Plasma vasoactive peptides after acute myocardial infarction in relation to left ventricular dysfunction.

We measured plasma concentrations of vasoactive peptides in 32 patients with acute myocardial infarction and evaluated their value as markers of left ventricular dysfunction. Plasma levels of atrial natriuretic peptide (ANP), the N-terminal fragment of proANP (NT-proANP), B-type natriuretic peptide (BNP) and endothelin-1 were measured serially by radioimmunoassays. The infarct size was estimated from the creatine kinase MB release curve. Coronary angiography and left ventricular cineangiography were performed in all patients during hospitalization and 6 months later in 15 patients. Myocardial infarction caused an increase in vasoactive peptides, the highest values for ANP (36.5+/-6.79 pmol/l), NT-proANP (1130+/-170 pmol/l) and endothelin-1 (9.72+/-0.68 pmol/l) being found on admission and those for BNP (56.0+/-7.13 pmol/l) on Day 2. Plasma levels of natriuretic peptides were dependent on infarct size, its location and degree of myocardial dysfunction and that of BNP also on infarct artery patency. Plasma endothelin-1 level was higher in patients with TIMI 3 than TIMI 0-2 flow. Plasma vasoactive peptides remained elevated during the 6-month follow-up period and they were dependent on the degree of myocardial dysfunction. BNP measured on any day of hospitalization showed the best correlation with ejection fraction measured during the acute phase of infarction or at 6 months. The results show that BNP is the best indicator of left ventricular dysfunction after myocardial infarction and its reliability is not dependent on the time point of measurement.

Collagen scar formation after acute myocardial infarction: relationships to infarct size, left ventricular function, and coronary artery patency.

BACKGROUND: Left ventricular function after acute myocardial infarction (AMI) is determined by the expansion of the infarct zone and remodeling of the noninfarcted myocardium. An occluded infarct-related artery (IRA) is an independent risk factor for remodeling. METHODS AND RESULTS: Changes in myocardial collagen metabolism were evaluated in 36 patients with suspected AMI. The plasma creatine kinase MB fraction and myoglobin release curves were analyzed for assessment of early reperfusion and infarct size. Collagen scar formation was evaluated by measurement of serum concentrations of the aminoterminal propeptide of type III procollagen (PIIINP), the aminoterminal propeptide of type I procollagen (intact PINP), and the carboxyterminal propeptide of type I procollagen (PICP). Plasma renin activity and urine excretion of cortisol and aldosterone were also measured. Coronary angiography and left ventricular cineangiography were performed during early hospitalization. The serum concentration of PIIINP increased from 3.50+/-0.20 to a maximum of 5.08+/-0.36 microg/L (n=32) in the patients with AMI, whereas the concentrations of intact PINP and PICP tended to decrease. The area under the curve (AUC) of PIIINP during the first 10 postinfarction days was larger in patients with severe heart failure or ejection fractions < or = 40% than in those with no heart failure or with an ejection fraction > 40% (P<.05 and P<.01, respectively), and it was also larger in the patients with TIMI grade 0 to 2 flows than in those with TIMI 3 flows (P<.05), despite similar enzymatically determined infarct sizes. No significant correlations between PIIINP and neurohumoral parameters were observed. The AUC of PIIINP and the change in PIIINP during the first 4 days were significantly correlated with indices of cardiac function. CONCLUSIONS: Collagen scar formation after AMI can be quantified by measurement of serum PIIINP concentrations. Scar formation is more prominent in large infarctions causing left ventricular dysfunction and in patients with occluded IRAs.

Changes in interstitial collagen metabolism during acute myocardial infarction treated with streptokinase or tissue plasminogen activator.

