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Biomedical subjects

A Mehra

Publications and source records attributed to A Mehra.

At least 37 records · Page 2Linked to original sources
PubMed1997

Incidence of arrhythmias in normal pregnancy and relation to palpitations, dizziness, and syncope.

We assessed the relation between symptoms and cardiac arrhythmias in 110 consecutive pregnant patients without evidence of heart disease referred for evaluation of palpitations, dizziness, and syncope (study group) and in 52 consecutive patients referred for evaluation of an asymptomatic functional precordial murmur (control group). Both groups had a high incidence of arrhythmias on Holter monitoring with atrial premature complexes (APCs) of 56% in the study group and 58% in the control group, > 100 APCs in 7% and 4% of the patients, respectively, and isolated ventricular premature complexes (VPCs) in 59% and 50%, respectively. The number of isolated VPCs was higher and > 50 VPCs/hour were seen in more patients in the study group (3,235 +/- 6,397 vs 678 +/- 3,358 beats/24 hours p < 0.05 and 22% vs 2% p = 0.03). Similarly, the incidence of multifocal VPCs was higher in the study patients (12% vs 2%, p < 0.05). There was no correlation between the incidence of both VPCs or APCs and symptoms, and only 10% of symptomatic episodes were accompanied by the presence of arrhythmias. Repeated Holter monitoring 6 weeks postpartum in 9 women with multiple premature contractions during pregnancy (9,073 +/- 9,210/24 hours) showed a substantial reduction to 1,345 +/- 1,997/24 hours (p < 0.05). Thus, this study confirms an increased incidence of arrhythmias during normal pregnancy. These arrhythmias consist mostly of APCs and VPCs. The number of simple and multifocal VPCs is higher in patients presenting with symptoms of palpitations, dizziness, or syncope; however, there is no correlation between the incidence of arrhythmias and symptoms, and only 10% of symptomatic episodes were accompanied by the presence of arrhythmias.

Adolescent↗
PubMed1997

Mothers against dpp participates in a DDP/TGF-beta responsive serine-threonine kinase signal transduction cascade.

Mothers against dpp (Mad) is the prototype of a family of genes required for signaling by TGF-beta related ligands. In Drosophila, Mad is specifically required in cells responding to Decapentaplegic (DPP) signals. We further specify the role of Mad in DPP-mediated signaling by utilizing tkvQ199D, an activated form of the DPP type I receptor serine-threonine kinase thick veins (tkv). In the embryonic midgut, tkvQ199D mimics DPP-mediated inductive interactions. Homozygous Mad mutations block signaling by tkvQ199D. Appropriate responses to signaling by tkvQ199D are restored by expression of MAD protein in DPP-target cells. Endogenous MAD is phosphorylated in a ligand-dependent manner in Drosophila cell culture. DPP overexpression in the embryonic midgut induces MAD nuclear accumulation; after withdrawal of the overexpressed DPP signal, MAD is detected only in the cytoplasm. However, in three different tissues and developmental stages actively responding to endogenous DPP, MAD protein is detected in the cytoplasm but not in the nucleus. From these observations, we discuss possible roles for MAD in a DPP-dependent serine-threonine kinase signal transduction cascade integral to the proper interpretation of DPP signals.

Animals↗
PubMed1996

Renal vasodilatory effect of endothelial stimulation in patients with chronic congestive heart failure.

