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Biomedical subjects

M Lesch

Publications and source records attributed to M Lesch.

At least 55 records · Page 3Linked to original sources
PubMed1989

Angiographic coronary morphology in postinfarction angina.

To investigate the pathophysiologic relevance of angiographically irregular coronary stenoses in postinfarction angina (PIA), we analyzed the clinical course and coronary angiograms of 73 patients studied within 30 days of infarction. Coronary lesions were classified as smooth or irregular. Thirty-six patients had PIA (Group 1) and 37 had an uncomplicated course (Group 2). Irregular lesion(s) in patent infarct-related arteries were found in 77% of Group 1 vs. 24% of Group 2 patients (P less than 0.005). Irregular lesion(s) in any coronary artery were found in 58% of Group 1 versus 19% of Group 2 patients (P less than 0.002). Other univariate predictors of PIA included older age, hypertension, angina before myocardial infarct, lower peak creatine kinase, three-vessel disease, and higher modified Gensini score. Multivariate analysis ranked lesion irregularity as the strongest predictor of PIA. Our data suggests that ruptured atherosclerotic plaques may be important in the pathogenesis of PIA. It is possible that lesion irregularity is associated with an active process and/or a residual thrombus, which may be responsible for postinfarction angina.

Angina Pectoris↗
PubMed1989

Protein synthesis and degradation during regression of thyroxine-induced cardiac hypertrophy.

To characterize changes in rates of protein turnover during regression of thyroxine-induced left ventricular hypertrophy, New Zealand White rabbits received intravenous thyroxine (200 micrograms/kg/d) for 9 days. Thyroxine was withheld, and in vivo protein turnover was evaluated on the 10th, 15th and 20th days. Animals not receiving thyroxine served as controls. Heart rate, blood pressure, and rate-pressure product were measured to correlate changes in cardiac work with protein turnover rates during the development and regression of hypertrophy. Thyroxine administration produced left ventricular hypertrophy by increasing the rate of protein synthesis (from 37.9 +/- 8.9 to 64.1 +/- 15.3 mg/day; P less than 0.05) to a greater degree than protein degradation (from 29.8 +/- 8.9 to 48.2 +/- 15.3 mg/day for control and thyroxine-treated animals, respectively; P less than 0.05). Cessation of thyroxine administration resulted in an eventual return of left ventricular mass to that of normally growing control animals. The major observation noted during thyroxine withdrawal was a return of protein synthetic rates to normal. Absolute rates of protein degradation remained elevated, whereas fractional protein degradative rates (i.e. the fraction of total protein degraded per day) were unchanged by the administration and withdrawal of thyroxine. These results indicate that suppression of both physiological and hormone-induced growth following cessation of thyroxine resulted from a decrease in cardiac protein synthetic rates and an increased rate of flux through the protein degradative pathway(s), while fractional rates of protein degradation (and thus average protein half-life) remained unchanged. The development and regression of thyroxine-induced hypertrophy correlated with thyroxine-mediated alterations in cardiac work.

Animals↗
PubMed1989

Effects of cysteine protease inhibitors on rabbit cathepsin D maturation.

To examine the effects of cysteine protease inhibitors on cathepsin D intracellular transport, proteolytic processing, and secretion, primary cultures of rabbit cardiac fibroblasts were grown to confluence and exposed (24 h) to media containing leupeptin (0-10 mM), E 64 (0-10 mM), or chloroquine (0-50 microM). Cathepsin D maturation was then evaluated in pulse-chase biosynthetic labeling experiments. None of the three agents affected the charge modification of procathepsin D (Mr 53,000) within the Golgi apparatus. However, all three agents interfered with the subsequent proteolytic processing of procathepsin D isoforms to active cathepsin D (Mr 48,000). Both leupeptin and E 64 caused the intracellular accumulation of large amounts of a Mr 51,000 processing intermediate (not detectable in control fibroblasts). Trace amounts of this intermediate were also detected in chloroquine-treated cells. Combined activity assay and radioimmunoassay of cell lysates indicated that this partially processed form of cathepsin D possessed proteolytic activity. Whereas low medium concentrations of leupeptin (10-100 microM) but not E 64 appeared to stimulate procathepsin D secretion, neither agent appeared to have a major effect on the rate of proenzyme secretion at doses required to inhibit proteolytic maturation (1-10 mM). Furthermore, pretreatment of cells with 10 mM leupeptin appeared only to delay, but not prevent, the intracellular transport of cathepsin D to lysosomes. In contrast, chloroquine increased procathepsin D secretion in a dose-dependent manner, diverting the majority of newly synthesized procathepsin D from the intracellular protease(s) responsible for proteolytic processing. These results suggest that cysteine proteases participate in the proteolytic maturation of procathepsin D during the transport of newly synthesized enzyme to lysosomes, but cysteine protease-mediated proteolytic processing is not required for cathepsin D activation or lysosomal translocation.

