Search

Background: Recent trials have demonstrated better outcomes with intensive than with moderate statin treatment. Intensive treatment produced greater reductions in both low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP), suggesting a relationship between these two biomarkers and disease progression.Methods: We performed intravascular ultrasonography in 502 patients with angiographically documented coronary disease. Patients were randomly assigned to receive moderate treatment (40 mg of pravastatin orally per day) or intensive treatment (80 mg of atorvastatin orally per day). Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis. Lipoprotein and CRP levels were measured at baseline and follow-up.Results: In the group as a whole, the mean LDL cholesterol level was reduced from 150.2 mg per deciliter (3.88 mmol per liter) at baseline to 94.5 mg per deciliter (2.44 mmol per liter) at 18 months (P<0.001), and the geometric mean CRP level decreased from 2.9 to 2.3 mg per liter (P<0.001). The correlation between the reduction in LDL cholesterol levels and that in CRP levels was weak but significant in the group as a whole (r=0.13, P=0.005), but not in either treatment group alone. In univariate analyses, the percent change in the levels of LDL cholesterol, CRP, apolipoprotein B-100, and non-high-density lipoprotein cholesterol were related to the rate of progression of atherosclerosis. After adjustment for the reduction in these lipid levels, the decrease in CRP levels was independently and significantly correlated with the rate of progression. Patients with reductions in both LDL cholesterol and CRP that were greater than the median had significantly slower rates of progression than patients with reductions in both biomarkers that were less than the median (P=0.001).Conclusions: For patients with coronary artery disease, the reduced rate of progression of atherosclerosis associated with intensive statin treatment, as compared with moderate statin treatment, is significantly related to greater reductions in the levels of both atherogenic lipoproteins and CRP. [ABSTRACT FROM AUTHOR]

Objectives: We studied the modifier effect of platelet antigen polymorphism (PlA2) on platelet inhibition by acetylsalicylic acid (ASA, i.e., aspirin), clopidogrel, or their combination in patients with coronary heart disease., Background: Clopidogrel, when administered with ASA, was shown to significantly improve the outcome of patients with acute coronary syndromes compared with patients receiving only ASA. We have shown previously that the effect of ASA on platelets is modified by the glycoprotein IIIa single nucleotide polymorphism PlA2. Hence, an important pharmacogenetic question remains whether the antiplatelet effect of clopidogrel is uniform for all patients or, like acetylsalicylic acid, more selective., Methods: Thirty PlA1/A1 and 30 PlA1/A2 patients were assigned randomly to ASA 325 mg/day, clopidogrel 75 mg/day, or both. After 10 days, platelet function was studied., Results: Clopidogrel provided stronger platelet inhibition than ASA with adenosine diphosphate as the agonist, and combination therapy resulted in greater inhibition than either inhibitor used alone (p < 0.0001). The use of ASA resulted in greater inhibition compared with clopidogrel with epinephrine (p < 0.0001) and collagen as agonists (p < 0.0001). With collagen as the agonist, platelets from PlA1/A2 donors were markedly and significantly less inhibited by ASA (p = 0.005). In contrast, with clopidogrel, no significant difference could be detected between inhibition of Pl(A1/A1) and Pl(A1/A2) platelets., Conclusions: The combination of ASA and clopidogrel appears superior to either agent alone in inhibiting platelet function. Pl(A2) functions as an important modifier for platelet responsiveness to ASA but not to clopidogrel. These findings could have significant impact on the future design of pharmacogenetic antithrombotic strategies for patients with coronary heart disease.

Background: Cardiac allograft vasculopathy (CAV) is the major cause of late mortality in heart transplant recipients. Because immunosuppressive therapy has been convincingly shown to suppress cellular rejection and prolong cardiac allograft survival, we assessed the efficacy of advancing immunosuppressive therapy in reversing or delaying CAV by switching azathioprine to combination mycophenolate mofetil and prednisone (MMF-P)., Methods and Results: Seventeen adult posttransplant patients, whose CAV was prospectively approached with the MMF-P protocol, were studied. The development of significant CAV was declared on the index coronary angiogram and the MMF-P protocol was instituted. The degree of occlusion for all coronary lesions was quantitated for the index angiogram, and for the angiograms performed 1 year before (baseline) the index angiogram and annually for 2 years after the index angiogram (MMF-P years 1 and 2). There was a significant change in percent occlusion over time (P < .001). Percent occlusion increased significantly from the baseline year to the index CAV year, but then decreased significantly from the index CAV year to the MMF-P treatment years 1 and 2., Conclusion: Advancing immunosuppression with MMF-P can delay the progression of and partially reverse lumen narrowing of CAV in heart transplant recipients.

