Jose Meller

Hemodynamic and clinical tachyphylaxis to prazosin-mediated afterload reduction in severe chronic congestive heart failure.

Sequential doses of 5 mg of oral prazosin hydrochloride were administered to eight patients with severe chronic congestive heart failure refractory to conventional therapy. Initial doses of the drug produced marked increases in cardiac index (+0.87 I/min/m2) associated with substantial decreases in left ventricular filling pressure (-10.7 mm Hg), total systemic vascular resistance (2118 to 1154 dyn-sec-cm-5), and heart rate (89 to 76 beats/min). However, serial administration of the same dose at 12-24-hour intervals was accompanied by the rapid development of tachyphylaxis, such that the magnitude of hemodynamic effects with second doses was less than 50% of the magnitude of effects seen with first doses (p < 0.01), and third doses produced no overall significant hemodynamic responses. Diuresis with furosemide failed to restore the circulatory effects of prazosin, and the use of 10-mg doses improved cardiovascular performance to only a small extent. Only two of eight patients had sustained hemodynamic responses large enough to justify chronic oral ambulatory therapy. Administration of oral hydralazine caused hemodynamic improvement superior to even high-dose prazosin therapy (p < 0.02).

Coronary flow studies in patients with left ventricular hypertrophy of the hypertensive type: Evidence for an impaired coronary vascular reserve

Increased myocardial blood flow occurs in ventricular hypertrophy, but flow per 100 grams of myocardium remains normal. The increase in flow may be obtained at the expense of the existing coronary vascular reserve or by an increase in the vascular bed. The coronary vascular reserve was studied by analyzing the hyperemic reaction to selective injection of contrast agent into the coronary arteries in 25 patients: a control group (9 patients) with chest pain syndrome, normal coronary arteries and a normal left ventricle (Group I) and 16 patients with aortic stenosis, left ventricular hypertrophy and normal coronary arteries (Group II). The hyperemic response in Groups I and II was 73.3 +/- 2.2 and 65.8 +/- 9.1 percent, respectively (difference not significant). Group II was subdivided into two groups: Group IIA had five patients with a left ventricular mass of less than 200 g (mean 158.8 +/- 25.9); this group had a hyperemic response of 102.3 +/- 9.9 percent. Group IIB had 11 patients with a left ventricular mass of more than 200 g (mean 308.9 +/- 22.5) and a hyperemic response of 49.27 +/- 10.42 percent. The hyperemic response was correlated with the diastolic left ventricular-aortic gradient (r = +0.64, p less than 0.001), left ventricular mass (r = -0.51, p less than 0.01) and aortic diastolic pressure (r = +0.636, p less than 0.001). Group I had a left ventricular mass similar to that of Group IIA (124.9 +/- 9 and 158.8 +/- 26 g, respectively) but a lower hyperemic response (73.3 +/- 2 and 102.3 +/- 10 percent, respectively). These data suggest that severe left ventricular hypertrophy is associated with a reduction in coronary vascular reserve; it is speculated that this decrease in the vascular reserve capacity may be related to the ischemic component of hypertrophic heart disease.

Hemodynamic consequences of combined beta-adrenergic and slow calcium channel blockade in man.

The administration of verapamil to patients receiving, β-adrenergic blocking drugs is reported to produce adverse circulatory reactions, but a systematic investigation of this potential drug interaction has not been performed in man. We administered 40-, 80- and 120-mg doses of verapamil orally to 15 patients with angina pectoris who were receiving high doses of propranolol or metoprolol. Verapamil produced dose-dependent decreases in cardiac performance: with 120 mg, cardiac index decreased by 0.38 I/min/m2, stroke volume index decreased by 2.8 ml/beat/m2 and heart rate decreased by 6 beats/min, associated with increases in pulmonary capillary wedge (2.2 mm Hg) and mean right atrial pressures (1.7 mm Hg) (all p < 0.01); two patients had marked, but asymptomatic, hypotensive reactions. In contrast, repeat administration of 120-mg doses of verapamil 24–30 hours after withdrawal of A blockade produced no significant cardiodepressant effects despite significantly higher plasma levels of verapamil than during propranolol therapy (383.1 vs 205.1 ng/ml, p < 0.01). In conclusion, verapamil produces significant negative inotropic and chronotropic effects in patients treated with 3-adrenergic antagonists; combination therapy should therefore be used with caution in patients with angina pectoris.

