Juhani Heikkilä

“Acute pericarditis”: Myocardial enzyme release as evidence for myocarditis

The relationship between the serial ECG ST-T wave changes held to be characteristic of acute pericarditis and serum cardiac enzyme levels was studied in 18 young men with symptoms of acute infectious disease. Creatine kinase MB enzyme (CK-MB) was detected in 14 patients (78%); its peak levels were as high as 186 U/L during the first days of ST segment elevation. Normal values were only noted during the subsequent T wave inversion stage of the disease. ST segment elevation was more marked (p less than 0.01) and T wave inversions were deeper (p less than 0.01) and more prolonged (p less than 0.05) in the 12 patients with CK-MB levels over 10 U/L than in those with values under 10 U/L. Pericardial friction rub and/or pericardial effusion by echocardiography occurred in only one third of the patients. We conclude that the serial ECG changes of ST segment elevation, with subsequent T wave inversions in connection with acute infection, are caused by acute myocardial injury, myocarditis, as reflected by myocardial enzyme release.

Comparison of dipyridamole-handgrip test and bicycle exercise test for thallium tomographic imaging

Seventy-three patients with angina pectoris and 20 with atypical chest pain, who underwent coronary angiography, were examined by single-photon emission computed thallium tomography (TI-SPECT) using a combined dipyridamole-handgrip stress test. Perfusion defects were detected in 78 of 81 patients with angiographically significant coronary artery disease (CAD) (sensitivity 96%). In 9 of 12 patients without CAD, the thallium images were normal (specificity 75%). Thirty-five patients with CAD were reexamined by TI-SPECT using a dynamic bicycle exercise stress test. The sensitivity of the dipyridamole-handgrip test did not differ from the bicycle exercise test in diagnosing the CAD (97% vs 94%). Multiple thallium defects were seen in 19 of 22 (86%) patients with multivessel CAD by the dipyridamole-handgrip test but only in 14 of 22 (64%) by the bicycle exercise test. Noncardiac side-effects occurred in 17 of 93 (18%) patients after dipyridamole infusion. Cardiac symptoms were less common during the dipyridamole-handgrip test than during the bicycle exercise (15% vs 76%, p less than 0.01). These data suggest that the dipyridamole-handgrip test is a useful alternative stress method for thallium perfusion imaging, particularly in detecting multivessel CAD.

Detection of coronary artery disease by thallium imaging using a combined intravenous dipyridamole and isometric handgrip test in patients with aortic valve stenosis

Detection of coronary artery disease (CAD) in patients with aortic valve stenosis (AS) is clinically difficult. Thallium-201 images were generated in 27 patients with AS during combined intravenous dipyridamole and handgrip test, which induces a marked acute increase in coronary blood flow. Isolated AS was noted in 21 patients and combined AS and aortic regurgitation in 6. Thirteen patients had more than 50% diameter stenosis in 1 or more coronary arteries on angiography. Eleven of them had reversible perfusion defects on post-stress thallium scans (sensitivity 85%). Two patients had thallium defects without angiographic evidence of significant CAD (specificity 86%). In the other 12 patients with normal coronary angiographic findings, the thallium scans were normal. Two patients had dizziness and hypotension after dipyridamole infusion, which disappeared during the handgrip test; 2 others had chest pain during handgrip. One of them was treated with aminophylline and the other with aminophylline and nitroglycerin. No other adverse effects were reported by the patients and no major complications occurred during stress testing. Thus, thallium imaging during combined intravenous dipyridamole and handgrip test appears to be a promising noninvasive method of revealing CAD in patients with AS.

Usefulness of technetium-99m-MIBI and thallium-201 in tomographic imaging combined with high-dose dipyridamole and handgrip exercise for detecting coronary artery disease

Forty-two patients with known stable coronary artery disease, referred for coronary angiography, were examined with technetium-99m-hexakis-2-methoxy-2-methylpropyl-isonitrile (MIBI) tomography combined with a high-dose dipyridamole infusion (0.7 mg/kg) and handgrip stress. MIBI tomography was unable to show coronary artery disease only in 2 patients, thus yielding a sensitivity figure of 95%. MIBI tomography correctly identified 27 (82%) of 33 stenotic lesions (greater than or equal to 50% diameter stenosis) of the left anterior descending artery, 17 (61%) of 28 of those of the left circumflex artery, and 28 (90%) of 31 of those of the right coronary artery. The overall vessel sensitivity was 78%. The computed lumen diameter stenoses were more advanced in cases detected than in those not detected with MIBI tomography: 87 +/- 14 vs 76 +/- 14% (p less than 0.01). The 50 to 69% stenoses did not show any tendency to produce less positive findings than those with greater than or equal to 70% stenoses. In the subgroup of 21 patients who also presented for thallium scintigraphy, the overall diseased vessel identification rate was 76% for thallium tomography and 83% for MIBI tomography (p = not significant). Minor noncardiac side effects related to the dipyridamole-handgrip test occurred only in 5% of 63 study sessions. A high-dose dipyridamole combined with isometric exercise is a safe stress method, and when used during scintigraphy, MIBI tomography is at least as efficient a tool as thallium tomography in detecting diseased vessel territories in patients in coronary artery disease.

