients). The feasibility of dipyridamole echocardiography test was 80.5% in young and 82% in elderly patients (P = ns). The incidence of side effects during dipyridamole echocardiography was similar in the two groups, except for dyspnea, which was observed in 20.5% of older and 3.2% of younger patients (p < 0.05). These data demonstrate that the dipyridamole test combined with echocardiographic monitoring of regional myocardial contractility may be considered a valid noninvasive method of evaluating coronary artery disease in the elderly.

Age-related effects of platelet activating factor (PAF) in the isolated perfused rat heart.

Platelet Activating Factor (PAF) is a phospholipid that has been implicated as an important mediator of anaphylactic cardiac dysfunction and involved in the toxic effects of the ischaemia-reperfusion process. In the elderly, these phenomena are thought to be exaggerated by the age-related changes in response to several chemical factors and myocardial ischaemia. We evaluated the effects of PAF (acetyl-o-alkyl-l-phosphatidylcholine) on left ventricular systolic (LVSP) and diastolic (LVDP) pressure, coronary flow rate (CFR) and heart rate (HR) in adult (6 months, AH) and senescent (24 months, SH) rat hearts. The perfusion of PAF (10(-8), 10(-7) and 10(-6) M) induced a concentration-related reduction of LVSP, CFR and HR and a linear increase in LVDP. Contractile modifications were more pronounced in senescent hearts: LVSP decreased (P < 0.01) and LVDP increased with respect to younger animals (P < 0.01 vs. AH). This negative inotropic effect was also present in electrically paced hearts. PAF produced conduction arrhythmias ranging from second-degree atrio-ventricular conduction block to cardiac standstill both in adult and senescent hearts; at a higher dose (10(-6) M), cardiac standstill appeared after 96.5 +/- 15.3 s in adult hearts and after 45.5 +/- 17.6 s in senescent hearts (P < 0.01). Lyso-PAF did not modify while specific PAF antagonist compounds CV-3988 inhibited all electromechanical responses both in adult and senescent hearts. These data suggest that age influences the effect of PAF on contractile parameters, coronary flow and conduction arrhythmias by acting on receptors, whose function is unaffected by age.

Effect of flecainide acetate on reperfusion- and barium-induced ventricular tachyarrhythmias in the isolated perfused rat heart.

Flecainide acetate is a new antiarrhythmic drug which suppresses different kinds of experimental arrhythmias. We studied the efficacy of flecainide acetate on reperfusion- and barium-induced ventricular tachyarrhythmias in the isolated perfused rat heart by monitoring heart rate, coronary flow rate, left ventricular systolic pressure, dp/dtmax, and the voltage of the epicardial electrogram. Seventy-five male rats were randomized into 5 groups. In group I, after a 15 min period of stabilization, hearts were perfused by ischemic perfusion and then reperfused. In group II, flecainide acetate (10(-6) M) was given after stabilization and before ischaemic perfusion. In group III, barium chloride (10(-3) M) was given after stabilization. In group IV, flecainide acetate was given after stabilization and before barium chloride administration. In group V, acetylcholine chloride (10(-6) M) was given after stabilization and before barium chloride administration. In group I, we noted during ischemia a reduction in heart rate, coronary flow rate, left ventricular systolic pressure and dp/dtmax and an increase in the voltage of the epicardial electrogram. In group II, after administration of flecainide acetate, we observed a reduction in heart rate, left ventricular systolic pressure and dp/dtmax; during the ischaemic period there was no difference in these parameters with respect to group I. Reperfusion induced ventricular arrhythmias in 12 out of 15 hearts in group I and in only 3 out of 15 in group II (p less than 0.005). Barium induced ventricular arrhythmias in the 15 hearts studied in group III as well as in group IV. On the contrary, acetylcholine chloride in group V prevented the occurrence of barium-induced ventricular arrhythmias (p less than 0.005 vs group III and IV). Thus, flecainide acetate is able to reduce reperfusion-induced ventricular arrhythmias, but is unable to reduce barium-induced ventricular arrhythmias, presumably because of a different mechanism of these two types of arrhythmias.

Age-related effects of ischemia, lidocaine and verapamil on overdrive-induced suppression of ventricular pacemakers in isolated rat heart.