Rebound Hemodynamic Events after the Abrupt Withdrawal of Nitroprusside in Patients with Severe Chronic Heart Failure

We studied the hemodynamic events that followed abrupt withdrawal of nitroprusside in 20 patients with severe chronic heart failure. With nitroprusside, cardiac index increased from 1.96 to 2.87 liters per minute per square meter of body-surface area, but it decreased to 1.66 (P less than 0.001) after withdrawal of nitroprusside. Left ventricular filling pressure and systemic vascular resistance decreased from 23.9 to 15.3 mm Hg and from 1642 to 921 dyn.sec.cm-5, respectively, with nitroprusside, but increased to 30.4 mm Hg and 2109 dyn.sec.cm-5 (both P less than 0.001) upon its discontinuation. These rebound changes were maximal 10 to 30 minutes after nitroprusside withdrawal and returned to control levels one to three hours later. Although in 17 of 20 patients, these rebound changes caused no or minimal exacerbation of symptoms, pulmonary edema, which resolved in three patients. Activation of reflex vasoconstrictive forces during vasodilator therapy may explain these effects of withdrawal.

Pulsed doppler echocardiographic measurement of beat-to-beat changes in stroke volume in dogs.

Measurement of stroke volume by pulsed Doppler echocardiography has not been validated against a reference method in vivo. We compared Doppler systolic frequency shift integrals with electromagnetic flowmeter stroke volume in seven open-chest dogs. A pulsed Doppler echocardiographic transducer was held on the aortic arch with the sample volume in the ascending aorta. Stroke volume was varied by epinephrine or pentobarbital infusions, fluid administration or inferior vena caval constriction. Linear regression analysis of stroke volume vs Doppler systolic frequency shift integrals revealed strong correlations and intercepts close to zero (r = 0.74–0.096, p < 0.001). Minor changes in transducer position did not influence Doppler frequency shift integrals substantially. Therefore, pulsed Doppler echocardiography served as an excellent measurement of stroke volume changes in this model. However, serious limitations are presented that may limit its clinical application.

Septal perforator compression (Narrowing) in idiopathic hypertrophic subaortic stenosis

Thirteen patients with idiopathic hypertrophic subaortic stenosis were compared with two groups of subjects: 10 patients with chest pain, normal coronary arteries and a normal left ventricle, and 10 patients with left ventricular hypertrophy. Five of the latter had aortic stenosis and five had idiopathic left ventricular hypertrophy. Coronary arteriography revealed that the septal branches of the left anterior descending artery closed or narrowed during systole in patients with idiopathic hypertrophic subaortic stenosis and did not do so in the other patient groups. This narrowing is possibly related to an abnormal position of the septal arteries within the septum in idiopathic hypertrophic subaortic stenosis. Systolic compression of the septal perforator arteries is not a pathognomonic sign of idiopathic hypertrophic subaortic stenosis.

Myocardial infarction due to coronary atherosclerosis in three young adults with systemic lupus erythematosus

Three patients, 24, 24 and 25 years of age, with systemic lupus erythematosus had signs of myocardial infarction. Two had serial electrocardiographic changes indicative of infarction without any cardiac symptoms. The third patient had clinical evidence of an acute massive myocardial infarction, which was proved at autopsy to be due to coronary atherosclerosis. This case is presented in detail and the association between systemic lupus erythematosus and myocardial infarction is reviewed. It is postulated that the relation between lupus erythematosus and coronary atherosclerosis is more than coincidental.

