Acute hemodynamic effects and preload-dependent cardiovascular profile of the partial phosphodiesterase inhibitor nanterinone in patients with mild to moderate heart failure.

Nanterinone (UK-61,260) is a novel positive inotropic and balanced-type vasodilating drug, only partially based on phosphodiesterase III inhibition. Preliminary data from controlled studies suggest satisfactory long-term efficacy and safety. As its acute hemodynamic effects in humans are unknown, an oral dose of 2 mg nanterinone was studied in 14 patients with heart failure (NYHA class II-III) on chronic diuretic and angiotensin-converting enzyme (ACE) inhibitor treatment. Before the study, patients were on a 2 g salt-balanced diet, and they received their last medication 16 hours before each study day. Hemodynamic measurements were carried out before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours after administration of the study drug. All patients received placebo and nanterinone on 2 consecutive days. Following nanterinone, systemic vascular resistance decreased immediately from 1699 +/- 82 (mean +/- SEM) at baseline to 1368 +/- 80 at 1 hour. Changes persisted for 12 hours. Concomitantly, there was an immediate and significant fall in pulmonary wedge pressure to 38% of baseline at 1.5 hours, together with a 20% reduction in pulmonary artery pressure. Heart rate remained unchanged and arterial pressures showed only a short, significant decrease. Cardiac index rose significantly from 2.28 +/- 0.15 at baseline to a highest value of 2.65 +/- 0.14 1/min/m2 at 1 hour. Changes persisted for 3 hours. Placebo had no effect on these variables. As, in view of its potential venodilating properties, hemodynamic improvement by nanterinone may depend on pre-existing left ventricular filling pressure, patients were subsequently grouped according to baseline pulmonary wedge pressure of > 12 mmHg (H-PCWP) and < or = 12 mmHg (L-PCWP). Cardiac index improved by 26% in H-PCWP and by 17% in L-PCWP (NS). In contrast, PCWP fell more markedly in H-PWCP than in L-PCWP (40% and 23%, respectively, p < 0.05). Thus, oral nanterinone results in a significant acute hemodynamic improvement and is well tolerated. Although changes in left ventricular filling pressure are more pronounced in patients with elevated pre-existing PCWP, cardiac pump function improves equally in patients with normal or low left ventricular filling pressure at baseline.

The development of protocols to cover clinical care in cardiology.

PROCAS (PRofiles Of CAre System) is one of the AIM projects whose objectives are to improve the quality and efficiency of medical treatment. These will be realised in establishing a methodology for defining and developing what are termed "Profiles of Care". These are sets of options for clinicians which are meant to create acceptable ways of managing patients with similar conditions and which represent good clinical practice. Moreover, a prototype system will be realised by the application of informatics and telematics, to enhance the provision of efficient and effective care in both hospitals and outpatient departments. Because of the retrospective nature of the ICD-9-CM system for the classification of cardiological patients, a draft for a Prospective Patient Data Model, which involves the assessment of somatic, psychosocial, environmental and demographic axes, is being presented. This multi-axial evaluation allows for the generation of the smallest unit of diagnostic-therapeutic procedures, based on the definition of the patient's health problem; that is: the patient-orientated diagnosis or the appropriate indication.

Long-term prognostic importance of a single pulmonary wedge pressure measurement after myocardial infarction: a ten-year follow-up study.

To assess the influence on short- and long-term survival of haemodynamic variables measured after acute myocardial infarction, a 10-year prospective follow-up study was undertaken. A total of 304 patients (259 males, 45 females) discharged from hospital after myocardial infarction and under 66 years of age were studied. Haemodynamic variables measured shortly after admittance included pulmonary wedge pressure, mixed venous oxygen saturation, blood pressure and heart rate. In the analysis, adjustments were made for differences in age, gender, clinical parameters and cardiovascular risk factors. Pulmonary wedge pressure was found to be a strong and independent predictor of both short-term and long-term survival. A gradual increase of the 10-year mortality risk with elevated wedge pressure could be demonstrated (relative risk, 1.09/mmHg; 95% confidence interval, 1.04-1.15). Relative risks of patients in the three highest categories of wedge pressure, 12-15 mmHg, 15-19 mmHg and 19 mmHg and higher, compared with patients in the lowest category, lower than 12 mmHg, were 2.25 (95% CI, 1.11-4.55), 2.43 (95% CI, 1.20-4.92) and 2.57 (95% CI, 1.04-6.37), respectively. The other measured haemodynamic variables were found to be associated with short-term mortality only. In conclusion, haemodynamic measurements after myocardial infarction are of prognostic importance after discharge. A single measurement of an elevated wedge pressure in particular unfavourably influenced both short-term and long-term survival.