Animals↗
PubMed1988

Factors determining programmed stimulation responses and long-term arrhythmic outcome in survivors of ventricular fibrillation with ischemic heart disease.

The clinical and angiographic features of 38 patients with ischemic heart disease and nonacute infarction pre-hospital ventricular fibrillation (VF) were examined as a function of their drug-free programmed electrical stimulation (PES) responses. Twenty-two patients (58%) had inducible ventricular tachycardia (VT) at drug-free PES (group I) and 16 patients (42%) did not (group II). Group I had more patients with: (1) remote infarction (22 of 22 vs 2 of 16; p less than 0.01; (2) history of congestive failure (16 of 22 vs 0 of 16; p less than 0.01); (3) prior cardiac arrest (11 of 22 vs 0 of 16; p less than 0.01); (4) left ventricular (LV) ejection fraction less than 40% (19 of 22 vs 1 of 16; p less than 0.01); and (5) akinetic or dyskinetic LV wall motion (22 of 22 vs 2 of 16; p less than 0.001). Group II had more patients with: (1) LV segments at "ischemic jeopardy" (16 of 16 vs 14 of 22; p less than 0.01) and (2) factors suggestive of ischemia at the onset of VF (13 of 16 vs 1 of 22; p less than 0.001). Inducible VT (IVT) was suppressed in 16 of the 20 group I patients surviving hospitalization while four were discharged with persistence of IVT despite therapy. At 27 +/- 15 months, all four with persistent IVT had a recurrence of their arrhythmia. In the 16 group II patients, therapy was limited to antiischemic measures: coronary bypass in 12, propranolol in 3, and angioplasty in one. At 38 +/- 9 months, no group II patient has had a recurrence of his arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1988

Low heart rate variability and sudden cardiac death.

Our results indicate the following. 1. HRV is markedly depressed in inducible SCD survivors, a group at high risk of a subsequent episode of SCD. 2. Studies on patients who developed SCD during Holter monitoring indicate that HRV is depressed prior to SCD. 3. HRV is markedly depressed in inducible "asymptomatic ventricular ectopy" patients, with the degree of reduction paralleling that observed in inducible SCD survivors. In contrast, HRV of noninducible "asymptomatic ventricular ectopy" patients did not differ statistically from normal. 4. The findings provide additional evidence that cardiac parasympathetic function is depressed in patients prone to development of SCD and that altered autonomic function contributes to the development of electrical instability in such individuals. This accords with findings that such risk factors for sudden death as coronary artery disease, myocardial infarction, congestive failure, and hypertension all have been associated with reduced parasympathetic activity or attenuation of parasympathetically mediated reflexes. It is tempting to believe that diminished cardiac parasympathetic activity, perhaps by failing to counter excess sympathetic activity, contributes to SCD. 5. It may be inferred that HRV measurements have potential for serving as an independent predictor of inducibility in response to programmed ventricular stimulation and that they could represent a noninvasive screen for patients referred for evaluation of risk of SCD because of asymptomatic ventricular ectopy or other causes. In a larger sense, the data suggest that HRV measurements may provide information pertinent to the identification of individuals at increased risk of SCD that is independent of that provided by other risk factors. Given the human and economic stakes, further study is clearly warranted.

Death, Sudden↗
PubMed1988

Attachment and maintenance of adult rabbit cardiac myocytes in primary cell culture.

