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J T Flaherty

Publications and source records attributed to J T Flaherty.

At least 37 records · Page 2Linked to original sources
PubMed1989

Nitrate tolerance. A review of the evidence.

Organic nitrates are well established in the treatment of a wide variety of cardiovascular disorders, most notably angina pectoris and congestive heart failure. However, attenuation of, or tolerance to, haemodynamic and anti-ischaemic effects may occur with all long-acting nitrate formulations. In the majority of patients continuous administration of long acting nitrates tends to promote the development of attenuation, while intermittent administration avoids it. Likewise, higher-doses appear to induce attenuation to a greater degree than lower doses. Attenuation of haemodynamic effects and exercise tolerance in heart failure patients, and of clinical end-points in angina patients, appears to be less than attenuation of exercise testing end-points in angina patients. While the use of intermittent therapy avoids the development of attenuation, it may expose the patient to an as yet undefined risk of silent and/or symptomatic anginal episodes occurring during the nitrate-free interval. Likewise, the role of concomitant therapy in avoiding this potential risk remains to be defined. Means of avoiding attenuation may include the coadministration of sulfhydryl donors such as N-acetylcysteine. Alternatively, angiotension-converting enzyme (ACE) inhibitors such as captopril may block renin-angiotensin system-induced reflex sympathetic stimulation. Attenuation may occur to a greater or lesser degree in individual patients. The proportion of attenuators vs non-attenuators remains to be defined, as does a means of identifying such patients prospectively by clinical and/or laboratory parameters. Conflicting results among smaller studies may reflect variable proportions of attenuators vs non-attenuators. However, conflicting results among larger studies may reflect differences in patient selection criteria, such as selecting patients with positive and reproducible stress tests and little in the way of spontaneously occurring angina versus selecting patients with positive but variable stress tests and frequent episodes of spontaneously induced angina. The former group may reflect pure fixed coronary artery disease with little in the way of vasospasm, or change in vasomotor tone, while the latter group may reflect greater variability in vasomotor tone and/or more in the way of plaque instability. The clinical efficacy of long acting nitrates might therefore be expected to be greatest in those patients with larger numbers of spontaneously occurring angina episodes. Recent data suggest that nitrates may have important direct effects on coronary vessels including dilating eccentric coronary stenoses, dilating intercoronary collateral channels and having greater dilating effects on more diseased segments as opposed to less diseased coronary segments.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

In vitro studies of isolated supported human hearts.

We developed methods to revive human hearts, obtained at the time of cardiac transplantation, and study them in the physiology laboratory. The hearts were arrested with cardioplegic solution at the time of explanation and transported to the laboratory at 4 degrees C. The hearts were perfused with a human blood based solution whose flow rate, temperature, and ionic concentration were controlled. Six hearts with various endstage cardiomyopathies were revived in this manner. Once perfusion was started, the hearts maintained a steady contractile state for approximately 30 min during which time data could be collected. Within this time period we could measure end-systolic and end-diastolic pressure-volume relations, the time courses of contraction and relaxation, and the influence of heart rate and premature stimulation on contractile state. The results suggest that evidence of specific cellular abnormalities in human heart disease might be obtained from measurements of global ventricular performance. Furthermore, the type of abnormality identified, namely sarcoplasmic reticulum dysfunction, in several forms of cardiomyopathy was in concordance with results obtained in muscle bath studies of similarly diseased human and animal myocardium.

Cardiomyopathy, Dilated↗
PubMed1988

Reperfusion injury.

Several lines of evidence point to a major role of oxygen free radicals in the pathogenesis of cell death or dysfunction in a variety of disease processes. Recent studies from this as well as other laboratories have demonstrated that oxygen free radicals play a major role in the pathogenesis of post-ischemic reperfusion injury in the heart. We have recently developed methods for direct measurement of radical species and/or specific byproducts of radical injury. Timely administration of oxygen radical scavengers reduced the quantity of free radicals generated following reperfusion and in addition improved recovery of post-ischemic ventricular function and metabolism. In a regionally ischemic model the free radical scavenger recombinant human superoxide dismutase also administered at the time of reflow was shown to limit infarct size. In this article we review the biophysical and molecular mechanisms of oxygen free radical generation that are viewed as contributing to post-ischemic reperfusion injury. We also discuss the mechanisms by which the body defends against free radical attack and the interrelationships of free radical injury to other mechanisms of tissue injury.