Preoperative diagnosis of coronary artery disease in patients with valvular heart disease using technetium-99m isonitrile tomographic imaging together with high-dose dipyridamole and handgrip exercise

Forty-seven consecutive patients (mean age 61 +/- 8 years) referred for cardiac catheterization due to moderate to severe aortic (n = 30) or mitral (n = 17) valvular heart disease were examined by technetium-99m isonitrile tomography together with a high-dose dipyridamole infusion (0.7 mg/kg) and handgrip stress. Tomography did not identify coronary artery disease (CAD) in 3 of the 21 patients with angiographically proven disease (sensitivity 86%) and suggested false positive results in 5 of the 26 without the disease (specificity 81% and negative predictive accuracy 88%). No patient without angina pectoris and with negative scintigraphy (n = 14) had angiographically significant (greater than or equal to 50% diameter stenosis) CAD. Overall vessel sensitivity was 63%, and specificity was 92%. The frequency of side effects during the dipyridamole-handgrip test was only 7%. No serious complications occurred during stress tests. Thus, technetium-99m isonitrile tomographic imaging, together with high-dose dipyridamole and handgrip exercise, is a useful noninvasive method in excluding significant CAD in patients with valvular heart disease.

Cardiac safety of acute beta blockade: intrinsic sympathomimetic activity is superior to beta-1 selectivity.

Regional myocardial function was assessed by multidirectional echocardiography from eight standardized segments around the left ventricle. Thirty-six subjects (healthy, severe angina pectoris, or acute myocardial infarction) were studied 15 minutes either after the beta 1-selective beta-blocking drug metoprolol had been administered in total doses of 2 and 10 mg intravenously or after pindolol, a beta blocker with intrinsic sympathomimetic activity (ISA), in total doses of 0.2 and 1.0 mg intravenously had been given. Metoprolol and pindolol reduced rate-pressure product (p less than 0.001 each), heart rate (p less than 0.001), and systolic blood pressure (p less than 0.05 to 0.001) in almost the same way. In patients with acute myocardial infarction, 0.2 mg pindolol improved ST segments by 33% and 2 mg metoprolol by 18%. Left ventricular diameter increased (p less than 0.001) and ejection fraction decreased (p less than 0.05) after metoprolol but not after pindolol. Pindolol did not reduce wall motion amplitudes of healthy myocardial segments, while metoprolol did ( p less than 0.01). The overall contractile function of the left ventricle is characterized by composite segmental amplitudes from both ischemic and healthy ventricular regions. In ischemic hearts this function remained unchanged after metoprolol but improved markedly after pindolol (p less than 0.005). Thus, while intravenous pindolol and metoprolol produced equal reductions in rate-pressure product, pindolol, a beta-adrenergic-blocking drug with intrinsic sympathomimetic activity, evoked less cardiac depression and thus provided a cardiac safety factor not afforded by the beta- 1-selective metoprolol.

Effects of verapamil in patients with acute myocardial infarction: hemodynamics and function of normal and ischemic left ventricular myocardium.

We evaluated the effects of intravenous verapamil, a calcium antagonist, on hemodynamics and regional left ventricular (LV) performance in patients with acute myocardial infarction (AMI). Twenty patients having uncomplicated infarction or moderate heart failure were randomized to receive either verapamil or placebo and were studied a mean of 12 hours after onset of symptoms. Verapamil, 7.5 mg intravenously, acutely reduced systolic arterial pressure (p less than 0.0005), systemic vascular resistance, and LV stroke work (p less than 0.005) and rate-pressure product (p less than 0.05); the heart rate did not alter. The Frank-Starling relationship by Swan-Ganz catheter did not change for 1 hour. Segmental wall motion amplitudes were recorded from eight standardized segments around the left ventricle by a multidirectional M-mode echocardiographic technique. The systolic wall motion of the uninvolved LV segments and LV cavity size did not change after verapamil. Verapamil improved mechanical performance in the ischemic segments (p less than 0.005). Therefore, the overall regional contractile function of the left ventricle improved as well (by 11% to 13%, p less than 0.05). This echocardiographic improvement continued after the acute vasodilatory response of intravenous verapamil subsided and was preserved for 1 week, the patients having had oral verapamil, 240 mg daily. Chest pain was relieved in five of the six patients having ongoing slight pain before verapamil injection. No sequential hemodynamic or echocardiographic changes occurred in the placebo-treated patients. Thus, in patients with uncomplicated AMI, verapamil improve contractile function of the acutely ischemic LV segments by hemodynamic unloading and/or by direct myocardial effect, without manifest depression of the uninvolved myocardium.

