Alessandra R. Lucarini

The atropine factor in pharmacologic stress echocardiography

Objectives. This study sought to compare, head to head, the two most popular pharmacologic stress echocardiographic tests-dipyridamole and dobutamin-with state of the art protocols in a large multicenter prospective study. Background. In the continuing quest for ideal diagnostic accuracy, pharmacologic stress echocardiography has quickly moved over the years from low to high dose regimens and is currently performed with atropine coadministration. Methods. Dobutamine (up to 40 μg/kg body weight per min) plus atropine (up to 1 mg over 4 h) and dipyridamole (up to 0.84 mg/kg per min over 10 h) plus atropine (up to 1 mg over 4 h) stress echocardiography was performed on different days, in random order and within 1 week in 360 patients with chest pain syndrome. Thirteen different echocardiographic laboratories, all fulfilling quality control criteria for stress echocardiographic reading, contributed to the study. Results. No major complications occurred during either test. The test was interrupted before achievement of predetermined end points for limiting side effects in 37 dobutamine-atropine and 7 dipyridamole-atropine stress echocardiographic studies (feasibility 90% vs. 98%, p < 0.01). Diagnostic accuracy was assessed in a subset of 110 patients with no obvious rest dyssynergy (akinesia or dyskinesia) who underwent coronary angiography independently of test results and within 1 week of testing. Significant coronary artery disease (≥50% diameter reduction in at least one major coronary vessel by quantitative coronary angiography) was found in 92 patients. Sensitivity for detection of coronary artery disease was 84% (77 of 92) for dobutamine-atropine and 82% (75 of 92) for dipyridamole-atropine stress echocardiography (p = NS), with a specificity of 89% (16 of 18) for dobutamine-atropine and 94% (17 of 18) for dipyridamole-atropine stress echocardiography (p = NS). A significant correlation was present between peak wall motion score index during dipyridamole-atropine and dobutamine-atropine stress echocardiography (r = 0.83, p < 0.0001). Conclusions. Dobutamine-atropine and dipyridamole-atropine stress echocardiography are safe and feasible, although submaximal studies are more frequent with dobutamine. The two stresses have comparable accuracy in the detection of angiographically assessed coronary artery disease, although dobutamine is marginally more sensitive and dipyridamole marginally more specific. Stratification of the ischemic response in the space domain is also comparable with the two stresses.

Dipyridamole echocardiography in essential hypertensive patients with chest pain.

The exerdse-electrocardiography test shows limited feasibility and diagnostic accuracy for the ooninvaslve detection of coronary artery disease in hypertensive patients. Recently, the dipyridamoleechocardiography test (two-dimensional echocardtographic monitoring with dipyridamole infusion, up to 0.84 mg/kg over 10 minutes) has been proposed as an exercise-independent method for the diagnosis of coronary artery disease. The diagnostic usefulness of the exerdse-electrocardiography test and the dipyridamole-echocardiography test was evaluated in 63 consecutive inpatients with history of chest pain, essential hypertension, and no previous myocardial infarction. The criterion of posltlvity for the exerdse-electrocardiography test was a horizontal or downsioping ST segment shift exceeding 0.1 mV and for the dipyridamole-echocardiography test, a transient dyssynergy of contraction. Fifteen patients could not perform a diagnostic exerdse-electrocardiography test because of an nubility to exercise adequately (two patients), severe hypertension in spite of full antihypertensive therapy (six patients), or excessive blood pressure rise at the first step of the exercise-electrocardiography test (seven patients). Five patients could not perform the dipyridamole-echocardiography test because of a poor acoustic window. The overall feasibility was 76% for the exercise-electrocardiography test and 92% for the dipyridamoleechocardiography test (p < 0.05). All 43 patients who performed both tests underwent coronary angiography; 30 had significant coronary artery disease (>70% lumen reduction of at least 1 major coronary vessel). Sensitivity was 67% for both the exercise-electrocardiography test and the dipyridamoleechocardiography test (p = NS); spedfidty was 46% for the exerdse-electrocardiography test and 92% for the dipyridamole-echocardiography test {p < 0.05). Thus, the dipyridamole-echocardiography test represents a good diagnostic alternative to the exercise-electrocardiography test in symptomatic hypertensive patients, as it has a similar sensitivity and higher feasibility and spedfidty for the detection of coronary artery disease.