Animals↗
PubMed1988

Nifedipine in acute myocardial infarction: an assessment of left ventricular function, infarct size, and infarct expansion. A double blind, randomised, placebo controlled trial.

The influence of nifedipine on left ventricular ejection fraction, infarct size, and infarct expansion was studied in a prospective, double blind, randomised, placebo controlled trial in 132 patients with low risk acute myocardial infarction of less than 12 hours duration, defined by an initial left ventricular ejection fraction greater than 35% and clinical Killip class of less than or equal to II. Sixty four patients were assigned to nifedipine 120 mg/day and 68 to placebo. Treatment was started on average (SEM) 8.0 (0.2) hours after onset of pain and continued for six weeks. Gated blood pool scans, thallium scans, and cross sectional echocardiograms were performed before treatment and at 10 days. There were no significant differences between the two groups in age, sex, cardiac risk factors, or use of other medications. Mean (SEM) global left ventricular ejection fraction was not different before treatment (nifedipine group 53 (2%), placebo group 55 (2%) and did not differ at 10 days (nifedipine group 54 (2%), placebo group 52 (2%). There were also no differences in regional wall motion or regional ejection fractions. Thallium defects quantified by computer analysis were similar in both groups before treatment (nifedipine 7.8 (0.7), placebo 7.9 (0.7)) and at 10 days (nifedipine 5.3 (0.7) placebo 5.3 (0.7)). In the subgroup of patients with transmural infarction who had good quality echocardiograms and serial studies (n = 30), there was no difference in mean (SEM) baseline infarct segment lengths between the two groups (nifedipine 70 (4) mm, placebo 65 (4) mm); however, the nifedipine group demonstrated no significant change in infarct segment length between the initial and 10 day studies ( + 0.6 (3) mm) while there was a significant increase in the infarct segment length in the placebo group (+ 7.8 (4) mm). The infarct segment length increased by >/= 1 cm in seven (47%) placebo patients but in only one (7%) nifedipine patient. The nifedipine group had a significant initial 10% decrease in mean arterial pressure whereas there was no change in the in the placebo group; this blood pressure difference persisted for 10 days. Thus although the early administration of nifedipine has no detectable effect on clinical outcome and infarction size, it may reduce early infarct expansion via an afterload reduction mechanism in patients with transmural infarction. These initial results must be interpreted with caution and need to be confirmed in a larger trial.

Adult↗
PubMed1987

A randomized trial of intravenous tissue plasminogen activator for acute myocardial infarction with subsequent randomization to elective coronary angioplasty.

Patients presenting within four hours of the onset of acute myocardial infarction were randomly assigned to receive 80 to 100 mg of recombinant human-tissue plasminogen activator (t-PA) intravenously over a period of three hours (n = 72) or placebo (n = 66). Administration of the study drug was followed by coronary arteriography, and candidates for percutaneous transluminal coronary angioplasty were randomly assigned either to undergo angioplasty on the third hospital day (n = 42) or not to undergo angioplasty during the 10-day study period (n = 43). The patency rates of the infarct-related arteries were 66 percent in the t-PA group and 24 percent in the placebo group. No fatal or intracerebral hemorrhages occurred, and episodes of bleeding requiring transfusion were observed in 7.6 percent of the placebo group and 9.8 percent of the t-PA group. As compared with the use of placebo, administration of t-PA was associated with a higher mean (+/- SEM) ejection fraction on the 10th hospital day (53.2 +/- 2.0 vs. 46.4 +/- 2.0 percent, P less than 0.02), an improved ejection fraction during the study period (+3.6 +/- 1.3 vs. -4.7 +/- 1.3 percentage points, P less than 0.0001), and a reduction in the prevalence of congestive heart failure from 33 to 14 percent (P less than 0.01). Angioplasty improved the response of the ejection fraction to exercise (+8.1 +/- 1.4 vs. +1.2 +/- 2.2 percentage points, P less than 0.02) and reduced the incidence of postinfarction angina from 19 to 5 percent (P less than 0.05), but did not influence the ejection fraction at rest. These data support an approach to the treatment of acute myocardial infarction that includes early intravenous administration of t-PA and deferred cardiac catheterization and coronary angioplasty.

