Anilkumar Mehra

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.

Cardiovascular Problems in Pregnant Women with the Marfan Syndrome

The Marfan syndrome is a hereditary disorder of the connective tissue [1-5] with an estimated prevalence of 4 to 6 cases per 10 000 persons; prevalence does not differ according to sex, race, or ethnicity [4]. The syndrome is caused by abnormalities in the relation between fibrillin and fibers that are caused by an abnormal gene for fibrillin [1, 2] on chromosome 15 [3]. A family history of the disease is present in 65% to 75% of patients and is sporadic in the rest. Cardiovascular involvement, including mitral and tricuspid valve prolapse with or without valvular regurgitation, dilatation of the aorta (primarily of the ascending portion), and aortic regurgitation, is a common feature of the disease [4, 6]. Life expectancy is greatly reduced in patients with this syndrome, predominantly because of cardiac complications (aortic dilatation, dissection, and rupture) [7]. Cardiovascular Risk of Pregnancy Pregnancy in women with the Marfan syndrome poses two problems: a potential catastrophic and often lethal acute aortic dissection and the risk for having a child who will inherit the syndrome. In a review of the literature published up to 1980, Pyeritz [8] found reports of 32 women with the Marfan syndrome who had had at least one pregnancy. Acute aortic dissection was diagnosed in 20 of these women, of whom 16 died during or shortly after pregnancy and 4 died later in the postpartum period because of aortic rupture or regurgitation. Most of these patients had had preexisting cardiovascular abnormalities, including aortic dilatation, aortic regurgitation, coarctation of the aorta, hypertension, cardiomegaly, and ductus arteriosus. A review of the literature since 1980 shows the description of 15 additional cases of pregnancy in women with the Marfan syndrome. Most of these reports describe cardiovascular complications during pregnancy (Table 1), including 1) dilatation of the ascending aorta with the development of aortic regurgitation and congestive heart failure and 2) proximal and distal dissections of the aorta with the occasional involvement of the iliac [9, 11] and coronary arteries [13]. Most women developed cardiac complications in the second and third trimesters, although aortic dissection occurred in isolated patients a few days after conception [15], during labor [9], and 8 days after delivery [16]. Aortic dissections occurring in the 14th, 28th, and 32nd gestational weeks each resulted in a maternal death [10, 14]. Live babies were delivered before surgery by cesarean sections at the 36th week in two patients [11, 12] and at the 38th week in one patient [13]. In all three of these patients, surgical repair was done successfully 3 days to 6 weeks after delivery. In two other patients, surgery was done during pregnancy. In one of these patients [15], aortic arch replacement and triple coronary artery bypass were done a few days after conception, and a normal baby was delivered by cesarean section in the 34th gestational week. In the other patient, who had a sinus of Valsalva aneurysm and aortic regurgitation, the aortic valve was successfully replaced in the 22nd week of pregnancy. The operation, however, was complicated by maternal hypotension that resulted in a decrease in fetal heart rate from 120 to 40 beats per minute. On day 10 after surgery, the patient had cardiac arrest caused by cardiac arrhythmia and was successfully resuscitated. Pregnancy was continued for 6 more weeks, after which the patient delivered a premature baby with the Marfan syndrome and respiratory distress. Table 1. A Summary of Cases Reported since 1980 in Which Peripartum Cardiovascular Complications Occurred in Women with the Marfan Syndrome The cause of the increased incidence of aortic dissection during pregnancy is not clear. An association between predisposition to dissection and the hyperdynamic and hypervolemic cardiocirculatory state of pregnancy is possible. In addition, estrogen has been reported to inhibit collagen and elastin deposition in the aorta, and progestogen has been shown to accelerate deposition of noncollagenous proteins in the aortas of rats [18]. Such structural changes in the arterial wall during pregnancy may also contribute to aortic dissection [19]. Although most reports describe severe complications related to pregnancy in women with the Marfan syndrome, these reports are probably an overpresentation of pregnancy-related complications caused by a bias toward reporting complicated rather than uncomplicated cases. Such an assumption is supported by Pyeritz [8], whose retrospective analysis of 105 pregnancies in 26 patients with the Marfan syndrome and prospective follow-up of 10 patients with the syndrome who had minimal or no preexisting cardiovascular disease showed only a low risk for maternal complications and death. In addition, two recent reports [20, 21] have described successful pregnancies in 3 patients despite mild to