The present observations demonstrate that quiescent calcium-tolerant adult rabbit cardiac myocytes can be isolated by collagenase-hyaluronidase perfusion and maintained in primary culture for at least 2 wk. Culturing large numbers of myocytes requires that the freshly isolated cells be attached to a suitable substratum such as laminin, type IV collagen, or fetal bovine serum. The cultured myocytes retain their rod-like morphology for approximately 7 days before gradually spreading into a flattened conformation by 14 days. During the 1st wk of culture, contaminating interstitial cells rapidly proliferate, making cultures unsuitable for long-term study. Pure myocyte populations can be established and maintained if freshly isolated cells are cultured in the presence of cytosine arabinoside (Ara-C, 10 microM). This antimetabolite does not appear to adversely affect high-energy phosphates, since ATP and creatine phosphate (CrP) content of the myocytes is maintained at levels normally found in biopsy samples of rabbit myocardium. These results illustrate that an energetically stable population of adult cardiac myocytes can be maintained in primary culture in sufficient numbers to make them useful for future investigations of myocyte function.

Adenosine Triphosphate↗
PubMed1988

Nonrandom turnover of actin and tubulin in cultured rabbit cardiac fibroblasts.

Total protein fractional rates of growth, synthesis, and degradation were assessed in primary cultures of rabbit cardiac fibroblasts. Differences in fractional growth rates were produced by subculturing cells at low density and growing them to confluence. Total protein fractional degradative rates were then derived by subtracting fractional growth rates from measured fractional synthetic rates (obtained in [3H]leucine pulse-labeling experiments). Actin and tubulin degradation were studied in similar rapidly and slowly growing cultures. [35S]methionine pulse-chase experiments, followed by dodecyl sulfate-polyacrylamide gel electrophoresis, fluorography, and densitometry were used to determine the amount of labeled actin and tubulin remaining in cultures at various times during the chase (0-96 h). The indirect study showed a substantially lower total protein fractional degradative rate during rapid vs. slow growth (0.04 +/- 0.13 vs. 0.42 +/- 0.01 d-1 at 2 and 15 days after subculture, respectively; P less than 0.01). At both growth rates, the disappearance of labeled actin and tubulin was delayed, suggesting a more complex model for their degradation than random decay. Serum deprivation of slowly growing fibroblasts increased the rate of disappearance of both proteins by eliminating the delay in their breakdown. Thus the suppression of protein degradation during rapid growth appears to result from the presence of relatively greater amounts of "new" actin and tubulin (and possible other long-lived proteins) that are kinetically distinct from the total intracellular pools of these proteins with respect to their susceptibility to proteolysis.

Actins↗
PubMed1988

Amiodarone-induced pneumonitis. Assessment of risk factors and possible risk reduction.

Problems with pulmonary toxicity have emerged as a potentially limiting factor for amiodarone use. We prospectively studied 33 subjects treated with amiodarone for refractory arrhythmias. Serial clinical, radiographic and pulmonary function tests were correlated with the dose and duration of amiodarone treatment to define: a) prevalence of lung toxicity, b) subgroups of patients at particular risk for toxicity, c) potential interaction between amiodarone dose and toxicity. Considering all subjects, no significant change in lung volumes or airflow indices were noted; carbon monoxide diffusing capacity (DCO) underwent a mean reduction of 20.3 percent during treatment. Symptoms of possible pulmonary toxicity occurred in 27.3 percent of subjects. No type or degree of pretreatment cardiopulmonary dysfunction predicted lung toxicity. However, maintenance dose was correlated with toxicity; patients treated with doses of less than or equal to 400 mg per day from the start of treatment had insignificant reductions in DCO and did not develop symptoms.

Adolescent↗
PubMed1987

Heart rate variability and sudden death secondary to coronary artery disease during ambulatory electrocardiographic monitoring.

Data are analyzed from 5 patients who died suddenly during ambulatory electrocardiographic monitoring. Three of the patients were also assessed in terms of 2 recently developed indexes of heart rate (HR) variability. One of these, the standard deviation of RR intervals during successive 5-minute segments averaged over 24 hours, has been reported to be a putative index of vagal tone. Comparisons were made with HR variability findings in 20 normal volunteers. Sudden death was due to ventricular tachycardia degenerating into ventricular fibrillation in all cases. Both early (3 patients) and late cycle (2 patients) ventricular premature complexes initiated the terminal dysrhythmia. An increased density of ventricular ectopic activity was noted in the hour before onset of ventricular fibrillation. HR variability as measured by the standard deviation was significantly (p less than 0.01) lower in the patients who died suddenly (30 +/- 10 ms) than in the normal subjects (76 +/- 14 ms). These findings support suggestions that HR variability analysis may be useful in identifying patients at a higher risk of sudden death.

Aged↗
PubMed1987

Vasodilators as first-line therapy for congestive heart failure: a comparative hemodynamic study of hydralazine, digoxin, and their combination.