We designed and implemented a digital flat-panel-based rotational X-ray coronary angiography technique hypothesizing that luminal disease could be identified with less radiation exposure and contrast usage compared to conventional angiography. Individuals scheduled for diagnostic coronary angiography were prospectively enrolled. In addition to conventional acquisitions in standard planes, subjects underwent one additional left coronary artery (LCA) or right coronary artery (RCA) rotational (spin) acquisition using a predefined trajectory. Radiation exposure and contrast volume were recorded for each run. Seventy-five subjects were enrolled. When compared with standard five-view cine acquisition, LCA spin angiography with one cranial and one caudal run resulted in 34.38% +/- 13.65% less radiation, 18.98% +/- 4.97% less contrast, and comparable assessment of stenosis severity. One spin acquisition compared with three standard cine acquisitions for RCA angiography resulted in 59.31% +/- 29.07% lower radiation, no significant change in contrast, and comparable assessment of stenosis severity. Rotational X-ray coronary angiography provides comparable visualization of coronary anatomy compared with traditional nonrotational coronary angiography with significantly less radiation exposure and contrast volume., ((c) 2004 Wiley-Liss, Inc.)

Poloxamer-188 is a surfactant polymer with antithrombotic and hemorheologic properties that make it potentially useful as an adjunct to acute reperfusion strategies. Animal studies and early human studies have documented poloxamer-188 to be effective at improving myocardial salvage when used as an adjunct to intravenous thrombolytic therapy for acute myocardial infarction. The current trial was a prospective pilot study involving 150 patients who were randomized in a 2:1 fashion to a poloxamer-188 infusion for 48-hours versus placebo. The poloxamer-188 infusion was well tolerated subjectively. The only clinically significant laboratory abnormality noted was an elevation in the serum creatinine above 2.0 g/dl in 12% (n = 12) of the 98 poloxamer-188 treated patients versus 1 of the 52 (2%) of the placebo treated patients (p = 0.048). Clinical end points including reinfarction (1% vs 4%), cardiogenic shock (7% vs 6%), and death (9% vs 4%) were statistically similar in the poloxamer-188 and placebo groups, respectively (p = NS). Using quantitative nuclear techniques, final infarct size and myocardial salvage were statistically similar in the poloxamer-188 and placebo groups. Mean left ventricular ejection fractions 1 week post after infarction were 51% +/- 12% in the poloxamer-188 group and 52% +/- 13% in the placebo group (p = NS). Final infarct size, was not altered by the poloxamer- 188 infusion; however, it was significantly correlated with normal perfusion (Thrombolysis in Myocardial Infarction grade 3 flow) in the infarct vessel after angioplasty. This study documented poloxamer-188 to be ineffective as an adjunct to primary angioplasty for acute myocardial infarction and resulted in azotemia in 12% of the patients.

Objectives: The aim of our study was to determine a superior thrombolytic regimen from three: anistreplase (APSAC), front-loaded recombinant tissue-type plasminogen activator (rt-PA) or combination thrombolytic therapy., Background: Although thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction, it has not been clear whether more aggressive thrombolytic-antithrombotic regimens could improve the outcome achieved with standard regimens., Methods: To address this issue, 382 patients with acute myocardial infarction were randomized to receive in a double-blind fashion (along with intravenous heparin and aspirin) APSAC, front-loaded rt-PA or a combination of both agents. The primary end point "unsatisfactory outcome" was a composite clinical end point assessed through hospital discharge., Results: Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) at 60 min after the start of thrombolysis was significantly higher in rt-PA-treated patients (77.8% vs. 59.5% for APSAC-treated patients and 59.3% for combination-treated patients [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.03]). At 90 min, the incidence of both infarct-related artery patency and TIMI grade 3 flow was significantly higher in rt-PA-treated patients (60.2% had TIMI grade 3 flow vs. 42.9% and 44.8% of APSAC- and combination-treated patients, respectively [rt-PA vs. APSAC, p < 0.01; rt-PA vs. combination, p = 0.02]). The incidence of unsatisfactory outcome was 41.3% for rt-PA compared with 49% for APSAC and 53.6% for the combination (rt-PA vs. APSAC, p = 0.19; rt-PA vs. combination, p = 0.06). The mortality rate at 6 weeks was lowest in the rt-PA-treated patients (2.2% vs. 8.8% for APSAC and 7.2% for combination thrombolytic therapy [rt-PA vs. APSAC, p = 0.02; rt-PA vs. combination, p = 0.06])., Conclusions: Front-loaded rt-PA achieved significantly higher rates of early reperfusion and was associated with trends toward better overall clinical benefit and survival than those achieved with a standard thrombolytic agent or combination thrombolytic therapy. These findings support the concept that more rapid reperfusion of the infarct-related artery is associated with improved clinical outcome.

