Coronary atherectomy. Clinical, angiographic, and histological findings and observations regarding potential mechanisms.

Between August 5, 1988 and August 1, 1989, we attempted percutaneous directional coronary atherectomy of 76 lesions, including 42 primary lesions and 34 restenosis lesions that developed after one or more prior interventions. The procedure was successful in 67 lesions (88%), with a decrease in diameter stenosis from 80 +/- 11% to 5 +/- 15% after atherectomy (p less than 0.01). One or more complications occurred in six patients (9%), including non-Q wave myocardial infarction (three patients, 4.5%), femoral arterial injury requiring surgical repair (two patients, 3%), and proximal dissection leading to emergency bypass surgery (one patient, 1.5%). Despite these favorable acute results, the 6-month lesion restenosis rate was 30% by life-table analysis. Light microscopy of retrieved tissue revealed atherosclerotic plaque in 94%, media in 67%, and adventitia in 27%. Intimal proliferation was present in 97% of the restenosis lesions but was also evident in 33% of primary lesions. Tissue weight from 27 lesions averaged 18.5 mg (range, 5.8-45.1 mg), which is not adequate to explain the entire angiographic improvement. Thus, part of the improvement in lumen diameter appears to be due to mechanical dilatation rather than to tissue removal alone. Atherectomy can predictably treat selected coronary lesions with overall safety comparable to that of conventional balloon angioplasty, although the procedure as currently performed does not derive all of its benefit from tissue removal and does not appear to prevent restenosis.

Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart failure.

Intracellular Ca2+ release and reuptake are necessary for normal contraction and relaxation of the human heart. Intracellular Ca2+ transients were recorded with aequorin during isometric contraction of myocardium from patients with end-stage heart failure. In contrast to controls, contractions and Ca2+ transients of muscles from failing hearts were markedly prolonged, and the Ca2+ transients exhibited two distinct components. Muscles from the failing hearts showed a diminished capacity to restore a low resting Ca2+ level during diastole. These data obtained in actively contracting human myocardium suggest that intracellular Ca2+ handling is abnormal and might cause both systolic and diastolic dysfunction in heart failure. The inotropic effectiveness of drugs that act to increase intracellular levels of cyclic adenosine monophosphate (AMP), such as beta-adrenergic agonists and phosphodiesterase inhibitors, was markedly reduced in muscles from patients with heart failure. In contrast, the effectiveness of inotropic stimulation with drugs that act by cyclic AMP-independent mechanisms, such as the cardiotonic steroids and DPI 201-106, were preserved. Stimulation of intracellular cyclic AMP production by the adenylate cyclase activator forskolin restored the inotropic response to phosphodiesterase inhibitors. These studies indicate that an abnormality in cyclic AMP production may be a fundamental defect in patients with end-stage heart failure that may markedly diminish the effectiveness of agents that depend on generation of this nucleotide for a positive inotropic effect. Moreover, deficient production of cyclic AMP seems, at least in part, to account for the reversal of the force-frequency relation that characterizes failing myocardium. Of interest, direct measurement of total cellular cyclic AMP content and protein kinase activity did not reveal significant differences between the control and myopathic tissue, suggesting the presence in human ventricular muscle of physiologically distinct compartmentalized pools of cyclic AMP. Finally, changes in the sensitivity of the contractile apparatus to Ca2+ also seem to play an important role in the differential responsiveness to drugs of myopathic versus normal human myocardium.

Activation of tyrosine 3-monooxygenase in pheochromocytoma cells by adenosine.

Adenosine increases the activity of tyrosine 3-monooxygenase in intact pheochromocytoma cells. The effect of adenosine is not dependent upon extracellular Ca2+, and is not accompanied by an increase in catecholamine secretion from the cells. Adenosine deaminase decreases the basal activity of tyrosine 3-monooxygenase, and almost completely abolishes the activation of this enzyme by adenosine. In cells treated with adenosine deaminase, 2-chloroadenosine causes a 2- to 5-fold increase in tyrosine 3-monooxygenase activity. 2-Chloroadenosine produces half-maximal activation at a concentration of 0.1 microM, and maximal activation at 10 microM. Incubation of cells with 2-chloroadenosine produces a stable activation of tyrosine 3-monooxygenase, as measured in vitro. Finally, 3-chloroadenosine increases the content of cAMP in pheochromocytoma cells, and increases the incorporation of 3H into cAMP in cells that have been preincubated with [3H]adenine. This rise in cAMP presumably mediates the activation of tyrosine 3-monooxygenase by 2-chloroadenosine. Adenosine appears to be an endogenous regulator of tyrosine 3-monooxygenase activity in pheochromocytoma cells.