OBJECTIVES: This study sought to examine the vasodilatory response of the renal circulation to endothelial stimulation in patients with chronic heart failure. BACKGROUND: Renal blood flow is often reduced in patients with chronic congestive heart failure and may lead to deterioration of renal function. Stimulation of renal endothelium has been shown to cause renal vasodilation in animals and in isolated human renal artery. The vasoregulatory role of the renal endothelium in patients with heart failure has not been evaluated. METHODS: Renal vasodilatory effect of endothelial stimulation with acetylcholine was assessed and compared with that of endothelial independent vasodilation with nitroglycerin. Both drugs were infused into the main renal artery. Renal artery cross-sectional area was measured with intravascular ultrasound and renal blood flow velocity with the aid of an intravascular Doppler technique. RESULTS: Both drugs caused a significant and comparable increase in renal artery cross-sectional area (maximal increase [mean +/- SE] 14 +/- 5% with acetylcholine, 15 +/- 5% with nitroglycerin; both changes < 0.05 vs. baseline). Acetylcholine also caused a significant reduction in renal vascular resistance (maximal reduction 55+/- 6%) and increase in renal blood flow (maximal increase 136 +/- 54%). In contrast, nitroglycerin administration showed no significant effect on renal vascular resistance and blood flow. CONCLUSIONS: Stimulation of endothelium-derived nitric oxide with acetylcholine results in a significant vasodilatory effect on both conductance and resistance renal blood vessels and leads to a marked reduction in renal vascular resistance and enhancement of renal blood blow. Nitroglycerin, an exogenous nitric oxide donor, caused a selective vasodilatory effect on renal conductance but not on resistance blood vessels and failed to increase renal blood flow. These data suggest the possibility that stimulation of endogenous nitric oxide production in the kidney could be used as a therapeutic target for enhancement of renal flow in patients with heart failure.

Acetylcholine↗
PubMed1995

Cardiovascular problems in pregnant women with the Marfan syndrome.

PURPOSE: To review the available information on the diagnostic, prognostic, and therapeutic aspects of cardiac complications in women with the Marfan syndrome during the peripartum period and to develop guidelines for the approach to these patients on the basis of this information. DATA SOURCES: A MEDLINE search and a manual search of bibliographies from reviewed articles. STUDY SELECTION AND DATA EXTRACTION: Articles that reported on pregnancy in patients with the Marfan syndrome or that discussed potentially relevant aspects of the syndrome. RESULTS: Pregnancy in the Marfan syndrome is associated with two primary problems: potential catastrophic aortic dissection and the risk for having a child with the syndrome. The risk for peripartum aortic dissection is especially high in women in whom aortic root dilatation is diagnosed before pregnancy. Gestation seems to be safer in women without preexisting cardiovascular disease; however, an event-free pregnancy cannot be guaranteed. The Marfan syndrome is inherited in an autosomal dominant manner, and the fetus has a 50% risk for inheriting the mutant gene. CONCLUSIONS: Women with the syndrome should be counseled before conception about the risks of pregnancy to both mother and fetus. Because preconceptual dilatation of the ascending aorta seems to be an important predictor for aortic dissection, it should be excluded before pregnancy. Transesophageal echocardiography seems to be preferable for noninvasive assessment of aortic dilatation before and during pregnancy. Prophylactic use of beta-blockers may be useful in preventing aortic dilatation. Surgery should be considered during gestation in patients with progressive aortic dilatation when or before the aortic root reaches 5.5 cm. Because of the potential risk of ionizing radiation to the fetus, noninvasive methods such as transesophageal echocardiography and magnetic resonance imaging are preferred to contrast aortography for the diagnosis of aortic dissection during pregnancy. Vaginal delivery can be done in patients with the Marfan syndrome who do not have cardiovascular system abnormalities. In patients with aortic dilatation, aortic dissection, or other important cardiac abnormalities, cesarean section should be the preferred method of delivery.

Delivery, Obstetric↗
PubMed1995

Escalating nitrate dose overcomes early attenuation of hemodynamic effect caused by nitrate tolerance in patients with heart failure.

This study was performed to examine the hypothesis that an early attenuation of nitrate effect caused by nitrate tolerance can be overcome by dose increase. We compared hemodynamic effects of constant dose (40 to 120 mg) of oral isosorbide dinitrate (ISDN) given every 6 hours for three doses followed by 12 hours of nitrate washout interval with those of escalating dose (40 mg, 80 mg, and 120 mg) in two similar groups of patients with chronic congestive heart failure. Escalating ISDN dose resulted in a progressive increase in ISDN blood level and overcame early attenuation of effect occurring with a constant dose. At peak effect of the third ISDN dose, a significantly greater reduction was seen in mean right atrial pressure (-59% +/- 27% vs -20% +/- 22%, p < 0.01), mean pulmonary artery pressure (-29% +/- 11% vs -11% +/- 15%, p < 0.01) and mean pulmonary artery wedge pressure (-39% +/- 19% vs -19% +/- 23%, p < 0.05) with the escalating dose. These findings demonstrate that early attenuation of hemodynamic effect caused by nitrate tolerance can be overcome by dose escalation.