Angina Pectoris↗
PubMed1987

Role of nitrates in acute myocardial infarction.

Management of patients after myocardial infarction includes several therapeutic options. Lysis of the coronary thrombosis with intravenous or intracoronary administration of streptokinase or intravenous administration of one of the newer, currently experimental agents, such as tissue plasminogen activation or prourokinase, can directly restore oxygen and substrate delivery to potentially salvageable myocardium. Percutaneous transluminal coronary angioplasty can likewise restore vessel patency with potential salvage of ischemic myocardium, if perfused sufficiently early after symptom onset. Another strategy is to administer intravenous thrombolytic therapy and then perform early angioplasty on patients with acute myocardial infarction who reach the hospital within 4 hours of symptom onset. These patients should have intravenous nitroglycerin begun before or simultaneously with beginning thrombolytic therapy. The infusion is titrated to lower systolic arterial pressure by 10% to 15%, and then maintained at a constant rate for up to 48 hours. Patients seen more than 4 hours after symptom onset, with evidence of viable myocardium (e.g., persistent R waves in those electrocardiographic leads demonstrating ST-segment elevation) may also receive intravenous nitroglycerin and thrombolytic or percutaneous transluminal coronary angioplasty therapy. The combined results of the several clinical trials of intravenous nitroglycerin in acute myocardial infarction would support its use in patients seen 4 to 12 hours after onset of symptoms or in patients seen earlier, in whom thrombolytic or percutaneous transluminal coronary angioplasty therapy cannot be utilized.

Clinical Trials as Topic↗
PubMed1987

Direct measurement of free radical generation following reperfusion of ischemic myocardium.

Electron paramagnetic resonance spectroscopy was used to directly measure free radical generation in perfused rabbit hearts. Hearts were freeze-clamped at 77 degrees K during control perfusion, after 10 min of normothermic global ischemia (no coronary flow), or following post-ischemic reperfusion with oxygenated perfusate. The spectra of these hearts exhibited three different signals with different power saturation and temperature stability: signal A was isotropic with g = 2.004; signal B was anisotropic with axial symmetry with g parallel = 2.033 and g perpendicular = 2.005; signal C was an isotropic triplet with g = 2.000 and hyperfine splitting an = 24 G (1 G = 0.1 mT). The g values, linewidth, power saturation, and temperature stability of signal A are identical to those of a carbon-centered semiquinone, whereas those of signal B are similar to alkyl peroxyl or superoxide oxygen-centered free radicals; signal C is most likely a nitrogen-centered free radical. In the control heart samples signal A predominated, whereas in ischemic hearts signal A decreased in intensity, and signals B and C became more intense; with reperfusion all three signals markedly increased. Free radical concentrations derived from the intensities of the B and C signals peaked 10 sec after initiation of reflow. At this time the oxygen-centered free radical concentration derived from the intensity of signal B was increased over six times the concentration measured in control hearts and over two times the concentration measured in ischemic hearts. Hypoxic reperfusion did not increase any of the free radical signals over the levels observed during ischemia. These experiments directly demonstrate that reactive oxygen-centered free radicals are generated in hearts during ischemia and that a burst of oxygen radical generation occurs within moments of reperfusion.

Animals↗
PubMed1987

Evidence for a reversible oxygen radical-mediated component of reperfusion injury: reduction by recombinant human superoxide dismutase administered at the time of reflow.