The effect of age on ventricular automaticity in the isolated perfused rat heart was determined under different conditions. When the ventricle is electrically stimulated at a faster rate, drive cessation is followed by a temporary suppression of ventricular automaticity (overdrive suppression). The effects of ischemia, lidocaine and verapamil on overdrive suppression were studied in isolated perfused adult and senescent rat hearts with complete atrio-ventricular block, by monitoring ventricular escape rate and escape rhythm recovery time after 1 minute of overdrive at a constant multiple (x3) of the spontaneous rate. The results demonstrated that: 1) lidocaine decreases ventricular automaticity especially in senescent hearts; 2) verapamil does not modify ventricular automaticity in basal conditions in either adult or senescent hearts; 3) myocardial ischemia causes a reduction in ventricular automaticity and more markedly in senescent hearts; and 4) lidocaine exaggerates the effect of ischemia, while verapamil seems to antagonize its depressant effect more in adult than in senescent hearts.

Role of metabolic therapy in cardiovascular disease.

The pathophysiological basis for the use of metabolic therapy in the treatment of heart failure is analyzed. Bioenergetical processes related to ATP bioavailability play a central role in regulating myocardial contractility at rest and on effort. Furthermore, a significant correlation has been demonstrated in diseased heart between ATP content, revealed at endomyocardial biopsy, and systolic and diastolic left ventricular indexes evaluated with invasive and noninvasive methods. Several international investigations demonstrate the beneficial effects of ubiquinone (coenzyme Q10) in the treatment of heart failure. Here the results of a study are reported that was conducted on patients with heart failure treated with ubiquinone. After 7 months of oral drug administration (100 mg/day), a significant improvement was observed in echocardiographic indexes of systolic function, cardiothoracic ratio, and clinical signs and symptoms of congestive heart failure. In conclusion, the introduction of metabolic drugs, such as ubiquinone, in the treatment of heart failure opens new horizons in the therapeutic approach to an ailment that entails substantial human and social costs.

Echocardiographic vs hemodynamic monitoring during isometric exercise in patients with coronary artery disease.

BACKGROUND: Isometric exercise is able to induce myocardial asynergies in patients with coronary artery disease as demonstrated by noninvasive monitoring performed during stimulation. AIMS OF THE STUDY: In the present study, a combined echocardiographic and hemodynamic monitoring of left ventricular contractility has been conducted in order to verify, with invasive and noninvasive techniques, the ability of isometric exercise in inducing transient myocardial ischemic phenomena. METHODS: The study population was composed of 20 patients with angiographic evidence of significant coronary stenosis (> or = 50%), and 10 subjects with normal coronary angiograms. All 30 subjects admitted to the study underwent an isometric exercise stress during echocardiographic and hemodynamic monitoring of left ventricular contractility. RESULTS: Nine out of 20 patients with coronary disease showed regional asynergy during the test (Group I). The remaining 11 patients showed normal myocardial contractility (Group II). None of the 10 control subjects showed mechanical signs of ischemia during the test. Left ventricular end diastolic pressure significantly increased in both Group I (10 +/- 2 to 24 +/- 4 mmHg) and Group II (12 +/- 3 to 26 +/- 3 mmHg) (p < 0.01) while it remained unchanged in the control group (9 +/- 2 to 13 +/- 2 mmHg; p = NS); dp/dt increase (% basal) was significantly higher in the control group (45 +/- 6%) than in either Group I (25 +/- 3%) or Group II (26 +/- 3%) (p < 0.01). CONCLUSIONS: Isometric exercise was able to induce left ventricular asynergies due to regional myocardial ischemia. Hemodynamic contractility monitoring easily distinguished the control subjects from the patients with coronary disease but was not able to discriminate patients with handgrip-induced regional asynergy. Thus, the echocardiographic technique offers more detailed information about regional myocardial function than do the common hemodynamic contractility indexes.

The hypothetical role of potassium conductance on the genesis of R-wave amplitude increase during ischemia in the isolated rat heart.

The effect of increased potassium conductance on the genesis of R-wave amplitude increase during acute myocardial ischemia has been studied in the isolated perfused rat heart by simultaneously recording the R-wave amplitude of epicardial electrograms (VEE), heart rate (HR), coronary flow rate (CFR), left ventricular diastolic pressure (LVDP), and left ventricular systolic pressure (LVSP). The experiments were performed during basal and partial or total ischemic conditions at spontaneous or fixed HR. In some experiments, potassium conductance was increased by means of high-calcium (8 mM) or acetylcholine chloride (10(-6) M) perfusion. In the control experiments, partial ischemic perfusion produced an increase in VEE and LVDP and a decrease in HR, CFR, and LVSP; total ischemic perfusion exaggerated these variations. High-calcium perfusion provoked an increase in VEE and LVDP and a decrease in HR, CFR, and LVSP during basal conditions (p less than 0.01 vs. control experiment); these modifications increased progressively during partial ischemic perfusion (p less than 0.01 vs. control experiment) and during total ischemic perfusion (p less than 0.01 vs. control experiment). Perfusion with acetylcholine chloride produced variations similar to those observed in high-calcium solution except that LVDP under basal conditions remained unchanged from control. When the HR was maintained at a constant value by means of atrial pacing the results were similar to those observed in the unpaced hearts. In conclusion, in the isolated perfused rat heart, increasing potassium conductance may influence the genesis of R-wave amplitude increasing during acute myocardial ischemia.