Although digitalis and vasodilators both enhance cardiac performance in patients with congestive heart failure, their relative efficacy is unknown. Accordingly, the acute hemodynamic effects of intravenous hydralazine (0.15 mg/kg), digoxin (1.0 mg), and the hydralazine-digoxin combination were evaluated in 14 normotensive heart failure patients at sitting rest, nine of whom were also studied during submaximal upright bicycle exercise. Hemodynamic responses at rest and exercise were similar. Cardiac output and stroke volume rose with both agents, the increase in cardiac output with hydralazine exceeding that with digoxin at rest. Left and right ventricular filling pressures declined equally. Systemic arterial mean pressure and total systemic vascular resistance fell with hydralazine, while, with digoxin, systemic arterial mean pressure increased and total systemic vascular resistance was unchanged. The hydralazine-digoxin combination produced increases in cardiac output and stroke volume that were greater than with either drug alone, and that equalled the sum of the drugs' individual effects; reductions in ventricular filling pressures were similar to the single-drug interventions. Thus, hydralazine is at least as effective as digoxin in improving cardiac function over the short term. Vasodilators may constitute an acceptable alternative to digitalis as initial therapy for congestive heart failure, except where a reduction in systemic arterial pressure is potentially deleterious. Use of combined treatment produces greater increases in cardiac output than with either drug alone, but requires risking the toxicities of two agents.

Aged↗
PubMed1987

Protein synthesis and degradation during starvation-induced cardiac atrophy in rabbits.

To determine the relative importance of protein degradation in the development of starvation-induced cardiac atrophy, in vivo fractional synthetic rates of total cardiac protein, myosin heavy chain, actin, light chain 1, and light chain 2 were measured in fed and fasted rabbits by continuous infusion of [3H] leucine. In addition, the rate of left ventricular protein accumulation and loss were assessed in weight-matched control and fasted rabbits. Rates of total cardiac protein degradation were then estimated as the difference between rates of synthesis and growth. Fasting produced left ventricular atrophy by decreasing the rate of left ventricular protein synthesis (34.8 +/- 1.4, 27.3 +/- 3.0, and 19.3 +/- 1.2 mg/day of left ventricular protein synthesized for 0-, 3-, and 7-day fasted rabbits, respectively). Inhibition of contractile protein synthesis was evident by significant reductions in the fractional synthetic rates of all myofibrillar protein subunits. Although fractional rates of protein degradation increased significantly within 7 days of fasting, actual amounts of left ventricular protein degraded per day were unaffected. Thus, prolonged fasting profoundly inhibits the synthesis of new cardiac protein, including the major protein constituents of the myofibril. Both this inhibition in new protein synthesis as well as a smaller but significant reduction in the average half-lives of cardiac proteins are responsible for atrophy of the heart in response to fasting.

Animals↗
PubMed1986

Programmed electrical stimulation to determine the need for antiarrhythmic therapy in patients with complex ventricular ectopic activity.

Patients with complex ventricular ectopy (greater than or equal to Lown grade III) and organic heart disease (OHD) are at increased risk for sudden cardiac death. Despite this fact, many such patients will remain free of symptomatic ventricular arrhythmia and thus are unnecessarily exposed to antiarrhythmic drug toxicity and arrhythmic potentiation. Programmed stimulation (PS) was used to direct therapy in 88 patients with asymptomatic ventricular ectopy complicating OHD. Thirty-three had inducible ventricular tachycardia (VT) and underwent treatment. The 55 patients without inducible VT (less than or equal to 6 repetitive ventricular responses) are the focus of this study. Three patients required treatment for persistent cardiac awareness. The remaining 52 have been followed for 22 months off antiarrhythmic drugs and all have remained free of subsequent major arrhythmic events. Therefore, in patients with complex ventricular ectopy, OHD, and absence of prior symptomatic ventricular arrhythmia, PS identifies patients at low risk for future disabling or life-threatening arrhythmic episodes and patients with absence of inducible VT can usually be managed without antiarrhythmic drugs.

Adult↗
PubMed1986

Spinal cord injuries associated with cardiopulmonary complications.

Twenty-two of 83 consecutive patients with traumatic quadraplegia admitted to a regional spinal injury center had significant bradycardia. These bradycardic patients accounted for 66% of the cervical spinal cord injured patients' mortality. In general, bradycardia in patients with cervical spinal cord injuries appears to be due to unopposed vagal tone. This bradycardia is self-limited within 3-5 weeks after the onset of paraplegia and does not require permanent pacemaker therapy.