Effects of tumour mass and circulating antigen on the biodistribution of111In-labelled F(ab′)2 fragments of human prostatic acid phosphatase monoclonal antibody in nude mice bearing PC-82 human prostatic tumour xenografts

We have evaluated the effects of tumour mass and circulating antigen (prostatic acid phosphatase, PAP) on the biodistribution and the incorporation of111In-labelled F(ab′)2 monoclonal antibody (MoAb) fragments directed against human PAP into human prostatic tumours (PC-82; 0.1–8.9 g) growing in nude mice. The radioactivities in the blood, liver, spleen, kidney and tumour were compared at 1, 3, 4 and 6 days after the intravenous administration of the antibody fragments. There was a significant correlation between the tumour size and the serum PAP concentration in the model employed. Even tissue of a small tumour (< 0.1 g) had a high concentration of PAP, but it was not secreted into the circulation in detectable amounts when measured by radioimmunoassay (the lowest standard was 0.5 μg/l). The percentage uptake by tumours of the injected dose per gram of tissue (%ID/g) was inversely proportional to the tumour size at 24 h after the administration of111In-labelled F(ab′)2 fragments. This relationship had levelled off by 72 h and most likely reflected a better vascularisation of the smaller tumours. Our results show that the increase in tumour size and in the concentration of circulating antigen in the blood led to decreased tumour-to-blood ratios, since there was a tendency for higher blood activities in mice with larger tumours and higher serum PAP concentrations. There was no correlation between tumour size and label uptake by the liver during the follow-up over 144 h, although serum PAP concentrations ranged from 3.1 μg/l to 352 μg/l. On the other hand, when compared with our previous data obtained with non-tumour-bearing mice, there was a significant increase in the uptake by the liver and spleen. These results indicate that even a small concentration of circulating antigen was able to trigger an abnormal change in the biodistribution of MoAbs.

Exercise capacity and hemodynamics in persons aged 20 to 50 years with systemic hypertension treated with diltiazem and atenolol

Hemodynamic responses and exercise capacity were studied during maximal exercise in 25 young hypertensive persons (mean age 40 years) taking placebo, diltiazem (mean 216 mg/day) and atenolol (mean 80 mg/day). The study was a crossover, double-blind, randomized trial, each medication period lasting 2 months. Sitting blood pressure (BP) was 160 +/- 19/109 +/- 8 mm Hg after run-in. Both drugs decreased BP significantly, diltiazem by 10/ 11 mm Hg and atenolol by 16/14 mm Hg (difference not significant between drugs). During exercise there were no differences among patients taking placebo, diltiazem and atenolol in peak workload and rating of perceived exertion. Atenolol significantly attenuated the increase in heart rate, BP and heart rate-BP product at each workload. Diastolic BP during exercise was significantly lower (6 to 10 mm Hg) during diltiazem therapy than during placebo at each workload. Thus, both diltiazem and atenolol decrease rest BP significantly without impairing exercise capacity.

Biodistribution in normal mice of an111in-labelled prostatic acid phosphatase-specific antibody and its F(ab′)2 fragments derivatized site-specifically or via bicyclic diethyl enetriaminepentaacetic acid anhydride

In this study we examined optimization of derivatization of monoclonal antibodies and their fragments intended for use as radiopharmaceutical in radioimaging and/or radioimmunotherapy of prostatic cancer. Two different principles were used to conjugate diethylene triaminepentaacetic acid (DTPA) to a monoclonal antibody (Mab, subclass IgG1) raised against human prostatic acid phosphatase (PAP). In addition, the F(ab′)2 fragments of this Mab were also derivatized. We used the cyclic anhydride of DTPA (CA-DTPA) as a chelating agent for these two protein moieties. Furthermore, the Mab and the F(ab′)2 fragments were modified site-specifically by attaching linkers,N-(p-aminobenzyl)diethylenetriaminetetraacetic acid (p-NH2-Bz-DTTA) and 1(p-aminobenzyl)diethylenetriaminepentaacetic acid (p-NH2-Bz-DTPA), to the carbohydrate components of the parent molecules. In this study, biodistribution of the111In-labelled derivatives was investigated in normal mice. All the derivatives of IgG1 demonstrated a slower blood clearance than the corresponding derivatives of the F(ab′)2 fragments. This property was particularly pronounced in the site-specifically conjugated derivatives of IgG1. All the derivatives studied accumulated in the liver, kidney, and spleen. The CA-DTPA derivatives of F(ab′)2 fragments showed the highest kidney-to-blood ratios of radioactivity compared with the other compounds studied. The derivatives of IgG1 showed a higher percentage of the injected dose in liver and spleen tissues than the derivatives of the F(ab′)2 fragments. The F(ab′)2 fragments studied also gave rise to site-specific derivatives, which demonstrated that carbohydrates were also present in this part of the molecule. They behaved similarly to the CA-DTPA F(ab′)2 derivative in other respects, but the kidney accumulation was lower at 72 and 120 h. The F(ab′)2 fragments studied would be better suited for radioimaging than the derivatives of the IgG1 studied due to the rapid blood clearance of the F(ab′)2 derivatives. In contrast, the derivatives of IgG1, especially thep-NH2-Bz-DTPA conjugate, which showed the lowest kidney uptake, might be more suitable candidates for the development of therapeutic agents.