Collagen plays a specific role in the maintenance of vascular integrity and in the thrombosis and scar formation processes. Therefore we found it interesting to study the changes in interstitial collagen metabolism during acute myocardial infarction treated with thrombolytic agents. Changes in collagen synthesis were evaluated by obtaining assays of the serum concentrations of the carboxyterminal propeptide of type I procollagen. Except fibrin plasmin is capable of degrading extracellular matrix components including collagen, and this capability was evaluated by monitoring the serum concentrations of the aminoterminal propeptide of type III procollagen. Twenty-four patients with suspected acute myocardial infarction and indications for thrombolytic therapy were randomized to receive either streptokinase (n = 11) or tissue plasminogen activator (n = 13). The patient groups were identical in their clinical characteristics. Serum levels of the aminoterminal propeptide of type III collagen increased rapidly on infusion of the thrombolytic agents, with the maximal mean increases of 44% and 16% in the streptokinase and TPA-treated groups, respectively. Levels of the carboxyterminal propeptide of type I collagen did not change during the thrombolytic therapy. A transient decrease occurred in the type I propeptide concentration at postinfarction day 2, and this decrease was followed by a secondary increase at days 4 to 6 in both patient groups studied. We conclude that thrombolytic agents stimulate the breakdown of interstitial collagen and that the collagen-degrading activity of TPA is lower than that of streptokinase. This factor may contribute to the relatively higher rethrombosis rate seen after TPA, because exposed collagen in the affected vascular wall stimulates thrombosis formation. On the other hand, increased collagen degradation followed by inhibition of collagen synthesis in the infarcted myocardium might increase the risk for cardiac rupture, especially after streptokinase treatment.

The efficacy and tolerability of enalapril in a formulation with a very low dose of hydrochlorothiazide in hypertensive patients resistent to enalapril monotherapy.

The antihypertensive efficacy and tolerability of formulations of enalapril and low (12.5 mg) and very low (6 mg) doses of hydrochlorothiazide (HCTZ) were compared with enalapril and placebo. Four hundred and two patients with mild to moderate essential hypertension were treated with 20 mg enalapril for 8 weeks. Patients (n = 296) with persistent supine diastolic blood pressure > 95 mm Hg after enalapril monotherapy were randomized to receive enalapril/placebo (group I), 6 mg enalapril/HCTZ (group II), or 12.5 mg enalapril/HCTZ (group III) for another 8 weeks in a double-blind design. The mean reductions in blood pressure were significantly larger in groups II and III compared to group I, 7.3 (95% CI, -9.0; -6.2), 7.7 (-9.2;-6.3), and 4.1 (-5.9;-2.9) mm Hg, respectively P < .01 for groups II and III compared to group I). No difference in side effects was observed between the three groups. A very low dose of 6 mg HCTZ acts synergistically when given together with enalapril, but is devoid of adverse metabolic effects.

Relation between low dose of hydrochlorothiazide, antihypertensive effect and adverse effects.

Thiazide diuretics are widely used in the drug treatment of hypertension but their dose-response curves for the antihypertensive and adverse metabolic effects differ. To characterize the lower end of the dose-response curve a double-blind, parallel group trial was performed as multicentre study in Scandinavia. One hundred and eleven patients with newly diagnosed or previously treated mild to moderate hypertension (untreated diastolic blood pressure of 95-115 mmHg after 4 weeks placebo) were randomly allocated to various doses of hydrochlorothiazide (3, 6, 12.5 or 25 mg) or placebo for 6 weeks. Blood pressure and biochemical variables (plasma renin activity, serum potassium, magnesium, urate, fasting glucose, total cholesterol, HDL-cholesterol, triglycerides and apolipoproteins A1 and B were measured. 12.5 mg hydrochlorothiazide had a borderline effect on blood pressure whilst 25 mg had a definite antihypertensive effect. Biochemical changes were seen in plasma renin activity, serum potassium and urate after the 12.5 and 25 mg dose. Three and 6 mg had no effect on blood pressure or metabolic parameters.

Plasma N-terminal atrial natriuretic peptide in acute myocardial infarction.

Plasma atrial natriuretic peptide (ANP) and the N-terminal (NT) fragment of the 126-amino acid prohormone of ANP (proANP; NT-proANP) were correlated with clinical findings in 41 patients with acute myocardial infarction and in 19 patients with angina pectoris. On admission to the hospital, the 39 patients with nonfatal infarction who subsequently had overt heart failure (n = 8) had plasma NT-proANP (2374 +/- 1038 pmol/L) and ANP (54 +/- 43 pmol/L) concentrations that were higher (p < 0.01) than those in the patients who remained without or who presented with minor signs of failure. In contrast to the relatively stable NT-proANP levels, ANP decreased markedly during the first 24 hours in the patients who had any signs of failure. Hence the plasma levels of NT-proANP and ANP did not go hand in hand in acute myocardial infarction, and NT-proANP appeared to be a better marker of cardiac dysfunction than ANP.

Effects of early administration of enalapril on radionuclide left ventricular ejection fraction and plasma N-terminal atrial natriuretic peptide after acute myocardial infarction.

The effects of enalapril therapy on radionuclide ejection fraction and plasma N-terminal atrial natriuretic peptide were investigated in a randomized, double-blind, placebo-controlled study of 52 patients with acute myocardial infarction. The medication was begun intravenously within 24 hours of the onset of symptoms. At discharge and the end point of 6 months, the radiographic size of the heart was significantly smaller in patients receiving (n = 28) than in those not receiving (n = 24) enalapril therapy (p < 0.03 vs < 0.01). However, left ventricular ejection fraction decreased simultaneously from 50 +/- 10% to 47 +/- 11% in patients treated with enalapril, whereas it increased from 48 +/- 13% to 50 +/- 14% in control patients (p < 0.05 for the difference of the changes). The decrease in ejection fraction was most marked in the infarct-related region of the left ventricle (p < 0.01). During the in-hospital period, plasma N-terminal atrial natriuretic peptide was decreased in patients treated with enalapril, whereas it was increased in those treated with placebo with complicated acute myocardial infarction (p < 0.05). During the following 6 months, the differences remained insignificant. Early administration of enalapril significantly attenuated heart enlargement after myocardial infarction and probably improved hemodynamics during the acute phase of complicated infarction. The decrease in ejection fraction during recovery indicates an impairment of systolic function. The decrease in infarct-related regional ejection fraction suggests that the impairment may be due to poor healing of the infarction scar.

Left ventricular mass, serum electrolyte levels and cardiac arrhythmias in patients with mild hypertension treated with cilazapril or hydrochlorothiazide.

Thirty-five patients with mild hypertension (WHO Class I) participated in a double-blind cross-over study involving two 8-week periods of treatment with cilazapril 2.5-5 mg once daily or hydrochlorothiazide 25-50 mg once daily, in each case preceded by a 4-week placebo period. Thirty-two patients completed the study, the aim of which was to compare the effects of the drugs on serum electrolyte levels, left ventricular mass and cardiac arrhythmias, as assessed by echocardiography and 48-h Holter monitoring. Both drugs significantly reduced systolic (P < 0.01) and diastolic (P < 0.001) blood pressures (comparisons with placebo periods). Cilazapril and hydrochlorothiazide had opposite effects on ventricular ectopic activity. The beneficial effect of cilazapril on ventricular extrasystole counts correlated significantly (P < 0.001) with the reduction of left ventricular mass index. Hydrochlorothiazide had no effects on left ventricular mass or diastolic function. Serum potassium values were significantly (P < 0.001) reduced by hydrochlorothiazide but there was no correlation between changes in potassium levels and changes in ventricular ectopic activity. The results of the study suggest that hydrochlorothiazide and cilazapril were equally effective in reducing blood pressure, but only cilazapril reduced left ventricular hypertrophy and suppressed ventricular ectopic activity.

A comparative study of nicardipine and pindolol as second-line treatments in essential hypertension.

A controlled, randomized, single-blind, parallel-group study compared the effects of nicardipine hydrochloride/hydrochlorothiazide (HCTZ) with those of pindolol/HCTZ in treatment of essential hypertension. The study included 43 patients aged 30-64 years with supine diastolic blood pressures between 95 and 125 mmHg at baseline. Patients initially received 50 mg/day HCTZ for 6 weeks and those patients whose diastolic blood pressure remained at or above 90 mmHg at week 6 (n = 29) completed a 6-week comparative phase in which they were given, in addition, either 30 mg nicardipine hydrochloride or 5 mg pindolol three times daily. Nicardipine was more effective than pindolol as a second-line treatment in controlling blood pressure but, because patients who were treated with nicardipine/HCTZ had higher baseline blood pressures, significance was lost when results were adjusted for the baseline blood pressure values. Treatment was described as 'very good' by 71.4% of patients in the nicardipine/HCTZ group and by 53.9% of those in the pindolol/HCTZ group; thus, both second-line antihypertensives were well accepted. Although 45% of patients in of each treatment group reported treatment-related adverse events, none experienced postural hypotension and no adverse event was unexpected.

Transdermal and oral clonidine.