Adult↗
PubMed1995

Prevention of tolerance to hemodynamic effects of nitrates with concomitant use of hydralazine in patients with chronic heart failure.

OBJECTIVES: This study was designed to determine the effect of oral hydralazine on the development of nitrate tolerance in patients with chronic congestive heart failure. BACKGROUND: Early development of nitrate tolerance with either continuous administration of intravenous or topical nitrate preparations or frequent dosing of oral nitrates leads to significant attenuation of nitrate-mediated hemodynamic and anti-ischemic effects. In recent animal experiments, prevention of nitroglycerin-induced hemodynamic tolerance with a concomitant use of hydralazine was demonstrated. This finding may have important clinical relevance. METHODS: Twenty-eight patients with chronic heart failure due to left ventricular systolic dysfunction were randomized to receive either a continuous infusion (24 h) of nitroglycerin alone (group I, 14 patients) or concomitantly with oral hydralazine (75 mg four times a day [group II, 14 patients]). The effect of nitroglycerin in each group was evaluated by analysis of variance for repeated measures. The power of the analysis to detect a 5.4-mm Hg (20%) change in mean pulmonary artery wedge pressure was 90%. RESULTS: Baseline hemodynamic variables as well as the initial hemodynamic response to nitroglycerin were comparable in both groups. Compared with the initial response to nitroglycerin, a significant attenuation of effect was found in group I at 24 h in mean (+/- SE) pulmonary artery pressure (27 +/- 4% vs. 10 +/- 3%, p < 0.05) and mean pulmonary artery wedge pressure (40 +/- 4% vs. 16 +/- 4%, p < 0.05). In group II, conversely, oral hydralazine prevented nitroglycerin-induced hemodynamic tolerance and resulted in a persistent effect on mean pulmonary artery and wedge pressures throughout the study period (31 +/- 3% vs. 27 +/- 4%, p = 0.13 and 37 +/- 4% vs. 34 +/- 6%, p = 0.40, respectively). In addition, the initial effect on blood pressure was attenuated at 24 h in group I (5 +/- 2% vs. 12 +/- 3%, p < 0.05) but not in group II (15 +/- 3% vs. 17 +/- 2%, p = 0.46). CONCLUSIONS: In patients with chronic heart failure due to left ventricular systolic dysfunction, the concomitant use of oral hydralazine prevents early development of nitrate tolerance and results in a persistent nitrate-mediated hemodynamic effect on systemic and pulmonary artery and left ventricular filling pressures. These data may support the concurrent use of hydralazine in patients with heart failure treated with organic nitrates.

Administration, Oral↗
PubMed1994

Potentiation of isosorbide dinitrate effects with N-acetylcysteine in patients with chronic heart failure.

