Tambe and colleagues' initial description of CSFP speculated that the phenomenon was due to an increased microvascular resistance. Structural biopsy studies and functional coronary hemodynamic studies have been under-
Table II Studies of Clinical Ischemic Markers in CSFP.
Exercise stress tests
Cesar (1996) Mangieri et al. (1996) Kurtoglu et al. (2001) Goel et al. (2001) Beltrame et al. (2002) Demirkol et al. (2002)
17 10 25 28 44 60
Myocardial perfusion scintigraphic studies
Ciavolella (1994) 21
Cesar (1996) 17
Beltrame et al. (2002) 39
Demirkol et al. (2002) 60
Fixed or Reversible defect Reversible defect Reversible defect Reversible defect
n a Summary of published findings from standard exercise stress test and myocardial perfusion scintigraphic studies in patients with the CSFP
taken to examine the role of microvascular dysfunction in CSFP.
Mosseri and coworkers performed right ventricular biopsies in six patients with CSFP. In contrast to syndrome X, they demonstrated significant structural microvascular changes including hyperplastic fibromuscular thickening of the small arteries with endothelial cell swelling and degeneration. Whether these small vessel changes were pathogenic in the CSFP or secondary to ventricular hypertrophy was controversial as many patients also had hypertension.
In a follow-up study, Mangieri and others performed left ventricular biopsies in 10 patients with the CSFP, none of whom had concurrent hypertension, diabetes, or myocardial hypertrophy on echocardiography. As in the previous study, the small vessels had markedly thickened walls with lumi-nal narrowing. Hence, independent studies have demonstrated structural microvascular abnormalities that could account for an increased coronary vascular resistance and thus slow distal vessel filling.
Coronary hemodynamic studies have confirmed the presence of an increased coronary vascular resistance in CSFP. In 12 CSFP patients, resting coronary sinus oxygen saturation was measured and found to be abnormally low as compared with controls (23 ± 4% versus 31 ± 4%, respectively; p < 0.001, Figure 2), reflecting an increased resting coronary resistance.
The structural small vessel disease demonstrated in the foregoing biopsy studies could account for the observed increased coronary resistance. However, pharmacological studies would suggest that there is a significant functional component. Mangieri and colleagues demonstrated that acute administration of a small vessel vasodilator (dipyri-damole) alleviated the delayed vessel opacification whereas a large vessel vasodilator (nitrates) had little impact. Kurtoglu and others extended these observations demonstrating resolution of the angiographic phenomenon with 1 month of oral dipyridamole therapy. A significant dynamic component to the increased resistance is also consistent with the clinical presentation of rest pain, since predominantly exertional pain would be anticipated with a fixed increased resistance.
Although evidence for structural and functional components of the increased coronary vascular resistance have been identified, the responsible biological mechanisms are unknown. Endothelin-1 is a potent small vessel vasoconstrictor that also has vascular remodeling properties and therefore is a potential candidate autacoid for this disorder. Consistent with this hypothesis, intracoronary administra-
Figure 2 Resting coronary sinus oxygen saturations in CSFP. Resting coronary sinus oxygen saturations (including mean ± SD) for eight control patients with normal angiography but without CSFP and 12 patients with CSFP. (From Beltrame et al., American Heart Journal, 146, 84-90, with permission.)
tion of endothelin-1 in rabbits and dogs has been shown to mimic CSFP. Likewise, intracoronary neuropeptide Y has been shown to produce CSFP in patients with chest pain and normal angiography, suggesting another potential mechanism. These potential mechanisms are interesting but further studies are required to elucidate the exact mechanisms responsible for CSFP.
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