The antihypertensive efficacy and side effects of transdermal clonidine (Catapres-TTS) and oral clonidine in equivalent doses on a weight basis were compared under double blind (double dummy) and cross over conditions in 16 outpatients with mild to moderate hypertension. After four weeks of placebo TTS and placebo tablet treatment, the patients were randomly placed into groups for six weeks of active treatment and, after an intervening week of placebo treatment, a second six week treatment period. Transdermal clonidine reduced supine and standing blood pressures (P less than 0.01) and heart rates (P less than 0.05) compared with the values at the end of the placebo periods, while oral clonidine did so to the extent of supine systolic blood pressure (P less than 0.01) and standing heart rate (P less than 0.05), respectively. There were, however, no differences in the values between transdermal and oral clonidine at the end of these six week periods. The plasma clonidine concentration was lower 12 hours after a dose of oral clonidine than after transdermal clonidine (P less than 0.05). The side effects did not differ. Seven patients said afterwards that they preferred the transdermal treatment, two preferred the oral treatment and four could not state any preference. It is concluded that transdermal clonidine is similar in its effect to oral clonidine in mild to moderate hypertension. Transdermal clonidine once a week may increase patients' compliance with antihypertensive treatment.

Thrombolytic therapy with streptokinase stimulates collagen breakdown.

BACKGROUND: Plasmin is capable of degrading extracellular matrix components such as collagen in vitro. To evaluate the significance of this for in vivo conditions, we set out to study the effect of streptokinase, which acts by converting plasminogen to plasmin, on the serum concentrations of the amino-terminal propeptide of type III procollagen (PIIINP) and the carboxy-terminal propeptide of type I procollagen (PICP). METHODS AND RESULTS: Twenty-three patients with suspected acute myocardial infarction were included in the study; 17 of them received thrombolytic therapy, and six were treated conservatively. PIIINP and PICP were assayed with radioimmunoassays. Kinetics of creatine kinase-MB release were determined to differentiate reperfusers from nonreperfusers. Composite curves of creatine kinase-MB release were constructed for different patient subgroups. During streptokinase infusion the serum concentrations of PIIINP increased rapidly, with a maximum mean increase of 50% (from 2.2 +/- 0.2 to 3.3 +/- 0.3 micrograms/l) in 45 minutes. A similar increase was also observed in two patients who received thrombolytic therapy but did not subsequently develop any myocardial infarction determined on the basis of enzyme release. The relative increase in PIIINP during streptokinase treatment was higher in those acute myocardial infarction patients with probable reperfusion than those with nonprobable reperfusion. Corresponding changes in PIIINP were not seen in the control group. Two days later there was a second increase in serum PIIINP for both patient groups. This change coincided with a similar increase in PICP. CONCLUSIONS: We conclude that streptokinase, probably by activation of plasminogen to plasmin, stimulates the breakdown of type III collagen during thrombolytic therapy. This phenomenon may decrease the risk of rethrombosis of the affected artery if the exposed collagen is responsible for thrombosis formation, but it could also be involved in the development of hemorrhagic complications during thrombolytic therapy. The second increase in PIIINP levels probably indicates type III collagen synthesis of the infarcted area. This investigation represents a pilot study, and more studies on the effects of various thrombolytic agents on interstitial collagen metabolism are obviously needed.

Nicardipine in combination with other antihypertensive drugs: calcium antagonist and prazosin have no additive antihypertensive effect?

The combined antihypertensive effects of a new 4-dihydropyridine derivate calcium antagonist, nicardipine, and propranolol, atenolol, labetalol, clonidine, prazosin or captopril were studied in 14 hypertensive outpatients. Nicardipine in combination with atenolol or clonidine most effectively lowered blood pressure. Prazosin combined with nicardipine had no additive antihypertensive effect at the doses used. Clonidine and prazosin in combination with nicardipine were not well tolerated. The antihypertensive effect of the drug combinations seemed to be related to their bradycardic effect.

The effect of potassium and potassium plus magnesium supplementation on ventricular extrasystoles in mild hypertensives treated with hydrochlorothiazide.

Eleven mild hypertensives with base-line ventricular extrasystoles underwent a 24-week period of treatment with hydrochlorothiazide 50 mg daily. After 8 weeks of treatment either potassium as hydrochloride 1 g twice daily, or a combination of potassium hydrochloride 1 g and magnesium hydroxide 500 mg twice daily was added to the diuretic therapy in a randomised, double-blind, cross-over design. Each treatment period lasted 8 weeks. Supplementation with potassium or potassium plus magnesium resulted in a clear trend for suppression of ventricular ectopic activity. There was no difference in ventricular extrasystoles between the two supplementation groups. Supplementation with potassium plus magnesium but not with potassium only, resulted in a significant rise in serum potassium values (P less than 0.01). Our study suggests that potassium should be supplemented in thiazide-treated hypertensives who are prone to develop ventricular extrasystoles. Addition of magnesium to potassium supplementation does not result in further improvement in ventricular ectopic suppression.