BACKGROUND: Supply of sulfhydryl groups with the administration of N-acetylcysteine (NAC) has been reported to reverse tolerance to nitroglycerin but not to isosorbide dinitrate (ISDN). Lack of interaction between NAC and ISDN was suggested as an explanation for these findings. The present study was therefore designed to further evaluate this hypothesis. For this purpose, we compared the hemodynamic and hormonal effects of ISDN when given alone and in combination with NAC. METHODS AND RESULTS: We performed a randomized, cross-over design evaluation of the hemodynamic and hormonal effects of ISDN and ISDN + NAC in 14 patients with chronic congestive heart failure due to left ventricular systolic dysfunction. The findings of this study demonstrated a substantial NAC-mediated potentiation of ISDN effect on mean right atrial pressure (-11 +/- 21% versus -38 +/- 27%, -17 +/- 20% versus -34 +/- 27%, and -7 +/- 20% versus -25 +/- 26% at 2, 3, and 4 hours, respectively; all P < .05), mean pulmonary artery wedge pressure (-18 +/- 16% versus -33 +/- 14%, -15 +/- 25% versus -33 +/- 19%, -14 +/- 22% versus -25 +/- 22%, and -16 +/- 16% versus -26 +/- 16% at 2, 3, 4, and 5 hours, respectively; all P < .05), mean pulmonary artery pressure (-8 +/- 11% versus -20 +/- 15% at 3 hours, P < .05), and cardiac output (an increase of 2 +/- 16% versus 25 +/- 20% at 4 hours, P < .05). Although there were no significant changes in serum catecholamine levels and plasma renin concentration with both regimens, ISDN + NAC resulted in a greater fall in plasma levels of atrial natriuretic peptide (296 +/- 251 pg/mL after ISDN versus 202 +/- 118 pg/mL after ISDN + NAC, P < .05). CONCLUSIONS: The results of this study provide strong evidence for the existence of an interaction between thiols and ISDN and further support the role of sulfhydryl groups in the activation and therapeutic action of organic nitrates. The discrepancy between the results of this study demonstrating NAC-induced potentiation of ISDN effects and a previous study showing failure to reverse ISDN tolerance with NAC may suggest that ISDN-NAC interaction requires normal intracellular levels of sulfhydryl groups and does not occur after intracellular sulfhydryl group depletion.

Acetylcysteine↗
PubMed1993

Calcium channel blockers in heart failure.

The rationale for the use of calcium channel blockers in patients with chronic heart failure lies in their vasodilator action, antiischemic effect, ability to lessen left ventricular diastolic dysfunction and data showing their effect in preventing progression of myocardial dysfunction in animals with cardiomyopathy. Despite initial studies reporting improvement of the hemodynamic profile with nifedipine, further evaluation showed variable results, with hemodynamic worsening seen in up to 29% of patients. Longer-term controlled studies evaluating symptoms and clinical status demonstrated worsening chronic heart failure in approximately 25% of patients within 8 weeks of nifedipine therapy. Although diltiazem has a lesser myocardial depressant effect and its short-term use was associated with less frequent hemodynamic and clinical worsening, long-term exposure to the drug in a large group of patients with chronic heart failure due to left ventricular systolic dysfunction after myocardial infarction resulted in an increased incidence of cardiac events, with worsening heart failure and death. The use of verapamil in a similar patient cohort showed the loss of its demonstrated protective effect in patients with clinical evidence of heart failure. In an attempt to improve the safety of calcium channel blockers, the following approaches were suggested: 1) use of second-generation drugs with less myocardial depressant effect; 2) concomitant use of angiotensin-converting enzyme inhibitors to prevent reported neurohormonal activation; and 3) development of drugs with favorable neurohormonal effects. These approaches led to mixed results.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium Channel Blockers↗
PubMed1993

Plasma cyclic guanosine monophosphate in chronic heart failure: hemodynamic and neurohormonal correlations and response to nitrate therapy.

This study evaluated the relation between plasma cyclic guanosine monophosphate (cGMP) and hemodynamic and neurohormonal parameters in patients with chronic congestive heart failure and assessed the effect of organic nitrate on plasma cGMP levels. Plasma cGMP was fourfold higher in 18 patients with congestive heart failure compared with 15 control subjects (16.7 +/- 9.7 versus 4.0 +/- 1.0 pmol/ml; p < 0.0001) but did not correlate with plasma levels of catecholamines, renin, atrial natriuretic peptide, or with baseline hemodynamic values. The administration of a hemodynamically effective dose of oral isosorbide dinitrate (40 mg) resulted in a transient reduction in plasma cGMP from 16.7 +/- 9.7 pmol/ml at baseline to 13.0 +/- 6.6 pmol/ml at 1 hour (p < 0.05). This change was associated with small and statistically insignificant changes in neurohormonal values and had no relation to any of the hemodynamic changes. We concluded that (1) elevated plasma cGMP in congestive heart failure does not correlate with other neurohormonal or hemodynamic parameters and may be an independent parameter of heart failure, (2) in contrast to previously documented nitrate-mediated increases in intracellular cGMP, nitrate therapy results in a reduction in plasma cGMP, and (3) changes in plasma cGMP cannot serve as a surrogate measurement of changes in intracellular cGMP.