Presence of Cardiovascular Structural Changes in Essential Hypertensive Patients With Coronary Microvascular Disease and Effects of Long-Term Treatment

In asymptomatic essential hypertensive patients with angiographically normal coronary arteries and without left ventricular hypertrophy, dipyridamole-induced ischemic-like ST segment depression may be a marker of coronary microvascular disease. In this study we evaluated, first, whether this cardiac abnormality is linked to structural or functional vascular abnormalities, and second, the effect of antihypertensive treatment by 12-month administration of the angiotensin converting enzyme (ACE) inhibitor captopril (50 mg twice a day orally). In essential hypertensives with dipypridamole echocardiography stress test (DET) (DET+, n = 8) and without (DET-, n = 8) ST segment depression greater than 0.1 mV during intravenous dipyridamole infusion (0.84 mg/kg over 10 min), we studied the forearm blood flow (FBF, venous plethysmography, mL/100) modifications induced by intrabrachial acetylcholine (Ach) (0.15, 0.45, 1.5, 4.5, 15 micrograms/100 mL/min x 5 min each), an endothelium-dependent vasodilator, and by sodium nitroprusside (SNP) (1, 2, 4 micrograms/100 mL/min x 5 min each), a smooth muscle cell relaxant compound. Minimal forearm vascular resistances (MFVR), an index of arteriolar structural changes, were also calculated. Both Ach and SNP caused greater vasodilation in DET- as compared to DET+ while MFVRs were lower in DET- compared to DET+. After treatment, both DET+ and DET- patients showed a significant and similar reduction in blood pressure and left ventricular mass index, while vasodilation to acetylcholine and sodium nitroprusside was increased only in the DET+ group. In addition, forearm minimal vascular resistances were significantly reduced only in DET+ patients, who showed disappearance of dipyridamole-induced ischemic-like ST segment depression. In conclusion, these data confirm that essential hypertensive patients with microvascular coronary disease are characterized by the presence of structural changes in the forearm vascular bed. Our results also indicate that both cardiac and forearm vascular abnormalities can be reversed by antihypertensive treatment with an ACE inhibitor.

Increased Myocardial Ultrasonic Reflectivity is Associated With Extreme Hypertensive Left Ventricular Hypertrophy A Tissue Characterization Study in Humans

We assessed myocardial reflectivity pattern in a large spectrum of left ventricular mass values, covering the extremes from absent to severe myocardial hypertensive hypertrophy. Quantitatively assessed ultrasonic backscatter is an index of ultrasonic tissue characterization directly related to the morphometrically evaluated collagen content in humans. We enrolled 88 essential hypertensives. With an echo prototype implemented in our Institute, integrated values of the radiofrequency signal of myocardial walls were obtained and normalized for those of the pericardium (Integrated Backscatter Index, IBI, %). Left ventricular mass index (LVMI) was measured by Devereux formula. There was a weak correlation between septal IBI and LVMI (r = 0.35; P < .001). On the basis of LVMI values, three groups of hypertensives were identified, with absent (Group I, n = 23; LVMI < 125 g/m2), mild to moderate (Group II, n = 44; LVMI from 125 to 174 g/m2), or severe (Group III, n = 21; LVMI > 175 g/m2) left ventricular hypertrophy. The Integrated Backscatter Index in the septum was lower in patients of Group I (IBI = 23.3% +/- 3.6%) and II (IBI = 26.5 +/- 7.6; P = NS v Group I), in comparison with patients of Group III (IBI = 31.1 +/- 5.9; P < .02 v II; P < .0001 v I). An increased myocardial wall reflectivity is detectable only in the presence of extreme forms of hypertensive left ventricular hypertrophy.