Abrupt change from a beta-adrenoceptor blocking drug to enalapril in hypertension.

The haemodynamic and hormonal effects of an elective change of antihypertensive therapy from a beta-adrenoceptor blocking drug to a converting enzyme inhibitor, enalapril, were monitored in 12 hypertensive in-patients (WHO I). Blood pressure and heart rate were determined every 2-4 h using an automatic sphygmomanometer during an abrupt cessation of the previous beta-adrenoceptor blocking drug and commencement of treatment with enalapril 20 mg o.d. 12 h later. Mean blood pressure values at rest and during the hand grip test were lower when on enalapril, but heart rate was significantly higher, and three patients suffered from palpitations during the change. The change resulted in an improvement in cardiac function both at rest and during isometric work, as shown by echocardiography. A rapid decrease in plasma angiotensin converting enzyme (ACE) activity and an increase in renin activity were also seen after the change, while plasma levels of atrial natriuretic peptide (ANP) decreased towards normal values. The results suggest that an abrupt change from a chronic beta-adrenoceptor blocking drug to enalapril is safe, feasible and is likely to produce favourable haemodynamic and hormonal effects in hypertensive patients.

Comparisons of verapamil administration twice and three times daily in hypertension.

The antihypertensive effect of verapamil administered either two or three times daily was compared in a double blind, cross over study in 15 patients with mild to moderate essential hypertension. During the dose titration period with t.i.d. administration, normotension was obtained with daily doses of 240 mg in 7 patients, 360 mg in 7 patients and with 480 mg in one patient. Systolic and diastolic blood pressures (BP) in the supine (13/14 mmHg) and standing (14/14 mmHg) positions were significantly (p less than 0.001) reduced during the dose titration period. There was no statistically significant difference in the BP values between the twice and three times a day regimens. Five to 7-fold individual variations in the serum verapamil concentrations between individuals were observed. No significant correlations were found between serum drug concentrations and the change in mean arterial BP. There was no significant difference in the incidence of side effects between the two treatment regimens. Our results suggest that verapamil administered twice daily is effective in mild to moderate hypertension.

5- and 10-year mortality in a rural middle-aged population at Haapavesi, Northern Finland, with special reference to ischaemic heart disease.

As a part of a larger prospective population study of ischaemic heart disease (IHD) the causes of 5- and 10-year mortality were analysed in 1554 rural inhabitants aged 40 to 59 years (90.0% of the population of this age group) in Northern Finland. The total mortality in 5 years was 2.3% among women and 6.3% among men. The respective 10-year mortality figures were 6.2% and 13.4%. The proportion of IHD as a cause of these deaths among women was 35% and 34% in 5 and 10 years, respectively; among men 46% and 46% of the deaths were due to IHD in 5 and 10 years, respectively. Among women the proportion of strokes was 22% and 19% in 5 and 10 years, respectively; the other causes of death among women amounted to 43% and 47% in 5 and 10 years, respectively. Among men, strokes resulted in the death of 14% and 7% in 5 and 10 years, respectively, the other causes of death amounted to 40% and 47% in 5 and 10 years, respectively. The incidence of IHD as a cause of death among women was higher than previously reported.

Combined action of enalapril or timolol with hydrochlorothiazide plus amiloride in hypertension.

59 mild to moderate hypertensives were treated for four weeks with 50 mg hydrochlorothiazide plus 5 mg of amiloride, then concomitantly with these diuretics with either enalapril (10-20 mg) or timolol (10-20 mg) in two parallel treatment groups for an additional 12 weeks in an open study. Addition of these drugs lowered the blood pressure by 25 +/- 3/16 +/- 2 mm Hg and 15 +/- 3/14 +/- 1 mm Hg, respectively. The difference of the reduction of the systolic blood pressure between enalapril and timolol group at the end of the combined treatment was statistically significant (p less than 0.01). The mean serum potassium was elevated by 0.3 mmol/l after addition of enalapril to the diuretic treatment, but none of the patients developed hyperkalaemia. No adverse effects on other routine laboratory values were observed. Both drug combinations can be considered efficient, well tolerated and safe in the treatment of mild to moderate hypertension.