moderate aortic root enlargement and mitral valve prolapse in all 3 patients and a moderate degree of left ventricular systolic dysfunction in 1 patient. In addition to the maternal risk associated with pregnancy in the Marfan syndrome, there is a risk for transmitting the disease to the fetus. The Marfan syndrome is inherited as an autosomal dominant disorder [22], and the fetus has a 50% chance of inheriting the mutant gene [5]. Preconceptual Evaluation and Consultation Because no large clinical trials of pregnancy in patients with the Marfan syndrome have been reported, our recommendations are made on the basis of general principles rather than trial data. Women with the Marfan syndrome should be counseled before conception about the risk for potential pregnancy-related complications and the risk for transmitting the syndrome to the offspring. Mildly affected patients should be informed about the different presentations of the disease and the possibility of more severe expression in the offspring [5]. It should be noted that because of better understanding of the gene defect of the Marfan syndrome [2, 3, 23-26], prenatal diagnosis of this disease may be possible in some patients of informative families in which the disease cosegregates with marker alleles [5, 27]. During preconceptual consultation, physicians should carefully counsel the patient and her family about the expected morbidity of the mother in years to come and the possibility of reduced life expectancy. Many pregnancy-related complications described in patients with the Marfan syndrome emphasize the great potential for risk associated with gestation, especially in patients with cardiovascular involvement. Such cardiovascular abnormalities should be carefully evaluated before and frequently throughout pregnancy. Preconceptual dilatation of the ascending aorta seems to be an important predictor of aortic dissection during gestation and should be excluded before pregnancy. Reports of aortic dissection in the Marfan syndrome in pregnant [12] and nonpregnant patients with normal aortic root diameter [28] show that event-free pregnancy cannot be guaranteed to any patient with this syndrome. Recently, Simpson and colleagues [29] showed that transesophageal echocardiography was superior to transthoracic echocardiography in the assessment of aortic diameter and the diagnosis of aortic dissection and other cardiovascular manifestations of the Marfan syndrome. The use of transesophageal echocardiography should, therefore, be preferred for preconceptual risk stratification in women with the Marfan syndrome. Surgery during Pregnancy If a pregnant patient with the Marfan syndrome has substantial dilatation of the aorta, therapeutic abortion or surgical intervention should be considered. Surgery for marked dilatation of the aorta [17] and for aortic dissection [15] has been reported during gestation. Cola and Lavin [15] recently reported successful aortic arch replacement and coronary artery bypass grafting for aortic dissection in a patient with the Marfan syndrome; the surgery was done a few days after conception with normal fetal outcome. Smith and coworkers [17] reported successful replacement of the aortic valve and the ascending aorta during the 22nd week of gestation; this was done because of symptomatic dilatation of the aorta from 5.5 cm to 7.7 cm during pregnancy. Gott and colleagues [30] showed a 5-year survival rate of 85% in 50 patients with the Marfan syndrome after composite graft repair of the ascending aorta. They recommended preventive replacement of the ascending aorta if the aorta reaches or exceeds 60 mm. A recent study by Murgatroyd and colleagues [28] reported aortic root dimension to be 5.1 1.3 cm in 11 patients who developed aortic dissection. In contrast, the average aortic dimension in patients with uncomplicated courses was 3.7 1.3. On the basis of these data, a recent editorial [31] recommended elective replacement of the aortic root when or before the root reaches 5.5 cm in patients with the Marfan syndrome who show progressive dilatation of the aortic root by serial echocardiographic assessment, in patients with a family history of aortic dissection, and in women who are planning pregnancy. Successful surgery for aortic dissection during pregnancy has been reported in a few cases [32-34]. It should be noted, however, that cardiac surgery in general has been shown to result in increased fetal loss [35]. For this reason, if fetal maturity can be confirmed, a cesarean section should be done before or concomitantly with thoracic surgery [8, 10, 12]. Prophylactic Use of -blockers Several preliminary studies [36-39] have suggested that -blocking agents may have a beneficial effect on the rate of aortic root dilatation in children and adolescents. These initial results are strongly supported by a recent report by Shores and colleagues [40], who did a randomized study of the effect of propranolol (mean dose, 212 68 mg/d) on the progression of aortic dilatation in adolescents and adults with the Marfan