It has been suggested that the beneficial effects of reperfusing ischemic myocardium might be in part reversed by the occurrence of "reperfusion injury." One possible mechanism could be the generation of oxygen free radicals. Superoxide dismutase enzymatically scavenges superoxide radicals by dismutation to hydrogen peroxide. This study tested the hypothesis that administration of recombinant human superoxide dismutase (h-SOD) at the time of reflow after a period of prolonged global ischemia would result in improved recovery of myocardial metabolism and function by preventing or reducing a potentially harmful component of reperfusion. We also sought to determine whether catalase, an enzymatic scavenger of hydrogen peroxide, was a necessary addition for optimal benefit. Langendorff perfused rabbit hearts were subjected to 30 min of normothermic (37 degrees C) total global ischemia. At the moment of reperfusion, 12 control hearts received a 10 ml bolus of normal perfusate followed by 15 min of reperfusion with normal perfusate (group I), 12 hearts received 60,000 IU of h-SOD as a bolus followed by a continuous infusion of 100 IU/ml for 15 min (group II), and 12 hearts received 60,000 IU of h-SOD and 60,000 IU of catalase as a bolus followed by 100 IU/ml of both enzymes for 15 min (group III). Myocardial ATP and phosphocreatine (PCr) content and intracellular pH during ischemia and reperfusion were continuously monitored with 31P nuclear magnetic resonance (NMR) spectroscopy. During 30 min of normothermic global ischemia intracellular pH dropped from 7.11-7.18 to 5.58-5.80 in all three groups of hearts. Likewise myocardial PCr content fell rapidly to 7% to 8% and ATP fell more slowly to 29% to 36% of preischemic control content. After 45 min of reperfusion PCr recovered to 65 +/- 5% of control in untreated (group I) hearts compared with 89 +/- 8% in h-SOD-treated (group II) hearts (p less than .01 vs group I) and with 83 +/- 6% of control in h-SOD/catalase-treated (group III) hearts (p less than .05 vs group I). Recovery of isovolumic left ventricular developed pressure was 68 +/- 5% of control in h-SOD-treated (group II) hearts and 66 +/- 6% of control in h-SOD/catalase-treated (group III) hearts after 45 min of reflow, compared with 48 +/- 6% of control in untreated (group I) hearts (p less than .005 for groups II and III vs group I). The NMR data confirmed equal depletion of ATP and PCr content in all three groups of hearts.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Improvement of postischemic myocardial function and metabolism induced by administration of deferoxamine at the time of reflow: the role of iron in the pathogenesis of reperfusion injury.

Reperfusion of ischemic myocardium has been postulated to result in a specific oxygen radical-mediated component of tissue injury. In a previous study we demonstrated improved recovery of ventricular function and metabolism when the superoxide radical scavenger superoxide dismutase was administered at the time of postischemic reflow. Studies in vitro, have suggested that superoxide toxicity might be mediated via the generation of more reactive hydroxyl radicals in an iron-catalyzed reaction. The present study was designed to test the hypothesis that myocardial reperfusion injury might be reduced by administration of the iron chelator deferoxamine at the time of reflow, most likely by preventing hydroxyl radical formation. Sixteen isolated Langendorff rabbit hearts, perfused within the bore of a superconducting magnet, were subjected to 30 min of normothermic (37 degrees C) total global ischemia followed by 45 min of reperfusion. At reflow eight treated hearts received a 10 ml bolus containing 50 mumol of deferoxamine followed by an infusion of 11 mumol/min for the first 15 min of reflow. The hearts were then perfused with standard perfusate for an additional 30 min. Eight untreated control hearts received a similar bolus of perfusate followed by 45 min of standard reperfusion. Serial 5 min 31P nuclear magnetic resonance spectra were recorded. Myocardial phosphocreatine (PCr) content fell to 5% to 7% of control during ischemia in both groups of hearts. Deferoxamine-treated hearts recovered 99 +/- 10% of control PCr content, while untreated hearts recovered 60 +/- 16% (p less than .05). Intracellular pH fell to 5.9 during ischemia in both groups, before showing more rapid and complete recovery in treated hearts (p less than .01). Recovery of developed pressure reached 70 +/- 6% of control in treated hearts compared with 35 +/- 10% in untreated hearts (p less than .05). Iron content of the perfusate was 7 microM, and by electron paramagnetic resonance spectroscopy was in the form of Fe3+-EDTA complexes. In the effluent of treated hearts iron was in the form of Fe3+-deferoxamine chelates. In summary, administration of the iron chelator deferoxamine at the time of postischemic reflow results in greater recovery of myocardial function and energy metabolism, which supports the hypothesis that iron plays an important role in the pathogenesis of reperfusion injury.