Acute hemodynamic and neurohumoral profile of dilevalol in hypertensive patients with ischemic heart disease.

Acute systemic and, possibly, coronary vasoconstriction may limit the usefulness of i.v. beta-blockade for the management of hypertension in ischemic patients. The acute hemodynamic and neurohumoral profile of i.v. dilevalol (50 mg/5 min), a nonselective beta-antagonist and selective partial beta 2-agonist, was evaluated for 1 h in nine patients with stable angina, significant (> 50%) coronary artery disease, and mild hypertension. Immediately after administration, arterial pressures fell significantly by 13% and remained lowered for the entire study period. Concomitantly, heart rate slowed from 76 +/- 2 (mean +/- SEM; control) to 67 +/- 2 beats/min (60 min postadministration, p < 0.05), and cardiac index and stroke work decreased significantly by 15 and 21%, respectively. Isovolumetric contractility indices (measured at fixed heart rates) fell progressively by 9-12%, whereas relaxation (Tau1 and Tau2) slowed by 10% (all p < 0.05 vs. control). Consequently, left ventricular end-diastolic and right atrial pressures increased significantly from 17 +/- 3 and 9 +/- 1.2 mm Hg at baseline to 21 +/- 2.5 and 12 +/- 2.1 mm Hg, respectively. Dilevalol did not affect systemic or coronary resistance. However, coronary flow decreased by 24% (p < 0.05 vs. control), accompanied by significant reductions in myocardial oxygen demand and consumption of 23 and 14%, respectively. Levels of circulating norepinephrine and dopamine increased by 35 and 71%, whereas those of renin and angiotensin II decreased by 26 and 33%, respectively (all p < 0.05 vs. control). Adverse side effects did not occur. None of the patients became ischemic. Thus, at the dose level used, dilevalol has predominant beta-blocking effects.(ABSTRACT TRUNCATED AT 250 WORDS)

[Long-term prognosis following a myocardial infarct: clinically prognostic variables and cardiovascular risk factors]. / De lange-termijnprognose na een hartinfarct: klinische voorspellende variabelen en cardiovasculaire risicofactoren.

The long-term prognosis after myocardial infarction; clinical predictive variables and cardiovascular risk factors. In predicting long-term survival of 304 consecutive patients discharged after myocardial infarction between 1978 and 1981, and under 65 years of age, the significance of both hospital data and cardiovascular risk factors was examined. After discharge from hospital, the ten-year all-cause total mortality was 35.5%. Sudden death accounted for 42% of the recorded causes of death. The patients were not yet treated with thrombolysis at that time. After multivariate analysis, age, previous myocardial infarction, abnormal chest X-ray (increased cardiothoracic ratio or pulmonary congestion) and an increased cholesterol level were found to be independent and significant predictors of the ten-year mortality. Hypertension and gender were not associated with mortality. Patients with a previous myocardial infarction had, after adjustment for differences in age and other variables, a relative risk of dying within ten years of 1.70 (95% confidence interval 1.05-2.75) compared with those with a first infarction. A gradual increase of the ten-year mortality with elevated serum cholesterol level could be demonstrated (relative risk 1.14 per mmol/l, 95% CI 1.01-1.28). In conclusion, several routinely obtained parameters after myocardial infarction were related to subsequent long-term survival. Of the prognostic factors that may lead to useful therapeutic intervention after myocardial infarction, hypercholesterolaemia was most clearly associated with a reduced survival in the present study.

Acute improvement of cardiac function with intravenous L-propionylcarnitine in humans.