Administration, Oral↗
PubMed1992

Possible mechanisms of nitrate tolerance.

Prolonged exposure to organic nitrates has been shown to lead to the rapid development of tolerance to the peripheral and coronary vasodilatory effects of these drugs. As a result of this phenomenon, the hemodynamic and anti-ischemic effects of nitrates may be rapidly attenuated in patients with ischemic heart disease, congestive heart failure, or both. This nitrate tolerance appears to be both dose- and time-dependent. Likely mechanisms proposed for its development are multifactorial and include depletion of sulfhydryl groups, a nitrate-mediated increase in blood volume, and neurohormonal stimulation with activation of vasoconstrictive mechanisms.

Coronary Circulation↗
PubMed1992

Persistent hemodynamic improvement with short-term nitrate therapy in patients with chronic congestive heart failure already treated with captopril.

To evaluate the therapeutic potential of organic nitrates in patients with chronic congestive heart (CHF) failure already treated with angiotensin-converting enzyme (ACE) inhibitors, the temporal hemodynamic effects of oral isosorbide dinitrate, 40 to 120 mg administered every 6 hours to 11 nitrate responders who had been treated with captopril 89 +/- 32 mg/day, were studied. The administration of isosorbide dinitrate resulted in a significant decline in mean right atrial pressure, from 13 +/- 6 mm Hg at baseline (mean value of measurements performed every 2 hours for 24 hours with captopril therapy) to 9 +/- 4 mm Hg at 1 hour with persistent effect for most of the study period. Mean pulmonary artery pressure decreased from 38 +/- 7 mm Hg at baseline to 29 +/- 9 mm Hg at 1 hour, with effect persisting for 24 hours. Mean pulmonary artery wedge pressure also decreased from 24 +/- 6 to 15 +/- 7 mm Hg at 1 hour and remained significantly reduced for 20 hours. Systemic blood pressure demonstrated a transient decrease lasting 2 hours after initiation of therapy which was asymptomatic in all patients. The results of this study demonstrate a preserved vasodilatory effect of organic nitrates in patients already treated with ACE inhibitors. Nitrates mediated improvement in right and left ventricular filling pressures, and reduction of pulmonary hypertension demonstrates a rationale for the use of these therapeutic methods in combination and suggest the need for long-term evaluation of the effect of nitrate therapy in patients with chronic CHF already treated with ACE inhibitors.

Adult↗
PubMed1992

Nitrate resistance and tolerance: potential limitations in the treatment of congestive heart failure.

Organic nitrates are commonly used in the treatment of chronic congestive heart failure (CHF). These drugs have been shown to improve exercise capacity and reduce symptoms and in combination with hydralazine to prolong life in patients with mild-to-moderate symptoms of CHF. Recent investigations, however, have indicated that nitrate-mediated benefit to patients with CHF may be limited by resistance to their hemodynamic effects seen in many patients and by early development of tolerance. The incidence, potential mechanisms, and possible methods for prevention of nitrate resistance and tolerance in patients with chronic CHF are reviewed.

Drug Administration Schedule↗
PubMed1991

Randomized study to evaluate the relation between oral isosorbide dinitrate dosing interval and the development of early tolerance to its effect on left ventricular filling pressure in patients with chronic heart failure.

