Anil Mehra

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)

Current evaluation and management of patients with mitral stenosis.

Case presentation: A 28-year-old woman with known mitral stenosis (MS) who was not taking antibiotic prophylaxis presented with new onset of chest pain, atrial fibrillation, and “heart failure.” She was treated for “heart failure” and converted spontaneously to sinus rhythm. Echocardiographic/Doppler studies showed a mitral valve gradient (MVG) of 7, a mitral valve area (MVA) of 1.2 cm2, 2+ mitral regurgitation (MR), no tricuspid regurgitation, normal left ventricular (LV) size and function, no left atrium (LA) thrombus, and a mitral valve score (University of Southern California [USC] scoring system) of 1, with no calcium in the commissures. At cardiac catheterization, mean pulmonary artery (PA) wedge was 23 mm Hg, mean PA pressure was 25 mm Hg, MVG was 10 mm Hg, and MVA was 1.2 cm2. On exercise, mean PA wedge was 30 mm Hg, mean PA pressure was 55 mm Hg, and MVG was 18 mm Hg. On angiography, the LV end-diastolic volume was 80 mL/m2, ejection fraction was 0.48, and 2+ MR, with normal coronary arteries. After catheter balloon commissurotomy (CBC), the MVA was 2.0 cm2, mean PA wedge was 13 mm Hg, and mean PA pressure was 20 mm Hg, with no MR. Her discharge medications were penicillin V 250 mg twice daily and antibiotic prophylaxis for prevention of infective endocarditis. ### Current Evaluations and Management of MS In almost all patients, MS is the result of previous rheumatic carditis with valve involvement. #### Severity of MS The relationship of the MVG as a function of the rate of mitral valve flow per diastolic second for various MVAs is shown in Figure 1. The threshold of onset of pulmonary edema is ∼20 mm Hg. Assuming a normal mean LV diastolic pressure (LVDP) of 5 mm Hg, a mean MVG of 20 mm Hg would be necessary1 to maintain …

Pregnancy-Associated Acute Myocardial Infarction: A Review of Contemporary Experience in 150 Cases Between 2006 and 2011

The incidence of coronary artery disease (CAD) in women of child-bearing age is low, and acute myocardial infarction (AMI) is uncommon.1,2 Pregnancy, however, has been shown to increase the risk of AMI ≈3-fold compared with the risk in nonpregnant women of similar age.2–5 Although previous studies have provided some data related to the incidence of pregnancy-associated MI (PAMI), clinical characteristics, risk factors, and outcome1,2,4 more information is needed on the mechanisms of AMI, the efficacy and safety of standard therapy, and the applicability of guideline recommendations designed for the general AMI population, to women with PAMI. The aim of this study was therefore to review contemporary data on PAMI in an attempt to provide recommendations for the management of this condition. A literature search for cases with AMI related to pregnancy was performed using PubMed and Google Scholar. References from these studies were cross-checked to obtain additional studies that may have been missed by the original search. All original articles were obtained online or by interlibrary communication. Articles published in languages other than English were translated by medical translators. A total of 134 cases published in the literature from 2006 to 2011 not included in a previous review4 were included in this study.6–124 In addition, 7 cases presented at the First International Congress on Cardiac Problems in Pregnancy in 2010 (Valencia, Spain) and 9 patients treated or consulted by the authors were also included in the analysis. Recommendations were made on the basis of available clinical information, with the understanding that the cases published in the literature and reviewed by us do not represent all the patients who developed PAMI during the period of the study and that reporting may therefore be incomplete and biased. …

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.

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 prevented 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 < 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 diffilculty 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.

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.

Pregnancy and the Risk of Spontaneous Coronary Artery Dissection: An Analysis of 120 Contemporary Cases

Background— Because of the rarity of this condition, information on pregnancy-associated spontaneous coronary artery dissection is limited. We reviewed a large number of contemporary pregnancy-associated spontaneous coronary artery dissection cases in an attempt to define the clinical characteristics and provide management recommendations. Methods and Results— A literature search for cases of pregnancy-associated spontaneous coronary artery dissection reported between 2000 and 2015 included 120 cases; 75% presented with ST-segment–elevation myocardial infarction, and 80% had anterior myocardial infarction. Left anterior descending coronary artery was involved in 72% of cases, left main segment in 36%, and 40% had multivessel spontaneous coronary artery dissection. Ejection fraction was reduced to <40% in 44% of cases. Percutaneous coronary intervention was successful in only 50% of cases. Coronary artery bypass surgery was performed in 44 cases because of complex anatomy, hemodynamic instability, or failed percutaneous coronary intervention. Maternal complications included cardiogenic shock (24%), mechanical support (28%), urgent percutaneous coronary intervention (28%), urgent coronary artery bypass surgery (27.5%), maternal mortality (4%), and fetal mortality (2.5%). During follow-up for 305±111 days, there was a high incidence of symptoms because of persistent or new spontaneous coronary artery dissections, and 5 women needed heart transplantation or ventricular assist device implantation. Conclusions— Pregnancy-associated spontaneous coronary artery dissection is commonly associated with left anterior descending, left main, and multivessel involvement, which leads to a high incidence of reduced ejection fraction, and life-threatening maternal and fetal complications. Percutaneous coronary intervention is associated with low success rate and high likelihood of complications, and coronary artery bypass surgery is often required. Recurrent ischemic events because of persistent or new spontaneous coronary artery dissection are common during long-term follow-up.

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.

Mechanical breakdown and thrombolysis in subacute massive pulmonary embolism: A prospective trial.

AIM To assess role of combined modality of mechanical fragmentation and intralesional thrombolysis in patients with massive pulmonary embolism presenting subacutely. METHODS Eight of 70 patients presenting in tertiary care centre of North India with massive pulmonary embolism within 4 years had subacute presentation (symptom onset more than 2 wk). These patients were subjected to pulmonary angiography with intention to treat basis via mechanical breakdown and intra lesional thrombolysis. Mechanical breakdown of embolus was accomplished with 5-F multipurpose catheter to re-establish flow, followed by intralesional infusion of urokinase (4400 IU/kg over 10 min followed by 4400 IU/kg per hour over 24 h). RESULTS Eight patients, mean age 47.77 ± 12.20 years presented with subacute pulmonary embolism (mean duration of symptoms 2.4 wk). At presentation, mean heart rate, shock index, miller score and mean pulmonary pressures were 101.5 ± 15.2/min, 0.995 ± 0.156, 23.87 ± 3.76 and 37.62 ± 6.67 mmHg which reduced to 91.5 ± 12.2/min (P = 0.0325), 0.789 ± 0.139 (P = 0.0019), 5.87 ± 1.73 (P = 0.0000004) and 27.75 ± 8.66 mmHg (P = 0.0003) post procedurally. Mean BP improved from 80.00 ± 3.09 mmHg to 90.58 ± 9.13 mmHg (P = 0.0100) post procedurally. Minor complications in the form of local hematoma-minor hematoma in 1 (12.5%), and pseudoaneurysm (due to femoral artery puncture) in 1 (12.5 %) patient were seen. At 30 d and 6 mo follow up survival rate was 100% and all the patients were asymptomatic and in New York Heart Association class 1. CONCLUSION Combined modality of mechanical fragmentation and intralesional thrombolysis appears to be a promising alternative to high risk surgical procedures in patients with subacute massive pulmonary embolism.

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.