As the myocardial carnitine content, a key control factor in myocardial oxidative metabolism and energy transfer, is reduced in heart failure, administration of L-propionylcarnitine (LPC), a potent analogue of L-carnitine, potentially may improve cardiac function, possibly through a positive inotropic effect. As its hemodynamic profile is unknown in humans, 32 fasting normotensive patients with coronary artery disease received either 15 mg/kg of LPC (n = 16) or vehicle (mannitol/acetate, n = 16) infused over 5 min. Hemodynamic, radionuclide [peak ejection and filling rates (PER and PFR, respectively)], and metabolic variables (myocardial O2, lactate, and carnitine uptake) were studied at baseline and 1, 3, 5, 10, 15, and 45 min postdrug. The baseline ejection fraction was depressed in LPC patients (40 +/- 3% vs. 48 +/- 4% in the vehicle group, p less than 0.05) as a result of a significant high incidence of previous infarctions. Immediately following LPC, the cardiac total carnitine uptake changed from 102 +/- 181 to 5,335 +/- 1,761 mumol/L (p less than 0.05). In both groups, left ventricular systolic and end-diastolic pressures increased significantly by 5 and 20%, respectively, during the first 5 min. In the vehicle group, contractility decreased by 5%, accompanied by a significant 11% fall in the stroke volume. In contrast, following LPC, isovolumetric contractility indices remained unaltered. Instead, both the PER and PFR improved by 16% at 45 min. Moreover, the cardiac output increased by 8%. LPC did not affect systemic or coronary hemodynamics. Lactate uptake increased by 42%, but myocardial O2 consumption did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Preload-dependent hemodynamic effects of milrinone in moderate heart failure.

Milrinone, a bipyridine derivative with positive inotropic and balanced type vasodilating properties, acutely improves cardiac pump function in patients with severe and moderate to severe heart failure. Whether it has similar effects in patients with mild to moderate heart failure is unknown. A hemodynamic evaluation of oral milrinone in dosage of 2.5, 5 and 10 mg was carried out on 3 consecutive days in 18 patients with NYHA class 2.7 heart failure. Patients continued with diuretics and digitalis, administered 15 h before each hemodynamic study. Peak milrinone plasma levels ranged from 77 to 252 micrograms/ml and were attained at 60-90 min following administration. Concomitantly, milrinone significantly reduced pulmonary wedge and right atrial pressures with 24, 47 and 44, and 25, 42 and 38% with the 2.5-, 5- and 10-mg doses, respectively. Milrinone had no effect on cardiac or stroke indices with either dose. Moreover, systemic vascular resistance only decreased by 12% with the highest dose, together with a 7% fall in mean arterial pressure and a 13% rise in heart rate (all p less than 0.05 vs. baseline). Patients were subsequently grouped depending on baseline pulmonary wedge pressure greater than or equal to 18 mm Hg (Gr I, n = 9) or less than 18 mm Hg (Gr II, n = 9). Changes in pulmonary wedge, pulmonary artery and right atrial pressure were similar in both groups following each dose. In contrast, the effect on cardiac pump function clearly differed in patients with high versus normal baseline wedge pressure. In Gr I, cardiac index increased significantly by 16% (5 and 10 mg). In Gr II, cardiac index decreased with 13% following the 10-mg dose (p less than 0.05 vs. baseline). When maximal individual changes in cardiac index were compared, 10 mg milrinone resulted in an improvement of cardiac index in all patients with baseline wedge pressures greater than 15 mm Hg, but in a decrease in cardiac index in patients with lower wedge pressures. It is concluded that milrinone induces contrasting effects on cardiac pump function in patients with mild to moderate heart failure, which may negatively affect its early and, possibly, also late efficacy in this patient group.

Is the ratio of apo B/apo A-I an early predictor of coronary atherosclerosis?

It is unknown which lipoprotein in childhood is the best predictor of atherosclerosis later on in life. We measured serum triglycerides, total cholesterol, its subfractions (LDL, HDL, HDL2, HDL3) and apoproteins (A-I, A-II, B) in two groups of children. They were offspring of fathers who had severe coronary atherosclerosis or no coronary sclerosis, as determined by coronary angiography. Fasting blood lipids were measured in 49 children of fathers with severe sclerosis, and in 37 children of fathers without sclerosis. Sons of fathers with severe coronary atherosclerosis had higher levels of apo B and of the ratio apo B/apo A-I than sons of fathers free of atherosclerosis. No differences in lipid levels in daughters were observed. These observations suggest that apolipoproteins play a part in early atherogenesis. They further indicate that it may be possible to detect children who have a high probability of developing severe coronary atherosclerosis later in life.