Adenosine Triphosphate↗
PubMed1987

Recombinant superoxide dismutase reduces oxygen free radical concentrations in reperfused myocardium.

It has been proposed that oxygen free radicals mediate damage that occurs during postischemic reperfusion. Recombinant human superoxide dismutase (r-h-SOD) has been shown to be effective at reducing reperfusion injury, but it is not known if this infused enzyme actually reduces oxygen free radical concentrations in the myocardial tissue. Electron paramagnetic resonance spectroscopy was used to directly measure the effect of r-h-SOD on free radical concentrations in the postischemic heart. Hearts were freeze clamped at 77 degrees K after 10 min of normothermic global ischemia followed by 10 s of reflow with control perfusate (n = 7) or perfusate containing 60,000 U r-h-SOD (n = 7). The spectra of these hearts exhibited three different signals: signal A isotropic, g = 2.004, identical to the carbon-centered ubiquinone free radical; signal B anisotropic with axial symmetry, g parallel = 2.033, g perpendicular = 2.005, identical to the oxygen-centered alkyl peroxyl free radical; and the signal C an isotropic triplet, g parallel = 2.000, an = 24 G, similar to a nitrogen-centered free radical such as a peroxyl amine. With r-h-SOD administration the concentration of the oxygen free radical, signal B, was reduced 49% from 6.8 +/- 0.3 microM to 3.5 +/- 0.3 microM (P less than 0.01) and the concentration of the nitrogen free radical, signal C, was reduced 38% from 3.4 +/- 0.3 to 2.1 +/- 0.3 microM (P less than 0.01). The concentration of the carbon-centered free radical, signal A, however, was increased 51% from 3.3 +/- 0.2 to 5.0 +/- 0.2 microM (P less than 0.01). Identical reperfusion with peroxide-inactivated r-h-SOD did not alter the concentrations of free radicals indicating that the specific enzymatic activity of r-h-SOD is required to decrease the concentrations of reactive oxygen free radicals. Additional measurements performed varying the duration of reflow demonstrate a burst of oxygen free radical generation peaking at 10 s of reperfusion. r-h-SOD entirely abolished this burst. These studies demonstrate that superoxide-derived free radicals are generated during postischemic reperfusion and suggest that the beneficial effect of r-h-SOD is due to its specific enzymatic scavenging of superoxide free radicals.

Animals↗
PubMed1985

Hemodynamic attenuation and the nitrate-free interval: alternative dosing strategies for transdermal nitroglycerin.

Various dosing strategies to determine therapeutic effects of nitroglycerin (NTG) preparations are reviewed. The importance of individual patient titration in establishing an effective NTG dosage is emphasized by reviewing a nitroglycerin ointment study and a crossover study. Studies reporting the development of hemodynamic attenuation ("tolerance") with longterm nitrate therapy are also discussed. The results of these and other studies suggest that the magnitude of the hemodynamic response to NTG or isosorbide dinitrate diminishes over time, with acute or first-dose effects far exceeding those obtained during long-term therapy. However, patients on long-term therapy continue to respond to sublingual NTG, which suggests that this phenomenon is not true NTG tolerance. The effect of a nitrate-free interval as a mechanism for avoiding hemodynamic attenuation of NTG therapy is reviewed. The results of 4 studies discussed found that intermittent nitrate protocols were not associated with the attenuated hemodynamic effect observed during chronic therapy. Two possible mechanisms for the vasodilatory effects of nitroglycerin are discussed. The first relates to the production of cyclic guanosine monophosphate in the smooth muscle cells of arteries and veins; the second to the synthesis of prostaglandin I2 by vascular endothelial cells. A mechanism by which nitrate receptors could be manipulated to increase vascular responsiveness is theorized, as well as a means by which a nitrate-free interval might avoid the development of hemodynamic attenuation in terms of cellular mechanisms and receptors.