Coronary Microvascular Disease in Hypertensives

Arterial hypertension can badly affect coronary circulation through several mechanisms that are not mutually exclusive, namely, coronary artery disease, left ventricular hypertrophy, and microvascular disease. Theoretical and experimental data suggest that coronary microvascular disease may exist in hypertensives, in whom it can cause both a reduction of coronary flow reserve and a shift to the right of the coronary flow autoregulation curve. To address this issue, we used dipyridamole- echocardiography test, which causes ischemic-like ST segment depression with no detectable changes in left ventricular function in different subsets of patients with microvascular disease (Syndrome X; Hypertrophic cardiomyopathy; acute heart rejection). We found that dipyridamole infusion can cause a similar pattern of response (i.e., echocardiographically silent ST segment depression) in mild-moderate essential hypertensives with normal epicardial coronary arteries, without left ventricular hypertrophy, with increased forearm minimal vascular resistances and with a reduced coronary reserve. This pattern of response identifies hypertensives with higher risk of ventricular arrhythmias, is amplified by acute reduction of diastolic blood pressure and can be reversed, together with the reduction of forearm vascular resistances by chronic antihypertensive treatment. Taken together these findings suggest that microvascular coronary disease can exist in hypertensives with two adverse consequences, consistent with the experimental background: the reduction of coronary flow reserve as well as a shift to the right of the coronary flow autoregulation curve.

Systemic and renal hemodynamic effects of celiprolol in essential hypertensives

To evaluate the humoral and hemodynamic (both systemic and renal) effects of celiprolol and to assess whether these effects are at least partially due to the activation of dopamine (DA) receptors, 9 out-patients with mild to moderate uncomplicated essential hypertension, without any therapy for at least 3 weeks, received celiprolol (400 mg once daily) and placebo, each for 1 month, according to a double-blind randomized trial pattern. At the end of each treatment period, blood pressure, heart rate, renal plasma flow, glomerular filtration rate, plasma renin activity, plasma aldosterone and plasma norepinephrine were measured after administration of saline solution and intravenous metoclopramide. Compared with placebo, celiprolol significantly reduced mean blood pressure, heart rate and plasma norepinephrine. Plasma renin activity showed a tendency toward a reduction during celiprolol treatment, which was not associated with changes in plasma aldosterone. Despite the decrease in mean blood pressure, renal plasma flow did not change, so that renovascular resistances were significantly reduced. Glomerular filtration rate was unchanged and the filtration fraction showed a trend toward a reduction during celiprolol treatment. Percent decrements of renovascular resistances and of mean blood pressure induced by celiprolol tended to correlate with changes in plasma norepinephrine. Metoclopramide did not influence the hemodynamic (systemic and renal) effects of celiprolol nor plasma renin activity and plasma norepinephrine, and it increased aldosterone levels to a similar extent before and after administration of celiprolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Low dose atrial natriuretic factor in primary aldosteronism: renal, hemodynamic, and vascular effects.

Whether atrial natriuretic factor (ANT) plays a physiological role in primary aldosteronism has yet to be determined. In the present study, the renal, hemodynamic, humoral, and vascular effects of a synthetic (WY- 47663) human analogue were studied in five water-loaded (15 ml H2O/kg) patients with adenomatous primary aldosteronism, a salt-sensitive, low renin, volumeexpanded syndrome. ANF was infused for 3 hours at a low rate (0.005 μg/kg/min), which approximately doubled circulating immunoreactive ANF. Glomerular filtration rate and renal blood flow (inulin and para-aminohippurate clearance) remained stable, but sodium excretion increased significantly suggesting a dissociation between renal hemodynamics and natriuresis as well as a direct inhibitory effect on tubular sodium reabsorption by ANF. Intra-arterial diastolic blood pressure, heart rate, forearm blood flow (plethysmographic method), and arterial plasma norepinephrine did not change, but systolic blood pressure declined and hematocrit rose suggesting plasma volume contraction by ANF. Plasma aldosterone levels were unchanged indicating a loss of ANF-mediated aldosterone inhibition, possibly related to qualitative or quantitative alterations of ANF receptors in tumoral adrenal tissue. Infusion of the analogue into the brachial artery was at a rate of 0.005 μg/dl forearm tissue/min×30 minutes, which also doubled local immunoreactive venous ANF concentrations and vasodilated forearm arterioles. These data suggest a physiological role for ANF in modulating body fluid volume even in human primary aldosteronism.