Protective role of chronic ubiquinone administration on acute cardiac oxidative stress.

Previous studies have shown that acute exogenous administration of coenzyme ubiquinone (CoQ10) can protect the heart against oxidant-mediated injury. The aim of this study was to investigate whether protection against cardiac oxidative stress could be obtained by increasing tissue levels of CoQ10, as achieved by chronic CoQ10 supplementation. Wistar rats were randomly divided into two groups: a control group given standard diet and a test group receiving diet supplemented with CoQ10 (5 mg/kg/day) for 4 weeks. Functional and metabolic changes induced by oxidative stress were investigated in isolated perfused hearts and in papillary muscles. Tissue concentrations of ubiquinones were significantly higher in the left ventricle of treated rats than in controls. H2O2 infusion (60 microM for 60 min) induced marked alterations of both developed pressure, which decreased to -58.8 +/- 16.8% of base line and end-diastolic pressure which increased almost 13-fold. These effects were reduced significantly (P < .05) in hearts from CoQ10-supplemented rats (-13.8 +/- 2.3 and +375.0 +/- 42.5%, respectively). In the same hearts, cumulative release of oxidized glutathione (a specific marker of oxidative stress) was 450.2 +/- 69.2 nmol/g of wet weight in the control group and only 89.6 +/- 22.3 nmol/g of wet weight in treated hearts (P < .01). In papillary muscles, after 60 min of perfusion with H2O2, active tension decreased, largely in controls whereas it was almost unchanged in the treated group (-34.4 +/- 7.5% of baseline vs. -0.1 +/- 0.05%, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of age on the role of atrial natriuretic factor in renal adaptation to physiologic variations of dietary salt intake.

The effects of normal, low, and high dietary salt intake on basal atrial natriuretic factor plasma levels, plasma renin activity, and aldosterone were evaluated in seven young (Group 1), seven middle-aged (Group 2), and seven elderly healthy volunteers (Group 3). In all subjects, progressively higher doses of human alpha-atrial natriuretic factor were infused at low-sodium diet conditions to obtain hormone plasma values during infusion similar to those obtained in the same subjects at high-sodium diet conditions. Atrial natriuretic factor plasma values were significantly higher in Group 3 than in the other two groups at both normal- and high-salt diet conditions, and at all steps of the infusion study. At low-sodium diet conditions, peptide concentrations averaged 23.2 +/- 6.2 in Group 3, 26.2 +/- 1.9 in Group 2, and 19.1 +/- 3.9 pg/mL in Group 1 (P = not significant between groups). Hormone plasma values at high-salt diet conditions averaged 47 +/- 6.9 pg/mL in Group 1, 60 +/- 6.5 pg/mL in Group 2, and 136.3 +/- 14.6 pg/mL in Group 3. Each value was not significantly different from the corresponding value gained at an infusion step of 2 ng/min per kg in Group 1 and 2 (57.1 +/- 11.9 and 62.7 +/- 6.5 pg/mL, respectively), and of 1 ng/min per kg (139.1 +/- 22.2 pg/mL) in Group 3. At these infusion steps and at high-salt diet conditions, the urinary sodium excretion rate was, respectively, 0.185 +/- 0.02 and 0.311 +/- 0.02 mEq/min in Group 1, 0.168 +/- 0.01 and 0.300 +/- 0.02 mEq/min in Group 2, and 0.110 +/- 0.01 and 0.256 +/- 0.01 mEq/min in Group 3. Hormone infusion induced a progressive fall of plasma renin activity and aldosterone level in all groups. By experimentally increasing plasma concentrations of atrial natriuretic factor in a low-salt diet condition to the levels occurring physiologically in a high-salt diet condition, a significant rise in urinary sodium excretion rate is evoked, which accounts for 52% in young, 47% in middle-aged, and 30% in older subjects of the rise that is necessary to balance the increased salt intake.