Enrique Ostrzega

Quantitative single photon emission computed thallium-201 tomography for detection and localization of coronary artery disease: optimization and prospective validation of a new technique

One hundred eight-three men underwent stress-redistribution thallium-201 myocardial perfusion tomography. After evaluation of various preprocessing filters in a phantom study, the Butterworth filter with a frequency cutoff of 0.2 cycles/pixel, order 5 (which provided optimal filter power) was used in the back projection algorithm of the patient studies. All short-axis and apical portions of vertical long-axis images were quantified by dividing each myocardial slice into 60 equal sectors and displaying the maximal count per sector as a linear profile. In a pilot group consisting of 20 normal men (less than 5% likelihood of coronary artery disease) and 25 men with coronary artery disease (greater than or equal to 50% coronary stenosis by angiography), profiles representing the lowest observed value below the mean normal profiles provided the best threshold for defining normal limits. Abnormal portions of the patient profiles were plotted on a two-dimensional polar map. The polar map was divided into 102 sectors, and sectors with a probability of greater than or equal to 80% for disease of each one of the three major coronary arteries were clustered to represent specific coronary artery territories. Receiver operating characteristic curve analysis for defect size showed that the optimal threshold for defining a definite perfusion defect was 12% for the left anterior descending and left circumflex and 8% for the right coronary artery territories. These criteria were prospectively applied to an additional 92 patients with angiographic coronary artery disease, 18 patients with normal coronary arteriograms and 28 patients with less than 5% likelihood of coronary disease. Sensitivity, specificity (in patients with normal coronary arteriograms) and normalcy rate (in patients with less than 5% likelihood of coronary artery disease) for overall detection of coronary disease were 96%, 56% and 86%, respectively. Sensitivity and specificity for identification of individual diseased vessels were, respectively, 78% and 85% for the left anterior descending, 79% and 60% for the left circumflex and 81% and 71% for the right coronary artery. These results were not significantly different from those of the pilot group. An optimized quantitative method for interpretation of stress thallium-201 myocardial perfusion tomography has been developed. Prospective application of this method indicates that the technique is accurate for the overall detection of coronary artery disease and identification of disease in individual arteries.

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

Quantification of left ventricular myocardial mass in humans by nuclear magnetic resonance imaging

The ability of NMRI to assess LV mass was studied in 20 normal males. By means of a 1.5 Tesla GE superconducting magnet and a standard spin-echo pulse sequence, multiple gated short-axis and axial slices of the entire left ventricle were obtained. LV mass was determined by Simpsons rule with the use of a previous experimentally validated method. The weight of the LV apex (subject to partial volume effect in the short-axis images) was derived from axial slices and that of the remaining left ventricle from short-axis slices. The weight of each slice was calculated by multiplying the planimetered surface area of the LV myocardium by slice thickness and by myocardial specific gravity (1.05). Mean +/- standard deviation of LV mass and LV mass index were 146 +/- 23.1 gm (range 92.3 to 190.4 gm) and 78.4 +/- 7.8 gm/m2 (range 57.7 to 89.4 gm/m2), respectively. Interobserver agreement as assessed by ICC was high for determining 161 individual slice masses (ICC = 0.99) and for total LV mass (ICC = 0.97). Intraobserver agreement for total LV mass was also high (ICC = 0.96). NMRI-determined LV mass correlated with body surface area: LV mass = 55 + 108 body surface area, r = 0.83; with body weight: LV mass = 26 + 0.77 body weight, r = 0.82; and with body height: LV mass = 262 +/- 5.9 body height, r = 0.75. Normal limits were developed for these relationships. NMRI-determined LV mass as related to body weight was in agreement with normal limits derived from autopsy literature data.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

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.

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.

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.