Spectrum of exercise thallium-201 myocardial perfusion imaging in patients with chest pain and normal coronary angiograms.

Abstract Twenty-seven consecutive patients with chest pain and no significant obstructive coronary lesions on arteriography were studied with thallium-201 myocardial imaging during exercise and at rest. Fifteen of the patients had typical and 12 atypical angina pectoris. All underwent treadmill exercise electrocardiographic testing; the results were abnormal in 10 patients (37 percent), normal in 14 (52 percent) and uninterpretable in 3 (11 percent). The exercise and resting thallium-201 myocardial images were normal in 23 patients (85 percent); the results of exercise testing were normal in 12 of these patients, abnormal in 8 and uninterpretable in 3. Four patients had a perfusion defect on exercise thallium-201 myocardial imaging; the defect filled in by 4 hours in two patients but persisted in the other two. In contrast, when thallium-201 myocardial imaging was performed in 28 consecutive patients with angiographic coronary artery disease, only 5 patients (16 percent) had normal exercise and resting thallium-201 myocardial images. Therefore, thallium-201 myocardial imaging offers a more effective means of identifying patients with chest pain and no obstructive coronary artery disease than the clinical history or the exercise electrocardiographic test, or both. However, 15 percent of these patients will have abnormal exercise thallium-201 myocardial images because of factors that have not yet been identified.

Importance of Left Ventricular Chamber Size in Determining the Response to Hydralazine in Severe Chronic Heart Failure

To examine the importance of left ventricular chamber size in determing the response to vasodilator therapy, we performed echocardiography in 40 patients with chronic refractory heart failure before they were treated with oral hydralazine. The left ventricular end-diastolic dimension (LVEDD) correlated significantly with the per cent change in stroke volume (r = 0.77), left ventricular filling pressure (r = -0.68), and stroke work index (r = 0.87) during short-term drug administration. After 14 to 21 days of maintenance therapy, 15 of 24 patients with an LVEDD greater than or equal to 60 mm were improved, and one was worse; mean blood urea nitrogen decreased from 45.6 to 30.6 mg per deciliter in the 21 patients in this group who completed the study (16.3 to 10.9 mmol per liter) (P less than 0.001). In contrast, only two of 16 patients with an LVEDD less than 60 mm improved, whereas 10 showed clinical deterioration; blood urea nitrogen increased from 49.3 to 64.2 mg per deciliter in the 13 patients in this group who completed the study (17.6 to 22.9 mmol per liter) (P less than 0.01). These findings indicate that left ventricular chamber size is an important factor in the response to hydralazine in patients with severe chronic heart failure.

Dose Requirements of Hydralazine in Patients With Severe Chronic Congestive Heart Failure

To evaluate the doses of hydralazine needed to obtain significant hemodynamic responses in severe chronic refractory heart failure, 45 consecutive patients received incremental doses of the drug during invasive hemodynamic monitoring. Twenty-six patients (group A) responded to the oral administration of single doses of 100 mg of hydralazine, whereas 19 patients (42 percent) (group B) did not. Of the patients in group B, 14 responded to 150 to 300 mg orally as a single dose, 3 patients required a single dose of 600 or 800 mg orally and 2 patients responded only to intravenous administration of the drug. In spite of the different dosage requirements of hydralazine, the hemodynamic responses to effective doses were similar in the two groups. The control etiologic, pathophysiologic and hemodynamic variables were similar in both groups, except that patients in group B had higher control values for mean right atrial pressure (14.0 ± 1.5 versus 9.2 ± 1.3 mm Hg; p In conclusion, the doses required for effective hydralazine therapy in patients with severe heart failure are variable and are generally higher than those utilized in hypertensive patients. This may be related to varying degrees of vascular hyporesponsiveness or drug malabsorption, or both, observed in states of high venous pressure. The failure of hydralazine to produce clinical improvement in an individual patient may therefore be due to the administration of subtherapeutic quantities of the drug.