Acetylcysteine↗
PubMed1985

Crossover from intravenous to transdermal nitroglycerin therapy in unstable angina pectoris.

The present study was designed to examine the safety and efficacy of titrating a nitroglycerin infusion to a fixed hemodynamic endpoint as initial therapy for patients admitted to a coronary care unit for medically refractory unstable angina, and to test the hypothesis that patients, responding to the addition of intravenous (i.v.) nitroglycerin to their previous antianginal regimen, could be crossed over to nitroglycerin administered by a new transdermal delivery system. In 9 patients the nitroglycerin infusion titrated upward at 3- to 10-minute intervals until a 10% reduction in mean arterial pressure was achieved. This titration schedule and hemodynamic endpoint proved safe and effective for controlling episodes of chest pain at rest in all 9 patients. Subsequently, this treatment strategy was tested in 17 consecutive patients with unstable angina treated in our coronary care unit during a 1-month period. In 10 of 15 successfully treated patients ischemia was the cause of chest pain as documented by cardiac catheterization. No change was made in antianginal or vasoactive drugs during the period of i.v. nitroglycerin administration or during crossover to transdermal therapy. In this well defined subgroup of patients with unstable angina, nitroglycerin infusion decreased the mean arterial pressure from 101 +/- 18 to 87 +/- 11 mm Hg (mean +/- standard deviation), using an infusion rate of 84 +/- 74 micrograms/min (range 10 to 200). The mean duration of i.v. therapy was 36 +/- 12 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1985

Regional wall motion improvement after coronary thrombolysis with recombinant tissue plasminogen activator: importance of coronary angioplasty.

To evaluate functional recovery in 20 consecutive patients with acute myocardial infarction who received recombinant tissue-type plasminogen activator, serial two-dimensional echocardiograms were performed before and immediately after tissue plasminogen activator administration and at 1 and 10 days postinfarction. Tissue plasminogen activator was administered intravenously (17 patients) or by intracoronary infusion (3 patients) after angiographic confirmation of total occlusion. Reperfusion, documented by angiography, occurred in 13 of the 20 patients. The mean time from onset of chest pain to thrombolysis was 5.1 +/- 1.1 hours. Echocardiograms were evaluated for regional function with a visual semiquantitative scoring system by two independent observers who had no knowledge of patient identity, temporal sequence, therapy or effect of therapy. There was no immediate or 24 hour improvement in wall motion. At day 10 compared with pretreatment, 28 of 33 reperfused infarct zone segments versus 6 of 20 nonreperfused infarct segments demonstrated improved wall motion (p = 0.01). This improvement did not relate to time from onset of chest pain to successful thrombolysis. Of reperfused infarct zone segments in the distribution of coronary artery balloon dilation, 19 of 23 segments exhibited improvement versus 7 of 17 (reperfused, no angioplasty) and 6 of 20 (nonreperfused, no angioplasty) segments (p = 0.001). Infarct zone segments reperfused at the time of ongoing chest pain demonstrated functional recovery compared with segments reperfused in the absence of chest pain (18 of 23 versus 10 of 20, respectively; p = 0.05). Thus, in this uncontrolled series, there was echocardiographically detectable improvement in function of reperfused infarct segments 10 days after coronary thrombolysis with recombinant tissue plasminogen activator.

Adult↗