BACKGROUND: Early development of nitrate tolerance has been shown in patients with chronic congestive heart failure (CHF) receiving continuous nitroglycerin therapy. The influence of dosing interval of oral isosorbide dinitrate (ISDN), the nitrate preparation most widely used for the treatment of CHF, has not been investigated. METHODS AND RESULTS: We performed a prospective, randomized study to evaluate the effect of various regimens of oral ISDN on the development of early tolerance to its effect on left ventricular filling pressure in patients with moderate to severe CHF. Forty-four responders (20% or greater reduction in mean pulmonary artery wedge pressure lasting 1 hour or longer) were divided into four groups of 11 patients each, and randomized to receive their effective ISDN dose (40-120 mg) Q 4 hours, Q 6 hours, Q 8 hours, or t.i.d. (drug given at 0, 6, 12, and 24 hours allowing 12 hours of ISDN washout interval between the third and fourth doses). All groups demonstrated a significant and comparable reduction in LV filling pressure following administration of the first ISDN dose. Early attenuation of hemodynamic response was demonstrated with frequent dosing (Q 4 hours and Q 6 hours) ISDN. Tolerance was with a Q 8-hour regimen as demonstrated by preserved hemodynamic response to each dose. The effect of each dose, however, was short-term, with return of pulmonary artery wedge pressure to baseline level at 2 to 4 hours, resulting in an intermittent effect totaling no longer than 12 hours of the 30-hour study period. The use of a t.i.d. regimen resulted in marked attenuation of response after the third dose with complete restoration of nitrate effect following a 12-hour washout period between the third and fourth doses. ISDN plasma concentration was measured in five patients in each of the Q 4- and Q 8-hour groups. In the Q 4-hour group, plasma levels were significantly higher after administration of the last dose than after the first dose (area under the curve, 242 +/- 216 versus 123 +/- 130 ng/ml, p less than 0.05), and trough levels before administration of the second and the fifth dose (15 +/- 17 and 27 +/- 27 ng/ml, respectively) were both markedly higher than the baseline value of 2 +/- 4 ng/ml. CONCLUSIONS: Our data demonstrate the development of tolerance and early attenuation of effect on left ventricular filling pressure with frequent oral dosing (Q 4 and Q 6 hours) with ISDN in patients with chronic CHF, which may be related to persistently elevated trough blood levels of ISDN. The development of tolerance can be reversed after a washout period of 12 hours and can be prevented with a Q 8-hour administration. These regimens, however, are limited by an inconsistent effect. Although long-term implications of these findings need further evaluation, the present study demonstrates the difficulty of maintaining a persistent ISDN-mediated reduction in left ventricular filling pressure in patients with chronic, moderate to severe CHF. These results suggest the need to use intermittent ISDN therapy allowing a daily nitrate washout interval and the rationale for combined vasodilator therapy in patients with CHF.

Drug Administration Schedule↗
PubMed1990

A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure.

We performed a prospective, randomized, double-blind, crossover study to compare the efficacy and safety of vasodilation with the calcium entry blocker nifedipine with that of isosorbide dinitrate (ISDN) and their combination as treatment for heart failure. Twenty-eight patients with New York Heart Association Functional class II or III chronic heart failure due to left ventricular systolic dysfunction were studied. All patients were maintained on a constant dose of digitalis and diuretics throughout the study. Eight weeks of therapy with nifedipine alone or in combination with ISDN resulted in a significantly higher incidence of heart failure deterioration necessitating hospitalizations and/or additional diuretics. Twenty-four percent of patients required hospitalization during nifedipine therapy and 26% required hospitalization during nifedipine-ISDN combination therapy in comparison to 0% requiring hospitalization during ISDN therapy alone. The total number of heart failure-worsening episodes was nine among patients on nifedipine, three among patients on ISDN (p less than 0.09 versus nifedipine), and 21 among patients on nifedipine-ISDN combination (p less than 0.001 versus nifedipine, p less than 0.0001 versus ISDN). Premature discontinuation of drug administration due to clinical deterioration or other side effects occurred in 29% of patients during nifedipine therapy, 5% of patients during ISDN therapy (p = 0.05 versus nifedipine), and 19% of patients during the combination therapy. A comparison of eight patients who demonstrated clinical deterioration on nifedipine with the remainder of the patients demonstrated no significant difference in left ventricular ejection fraction (0.24 +/- 0.06 versus 0.23 +/- 0.07) or maximal oxygen uptake during exercise (13 +/- 3 versus 14 +/- 2 ml/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