SUMMARY In order to investigate the possibility of regional variation of ventricular structure, 25 normal postmortem human hearts were studied by inspection of cavity shape and subepicardial fibre orientation, by dissection, and by the histology of sections in two orthogonal planes. Ventricular architecture was complex. Inlet and outlet long axes were separated by 30 degrees in the left ventricle. In the right the corresponding figure was 90 degrees. The thickest part of the left ventricular wall was at the base. At the apex there was potential endo-and epicardial continuity. Left ventricular cavity shape departed significantly from any simple geometric figure, there being, consistently, regions of both positive and negativecurvature on the diaphragmatic aspect. The presence of trabeculae caused considerable variation in wall thickness. Striking variation was found in the arrangement of subepicardial muscle fibres. Most pronounced was the contrast between the longitudinal arrangement of fibres observed on the oblique margin and the circumferential arrangement of those on the acute. On the diaphragmatic surface of the left ventricle, fibres near the crux and apex ran circumferentially while those between ran obliquely; those on the diaphragmatic surface of the right ventricle also ran circumferentially. Deeper in the myocardium the arrangement was simpler. In the mid-wall of the left ventricle fibres were circumferential, best developed towards the base and in the upper part of the septum. Near the apex of the left ventricle and in the mid-wall of the right ventricle such fibres were sparse. The subendocardial region consisted of longitudinally directed fibres forming the trabeculae and papillary muscles, while fibres deep to and between the trabculae coursed more obliquely. These findings were confirmed by histology. Models based on uniform myocardial fibre structure cannot explain wall movement in normal subjects, and are likely to have significant limitations if used to investigate left ventricular function in disease.Although there is a wealth of anatomical work devoted to the study of fibre orientation in the human heart, this topic has received little detailed attention over the past 20 years, apart from the studies of Streeter' and Torrent-Guasp.2 This is surprising since much attention has been focused on measurements of cavity volume, pressure, and their derivatives with time, with calculation of systolic and diastolic wall stress. Though such studies imply anatomical knowledge, little recourse has been made to actual morphology, but instead geometrical assumptions have been made concerning left ventricular architecture. With the development of improved methods of investigating the left ventricle, the need for precise anatomical information has become pressing. In this paper therefore a de-
Aims To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril.
Methods Patients with congestive heart failure (CHF, NYHA Class II–IV) and chronic renal insufficiency (creatinine clearance ≤30 ml min−1 ) were randomized to receive fosinopril, enalapril or lisinopril in two parallel‐group studies. In the first study 24 patients were treated with 10 mg fosinopril (n=12 patients) or 2.5 mg enalapril (n=12) every morning for 10 consecutive days. In the second study 31 patients were treated with 10 mg fosinopril (n=16 patients) or 5 mg lisinopril (n=15) every morning for 10 consecutive days. Samples of blood were collected for determination of pharmacokinetic parameters. The area under the curve (AUC) between the first and last days of treatment and the accumulation index (AI) were the primary outcome measures.
Results All three angiotensin converting enzyme (ACE) inhibitors exhibited a significant increase in AUC between the first and last days of treatment in both studies. The difference between the AI for fosinoprilat (1.41) and enalaprilat (1.96) was statistically significant (95% CI: 1.05, 1.84). Similarly, the difference between the AI for fosinoprilat (1.21) and lisinopril (2.76) was statistically significant (95% CI: 1.85, 2.69). All three ACE inhibitors completely inhibited serum ACE for 24 h. All treatments were well tolerated.
Conclusions Fosinoprilat exhibits significantly less accumulation than enalaprilat or lisinopril in patients with CHF and renal insufficiency, most probably because fosinoprilat is eliminated by both the kidney and liver, and increased hepatic elimination can compensate for reduced renal clearance in patients with kidney dysfunction.
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