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.

Renal Vasodilatory Action of Dopamine in Patients With Heart Failure Magnitude of Effect and Site of Action

Background— A “renal dose” of dopamine is often used to increase renal blood flow; however, data on the magnitude of effect and site of action in patients with heart failure are scarce. Methods and Results— Renal effects of intravenous dopamine (1, 2, 3, 5, and 10 &mgr;g · kg−1 · min−1) were evaluated in 13 patients with chronic heart failure. Renal blood flow was calculated from renal artery cross-sectional area measured with intravascular ultrasound and renal blood flow velocity-time integral measured by the intravascular Doppler technique. Cross-sectional area increased and was significantly higher than baseline (0.30±0.04 cm2) at 5 &mgr;g · kg−1 · min−1 (0.36±0.05 cm2) and 10 &mgr;g · kg−1 · min−1 (0.38±0.06 cm2). The velocity-time integral was significantly higher than baseline (22±3 cm) at doses of 3 and 5 &mgr;g · kg−1 · min−1 (both 31±4 cm). Renal blood flow increased, whereas renal vascular resistance decreased, reaching statistical significance at 2 &mgr;g · kg−1 · min−1 through 10 &mgr;g · kg−1 · min−1. Cardiac output gradually increased, reaching statistical significance at doses of 5 and 10 &mgr;g · kg−1 · min−1 (5.5±0.5 and 6.1±0.7 versus 4.5±5.2 L/min at baseline), but the increase in renal blood flow appeared proportionately larger than corresponding increases in cardiac output. Conclusions— Dopamine is associated with an increase in renal blood flow in patients with heart failure. This effect is due to dilation of both the large conductance and small resistance renal blood vessels. Further evaluation of the efficacy and safety of dopamine for improvement of renal function in hospitalized patients with heart failure is warranted.

Calcium channel blockers in heart failure.

A considerable effort has been made in the last 15 years to evaluate the safety and efficacy of calcium channel blockers (CCBs) in the treatment of patients with chronic congestive heart failure (CHF). Available studies have provided strong evidence for a potential detrimental effect of the first-generation calcium antagonists in patients with CHF, indicating the need for great caution when these drugs are used in patients with significant depression of left ventricular systolic function. A number of second-generation CCB have demonstrated a strong vasodilatory effect and favorable hemodynamic action but failed to show a similar improvement in exercise capacity, morbidity and mortality. Moreover, drugs such as nicardipine and nisoldipine have resulted in a detrimental effect in some patients and, therefore, cannot be considered safe when used in patients with moderate-to-severe heart failure. Available information from the V-HeFT III study demonstrate a lack of an unfavorable effect of felodipine on exercise tolerance in patients with chronic heart failure. Although mortality rate was similar in both the felodipine and the placebo group, because of the relatively small number of patients in this study, no clear conclusion can be drawn regarding the effect of felodipine on mortality in patients with CHF. An encouraging signal regarding a potential role of CCB in the treatment of chronic heart failure has been provided by the recently completed PRAISE study. This prospective large-scale study demonstrated the safety of amlodipine, a long-acting dihydropyridine derivative, when used in patients with heart failure due to coronary artery disease. Furthermore, this study demonstrated a substantial reduction in mortality in patients with CHF due to nonischemic cardiomyopathy and provided a strong indication for a potential therapeutic benefit of amlodipine when added to standard CHF therapy in this patient population. No clear explanation is available at the present time regarding the reason for the deleterious effect demonstrated with some of the dihydropyridines and the contrasting benefit seen with amlodipine. Finally, more information regarding the safety and efficacy of dihydropyridines should become available in the next year. The PRAISE II study is ongoing and will provide further information regarding the therapeutic role of amlodipine in patients with nonischemic dilated cardiomyopathy. The MACH-1 study is evaluating the effect of mibefradil, a predominant T-type channel blocker with an ideal activity profile, on morbidity and mortality in patients with chronic CHF.

Hemorheological abnormalities in stable angina and acute coronary syndromes

The pathophysiological abnormalities of stable angina (SA) and acute coronary syndromes (ACS) may, in part, be promoted by fluid forces associated with local blood flow and hence by the rheological properties of blood. This study evaluated several hemorheological parameters in 16 healthy controls and in 16 SA, 18 unstable angina (UA) and 19 acute myocardial infarct (AMI) patients; all patients underwent diagnostic angiography following blood sampling. Rheological measurements included whole blood viscosity, plasma viscosity and RBC aggregation via erythrocyte sedimentation rate (ESR) and Myrenne aggregometer indices. Compared to controls, RBC aggregation was significantly elevated in all patient groups (p<0.001), with the rank being AMI>UA>SA. RBC aggregability as tested in 70 kDa dextran exceeded control in all patients. Blood viscosity values calculated at 40% Hct, plasma viscosity and yield shear stress values followed the same pattern (AMI>UA>SA>control); increases of inflammatory markers (i.e., WBC count, hs-CRP) were elevated in all patient groups in the order AMI>UA>SA. Our study thus indicates an association between hemorheological abnormalities and the severity of coronary artery disease, and suggests the merit of evaluating whether therapeutic interventions that normalize blood rheology may reduce the incidence and/or progression of coronary artery disease.

