Previous attempts in animals failed to reproduce the metabolic, pathological, and clinical situations encountered in homocystinuric patients. Minipigs on a
methionine-rich caseinate-based diet, however, have a special long-lasting postprandial plasma accumulation of
methionine, the metabolic precursor of
homocysteine. We hypothesized that these minipigs develop
hyperhomocysteinemia in the long term.
Angiotensin-converting enzyme (ACE) inhibition prevents atherogenic alteration of viscoelastic functions of arterial pulsatility and compliance and reduces fragmentation of vascular elastic laminae in the minipigs. We consequently analyzed the
therapeutic effects of the
captopril-hydrochlorothiazide combination against the typical
hyperhomocysteinemia-induced alterations of vascular elastic features.
METHODS AND RESULTS: Thirty-two Götingen minipigs were randomized as control diet-fed (C),
captopril (25 mg/d)/
hydrochlorothiazide (12.5 mg/d)-treated C (C+Cp), caseinate-based diet-fed (M), and M+Cp minipigs. After 4 months, M and M+Cp animals had
hyperhomocysteinemia (9.64 +/- 4.10 mumol/L, n = 16) compared with C and C+Cp minipigs (5.67 +/- 1.14 mumol/L, n = 16) (P < .05). In the M group, one minipig died from thromboembolic syndrome, and one had
pulmonary infarction. M minipigs presented with systolic-diastolic
hypertension and extended
reactive hyperemia, as well as a mega-artery syndrome in hyperpulsatile arteries due to expanded volumetric compliance, curtailed stiffness, strengthened vascular tension, and prevalence of the viscous wall component. In their arterial tree, hypertrophic endothelial cells covered a thickened subendothelial space. Major elastic lamina dislocations were observed, as well as
hypertrophy and reorientation of smooth muscle cells, resulting in the settlement of spreading pathways for medial cells between muscular laminae. In C+Cp and M+Cp animals, serum and lung ACE activity were inhibited by 74% and 40%, respectively. Although the treatment with
captopril-hydrochlorothiazide did not modify the
hyperhomocysteinemia per se, the
therapeutic effects of the
drug combination are made evident by the absence of death and ischemic diseases in the M+Cp group. Specifically, the
drug combination prevented diastolic
hypertension and improved aortic blood flow by normalizing peripheral resistances, abolished the vascular hyperpulsatile characters, and restrained the fragmentation and the splitting of elastic fibers in capacitance arteries. In contrast, the drugs slightly prevented systolic and mean
hypertension. In addition, the aortic stiffness and stress response remained altered and vascular smooth muscle cell
hypertrophy was still observed in the M+Cp group.
CONCLUSIONS: