Biomedical subjects
Publications and source records attributed to Arnold M Katz.
Trans fatty acids (TFA) can modify cellular function by interacting with hydrophobic regions of membrane proteins. Because these interactions resemble those of pharmacological agents, it might be appropriate to view TFA as drugs.
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Recent advances in our understanding of the pathophysiology of heart failure have greatly increased the number of potential targets for therapy. The most important of these advances was the recognition that a major goal of therapy should be to modify long-term proliferative responses, as well as to achieve short-term functional improvement. This conclusion emerged from several clinical trials which showed that correction of functional abnormalities in these patients, although often of immediate clinical value, can worsen long-term prognosis. Although vasodilators alleviate the disability that is caused by excessive afterload, most increase long-term mortality: similarly, although inotropic drugs provide immediate relief of symptoms and are useful as temporary support in patients with damaged hearts, most inotropes also shorten long-term survival. Treatment of chronic heart failure should not be targeted simply at the signs and symptoms noted by Withering. Instead, a major goal of therapy should be to slow progression by modifying maladaptive growth responses in the failing heart, which were unknown when Withering discovered that digitalis can alleviate the signs and symptoms of heart failure. New targets for treatment, therefore, include the maladaptive proliferative signaling cascades that cause progressive ventricular dilatation (remodeling) and hastens cardiac cell death. The ability to inhibit maladaptive proliferative signaling in patients with heart failure was greatly enhanced by the rapid pace of discovery in molecular biology. New understanding of the ability of neurohumoral mediators, such as norepinephrine and angiotensin II, to stimulate remodeling, apoptosis, and other deleterious features of the hypertrophic response has opened important areas for research into the causes and therapy of heart failure. Similarly, potential roles for cell adhesion molecules, cytokines, and peptide growth factors in activating maladaptive proliferative responses suggests additional targets for therapy. This and other new information regarding signal transduction pathways, notably the many crossovers between functional and proliferative signaling, provide promising opportunities in this rapidly advancing area of study.
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The hypertrophic response to overload plays an important role in the progressive deterioration of the failing heart--the "Cardiomyopathy of Overload"--and so contributes to the poor prognosis in patients with heart failure. Although increased myocyte size reduces the load on individual sarcomeres, hypertrophy also has maladaptive features. The latter include molecular changes that weaken and impair relaxation in the overloaded heart, and accelerate cardiac myocyte death. Different types of overload lead to concentric and eccentric hypertrophy; as the latter tends to progress ("remodeling"), dilatation is associated with an especially poor prognosis. Concentric hypertrophy is due largely to cardiac myocyte thickening, while eccentric hypertrophy is caused by cell elongation. These differences, along with evidence that concentric hypertrophy is initiated by increased diastolic stretch while eccentric hypertrophy results from increased systolic stress, indicate that these growth responses are mediated by different signal transudation pathways. The beneficial effects of neurohumoral blockers in patients with heart failure are due partly to their ability to inhibit maladaptive features of overload-induced proliferative signaling. The molecular complexity of the hypertrophic response now being uncovered offers opportunities for the development of new therapy to inhibit remodeling and cell death in the failing heart.
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OBJECTIVE: Our purpose was to measure the effect of ventricular pacing in patients with atrial fibrillation (AF) on stroke volume and cardiac output. BACKGROUND: Unceasing variation in cycle length in AF decreases stroke volume and cardiac output. Because ventricular-inhibited pacing after atrioventricular node ablation has been reported to improve left ventricular performance, we tested the hypothesis that overdrive pacing would produce a similar benefit by regularizing cycle length. METHODS AND RESULTS: We studied 18 patients with chronic AF and permanent pacemakers. The aortic time velocity integral (TVI) was measured with continuous-wave Doppler and was used as a surrogate measure of stroke volume (stroke volume = TVI x aortic valve area, and aortic valve area is constant whether in AF or during pacing). For each patient, the linear relation between preceding cycle length and TVI in AF was used to estimate relative stroke volume (TVI compared within each patient) at a preceding cycle length of 666 ms in AF, and a similar comparison between AF and pacing was made at the minimum allowable pacing rate. Relative stroke volume in AF was then compared with relative stroke volume at both the fixed cycle (666 ms) and the minimum allowable rate. During pacing at 666 ms, relative stroke volume increased significantly by 18% (t = 2.8, P =.048), but there was no difference in cardiac output during pacing at the minimum possible rate and the corresponding preceding cycle length in AF. CONCLUSION: Our data suggest that regularization of ventricular rhythm by overdrive pacing in patients with AF only improves stroke volume (and by extension, cardiac output) at pacing rates at the outer limit of and above the normal physiologic range.
Therapy for heart failure has traditionally been directed to such short-term functional abnormalities as low cardiac output, high filling pressures, and fluid retention. More recently, it has become clear that therapy must also inhibit the proliferative responses that contribute to the progressive deterioration of the failing heart. That heart failure is more than a hemodynamic disorder became apparent when clinical trials showed that drugs that improve such functional abnormalities as high venous pressure and low cardiac output failed to improve long-term prognosis. Most vasodilators, in spite of alleviating short-term problems caused by excessive afterload, increase long-term mortality; the notable exceptions are ACE inhibitors, the ability of which to prolong survival and inhibit remodeling can be attributed to inhibition of proliferative signaling. Other clinical trials showed that inotropic drugs, while providing immediate relief of symptoms, generally shorten long-term survival, whereas beta-adrenergic receptor blockers, which inhibit proliferative signaling by norepinephrine, improve prognosis. These findings can be explained by crossovers between functional and proliferative signaling, among the most important of which is the ability of neurohumoral mediators, such as norepinephrine and angiotensin II, to stimulate maladaptive hypertrophy, remodeling, apoptosis and other deleterious proliferative responses in the failing heart. The emerging understanding of the role of cytoskeletal and cell adhesion molecules in activating maladaptive proliferative responses suggests additional targets for therapy, and the rapid pace of discovery in molecular biology promises additional opportunities to inhibit this abnormal signaling, which causes progressive ventricular dilatation (remodeling) and cardiac cell death, now recognized to be major problems in this syndrome.