Adolescent↗
PubMed1986

Limited proteolysis of rabbit cardiac procathepsin D in a cell-free system.

Rabbit cardiac cathepsin D is initially synthesized as an inactive, apparent molecular weight (Mr) 53,000, pI 6.6 precursor (procathepsin D) that is proteolytically processed during intracellular transport to produce the Mr 48,000 isoforms of active cathepsin D found in cardiac lysosomes. To examine potential proteases responsible for intracellular proteolytic processing, biosynthetically labeled procathepsin D was isolated from rabbit ventricular tissue perfused for 30 min with [35S]methionine. Procathepsin D was then incubated in vitro (40 degrees C, 1-240 min) with active cathepsin D, papain, and cathepsin B, either singly or sequentially, and the reaction products analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and two-dimensional electrophoresis. Incubation of 35S-labeled procathepsin D with active cathepsin D produced a single reaction product (Mr 51,000; pI 6.2). This limited proteolysis occurred at pH 3-5 and was inhibited by pepstatin. Incubation of 35S-labeled procathepsin D with papain or cathepsin B produced a major reaction product (Mr 48,000; pI 6.4) and a minor form (Mr 50,000; pI 6.0). These reactions occurred at pH 4-7 and were inhibited by leupeptin but not pepstatin. Only the Mr 48,000, pI 6.4 products of papain and cathepsin B-mediated proteolysis comigrated with the most basic isoform of active cathepsin D found in cardiac tissue. In addition, the Mr 51,000 intermediate produced by cathepsin D was susceptible to further limited proteolysis by cysteine proteases with resultant production of a Mr 48,000 product. Thus the intracellular proteolytic processing of rabbit cardiac procathepsin D does not result solely from autocatalysis but requires at least one other protease, possibly cathepsin B.

Animals↗
PubMed1986

Cardiac protein synthesis and degradation during thyroxine-induced left ventricular hypertrophy.

Assessment of cardiac protein metabolism in thyroxine-induced left ventricular hypertrophy requires measurements of both protein synthesis and degradation. In vivo protein degradative rates can best be measured as the difference between rates of protein synthesis and growth. Accordingly, rates of left ventricular protein accumulation were determined in growing rabbits, and in animals administered intravenous L-thyroxine (200 micrograms X kg-1 X day-1) for up to 15 days. Left ventricular protein fractional synthetic rates in euthyroid and thyroxine-treated rabbits were measured by continuous infusion of [3H]leucine (200 mu Ci/h X 6 h), and results converted to milligrams protein synthesized and degraded per day. Thyroxine administration produced left ventricular hypertrophy by increasing the rate of total protein synthesis (35.7 +/- 2.0, 71.0 +/- 7.0, and 62.6 +/- 4.0 mg of left ventricular protein synthesized per day for 0-, 3-, and 9-day, thyroxine-treated rabbits, respectively). However, the increased rate of total protein synthesis was greater than the measured rate of total protein accumulation (8.1 vs. 15.9 mg protein/day for euthyroid and thyroxine-treated animals), indicating that left ventricular protein degradative rates were increased as well. These studies indicate that accelerated proteolysis may be important in the molecular and architectural remodeling of the rapidly hypertrophying heart during thyrotoxicosis.

Animals↗
PubMed1986

Lysosomal changes during thyroxine-induced left ventricular hypertrophy in rabbits.

By use of a combined morphologic, immunocytochemical, and biochemical approach, this study demonstrates the changes in the lysosomal vacuolar apparatus that accompany thyroxine-induced cardiac hypertrophy. During the 1st wk of thyroxine administration, immunocytochemical studies revealed a decline in cathepsin D within many myocytes, but an increase within interstitial cells. These events transpired with only a modest rise in cathepsin D activity. During the 2nd wk, cathepsin D reappeared within most myocytes and continued to increase within the interstitial population and was associated with a general rise in lysosomal enzyme activity. These data demonstrate the importance of employing both immunocytochemical and biochemical approaches to evaluate the status of the lysosomal vacuolar apparatus, and suggests that the lysosomal vacuolar apparatus may be involved in the apparent remodeling that attends rapid cardiac growth, which may represent one component of the enhanced rates of proteolysis documented in this model of cardiac hypertrophy.

Animals↗