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.

Renal circulatory effects of adenosine in patients with chronic heart failure

OBJECTIVES We sought to study the renal circulatory effects of adenosine in patients with chronic congestive heart failure (CHF). BACKGROUND Renal blood flow (RBF) is often reduced in patients with chronic CHF and may lead to decreased renal function. The cause of reduced RBF is multifactorial and involves systemic as well as local vasoregulatory mechanisms. Stimulation of renal adenosine A1 receptors in animal models has resulted in a significant vasoconstriction of afferent and efferent glomerular arterioles and deterioration of renal function. Although adenosine serum levels have been shown to be elevated in patients with CHF, their effect on the renal circulation in this patient population has not been studied. METHODS Nine patients with CHF from left ventricular systolic dysfunction were studied. The effects of adenosine at a dose of 10(-5) mol/liter infused directly into the main renal artery on heart rate, renal artery blood pressure, renal artery cross-sectional area (measured by intravascular ultrasound), renal Doppler blood flow velocity (measured by a Doppler flow wire in the renal artery), RBF and renal vascular resistance (RVR) were evaluated. RESULTS Infusion of adenosine resulted in no significant effect on heart rate or renal artery blood pressure but caused a substantial increase in RVR (11,204 +/- 1,469 to 31,494 +/- 3,911 dynes x s x cm(-5), p = 0.0005), which led to a marked fall in RBF in every patient (mean values 376 +/- 36 to 146 +/- 22 ml/m2, p = 0.0002). These changes in RVR and RBF were associated with no significant change in renal artery cross-sectional area (0.389 +/- 0.040 to 0.375 +/- 0.033 cm2, p = 0.3). CONCLUSIONS Stimulation of renal adenosine receptors in patients with CHF results in marked renal vasoconstriction that leads to an important reduction in RBF. Lack of change in renal artery cross-sectional area suggests that adenosine affects intrarenal resistance blood vessels rather than large conductance vessels. These results may indicate a rationale for investigation of renal adenosine receptor blockade for enhancement of RBF and improvement of renal function in patients with chronic CHF.

Comparison of intracoronary Doppler guide wire and transesophageal echocardiography in measurement of flow velocity and coronary flow reserve in the left anterior descending coronary artery.

BACKGROUND The intracoronary Doppler tipped guide wire has been shown to be highly accurate in the measurement of coronary flow velocity (CFV). Recent studies have indicated that blood flow velocity in the left anterior descending coronary artery (LAD) can be determined by transesophageal echocardiography (TEE). The purpose of this study was to compare flow velocity recordings and coronary flow reserve measurements in the LAD by TEE with those obtained by Doppler guide wire. METHODS AND RESULTS The study population consisted of 14 patients with chest pain and normal coronary arteriograms. After routine coronary arteriography was performed, a 0.014-inch Doppler guide wire was advanced into the proximal part of the LAD. After baseline measurement of coronary flow velocity (CFV) was obtained, 140 microg/kg/min adenosine was administered intravenously for 3 minutes, and the flow velocity was recorded. TEE was performed within 24 hours of the cardiac catheterization. After baseline measurements of CFV in the LAD, heart rate, and blood pressure were obtained, 140 microg/kg/min adenosine was administered intravenously, and the CFV was recorded. Coronary flow reserve was calculated as the ratio of the peak diastolic CFV during adenosine infusion to the peak diastolic CFV at baseline. A good correlation was found (r = 0.91, p < 0.0001) between CFV by Doppler guide wire and that determined by TEE. A good correlation was also found between the coronary flow reserve assessed by Doppler guide wire and that determined by TEE (r = 0.92, p < 0.0001). CONCLUSION Our data indicate that CFV and coronary flow reserve in the LAD can be accurately measured by transesophageal echocardiography.

Microcirculatory Dysfunction in Cardiac Syndrome X: Role of Abnormal Blood Rheology

Objective: Cardiac syndrome X (CSX) is of clinical interest, yet the underlying pathophysiological mechanisms have not been fully elucidated. It is well known that elevated blood viscosity and red blood cell (RBC) aggregation can adversely affect microcirculatory blood flow. The present study was designed to explore whether CSX is associated with abnormalities of blood rheology.