Increased prevalence of ventricular arrhythmias in essential hypertensives with dipyridamole-induced ischemic-like S-T segment changes.

Essential hypertensives are at greater risk for ventricular arrhythmias than normotensive controls. A reduction in coronary flow reserve may be one of the mechanisms underlying this increased prevalence of ventricular dysrhythmias in hypertensives. It has previously been shown that dipyridamole infusion may provoke ischemic-like S-T segment depression in essential hypertensives with angiographically normal coronary arteries and reduced flow reserve. The aim of the present study was to assess whether electrocardiographic positivity (S-T segment depression greater than 0.1 mV from baseline) during dipyridamole testing (12-lead electrocardiogram and two-dimensional echomonitoring, with the infusion of 0.84 mg/kg dipyridamole over 10 min) might identify hypertensives at greater risk for ventricular dysrhythmias. We therefore studied 51 mild-to-moderate essential hypertensives by dipyridamole testing and 48-h Holter monitoring. All patients were off therapy for at least 2 weeks before testing and Holter evaluation. Left ventricular mass (by Penn convention) and ejection fraction (by Teichholtz rule) were evaluated by two-dimensional echocardiography. Lown classes 0-1 were found in 31 patients (Group 1) and Lown classes II-IV in 20 (Group 2). The two groups overlapped for mean blood pressure (121 +/- 9 versus 124 +/- 8 mmHg), left ventricular mass index (120 +/- 27 versus 141 +/- 42 g/m2) and left ventricular ejection fraction (54 +/- 6 versus 52 +/- 6). An electrocardiographically-positive dipyridamole test was found in seven of Group I and 16 of Group II patients (23 versus 80%, P less than 0.01). No patient showed a transient, either regional or global, systolic dysfunction during dipyridamole testing.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of dopamine-1 receptor blockade on the humoral and renal effects of low-dose atrial natriuretic factor in human hypertensives

To test whether dopaminergic mechanisms can modulate the humoral and renal effects of atrial natriuretic factor (ANF), seven untreated, mildly hypertensive patients without complications were given a placebo (saline for 60 min) followed by a low dose of ANF (0.005 microgram/kg per min), or D-sulpiride (0.05 mg/kg per min), a specific dopamine-1 antagonist, or ANF + D-sulpiride at the same doses, for 60 min. The sequence of the three treatments was random, with a 72-h interval between treatments. The ANF infusion, which increased plasma ANF within the physiological range, significantly increased urinary sodium excretion, fractional sodium excretion and haematocrit; it reduced plasma aldosterone and tended to reduce plasma renin activity without changing blood pressure, the heart rate, renal plasma flow or the glomerular filtration rate. D-Sulpiride, when given alone, significantly increased mean blood pressure and reduced absolute and fractional sodium excretion without changing the heart rate, glomerular filtration rate, renal plasma flow, haematocrit, plasma renin activity or plasma aldosterone. When infused with D-sulpiride, ANF did not change absolute or fractional sodium excretion or haematocrit. This study provides evidence that dopaminergic mechanisms play a role in the natriuretic and plasma volume effects of a synthetic human ANF analogue infused at a low dose in patients with essential hypertension.

Role of Dipyridamole-Echocardiography Tests in the Diagnosis of Coronary Artery Disease in Hypertensives

In hypertensive patients, the exercise-electrocardiography test shows limited feasibility and diagnostic accuracy for the noninvasive detection of coronary artery disease (CAD). Recently, the dipyridamole-echocardiograpy test (2-dimensional echo monitoring with a dipyridamole infusion of up to 0.84 mg/kg over 10 min) has been proposed as an exercise independent method for the diagnosis of CAD. In order to establish the relative diagnostic usefulness of the exercise-electrocardiography test (EET) and the ipyridamole-echocardiography test (DET) in the detection of CAD, the 2 tests were performed consecutively in 114 inpatients with a chest-pain syndrome and essential hypertension. Forty patients had previous myocardial infarction. Criteria of positivity were: for EET, a horizontal or downsloping ST segment shift > 0.1 mV; and for DET, a transient dyssynergy of contraction.