This study describes a method for the performance of cardiac catheterization using 5 French preformed Judkins catheters from a percutaneous right brachial approach, and compares that technique to the more traditional percutaneous right femoral approach with 6 French catheters. One hundred consecutive patients requiring diagnostic left heart catheterization and selective coronary angiography were randomized according to femoral versus brachial arterial technique. Procedural efficiency, radiation exposure, and diagnostic film quality favored the femoral approach, while patient comfort, hemostasis time, time to ambulation, and decreased need for post-procedure nursing care favored the brachial approach. No differences were identified in complications. Cardiac catheterization from a right brachial artery percutaneous approach with 5 French preformed catheters has both advantages and disadvantages when compared with a more traditional femoral approach with 6 French catheters. Multiple factors should be considered before selecting an approach to diagnostic cardiac catheterization and each patient should be individually evaluated for determination of the optimal technique.

Duteplase, 98% double-chain recombinant tissue-type plasminogen activator, was administered intravenously in 488 patients with acute myocardial infarction in a multicenter, open, safety and patency study. Duteplase dosing was based on body weight. Duteplase was administered as a bolus of 0.04 MIU/kg of thrombolytic activity followed by 0.36 MIU/kg over 1 hour and 0.067 MIU/kg/hour for 3 additional hours. The patency rate of the infarct-related artery at 90 minutes was 69% (330 of 478). The reocclusion rate at 3 to 48 hours was 6% (18 of 301). Reinfarction occurred in 7.6% of patients (37 of 488), but 12 reinfarctions occurred after coronary angioplasty. Serious bleeding occurred in 7.6% of patients (37 of 488), predominantly at the catheterization entry site. There were 3 instances of central nervous system bleeding, 1 fatal. Fibrinogen levels declined to 83% of baseline at 24 hours. Weight-based dosing may explain the low incidence of serious bleeding in this study. The in-hospital mortality was 6.6% (32 of 488). This study documents that the dose of duteplase used in the International Study of Infarct Survival-3 results in a 90-minute coronary artery patency rate and safety profile comparable to those reported in published studies on the approved dose of alteplase.

This study investigated the acute effects of the alpha 1 antagonist terazosin on myocardial circulatory responses at rest and during exercise. Ten patients with congestive heart failure (class III and IV) underwent hemodynamic evaluation before and after a 5-mg oral dose of terazosin. At rest and during exercise, terazosin significantly decreased pulmonary capillary wedge pressure, systemic vascular resistance and mean arterial pressure while cardiac index increased. Stroke volume index increased (p less than 0.01) during exercise while left ventricular stroke work index remained unchanged in both experimental conditions. Terazosin administration significantly decreased both rest and exercise myocardial oxygen consumption while exercise coronary sinus oxygen content increased and arterial-coronary sinus oxygen difference diminished (p less than 0.05). Parallel with these changes, alpha blockade decreased the ratio of coronary blood flow to total cardiac output. Coronary vascular resistance remained unaltered with alpha blockade both at rest and during exercise. Coronary blood flow tended to diminish with decreased myocardial oxygen demand. Alpha 1 blockade induces systemic vasodilation and improves myocardial circulatory parameters without inducing coronary dilation or altering metabolic autoregulation.

Fourteen patients with moderately severe congestive heart failure (CHF) were given clonidine orally (0.2 and 0.4 mg doses) to determine the hemodynamic effects of a typical centrally acting vasodilator. The 0.2 mg dose significantly reduced mean systemic (15%) and mean pulmonary artery (20%) pressure; the corresponding reductions in vascular resistance were not as great because of a diminished cardiac output. Pulmonary capillary wedge pressure decreased significantly (27%). Heart rate decreased 11% and stroke volume remained unchanged. At a higher dose (0.4 mg), clonidine augmented these reductions but increased stroke volume modestly (15%). Isovolumic developed pressure/duration of isovolumic contraction and the duration of the preejection period were used as indexes of inotropy. After both doses, isovolumic developed pressure/duration of isovolumic contraction decreased dramatically (greater than or equal to 33%) and the preejection period increased substantially (greater than or equal to 18%) (both p less than 0.05). Compared with currently employed vasodilating agents, the centrally acting agent clonidine appears unique in that the drug-induced systemic and pulmonary arterial vasodilation are not accompanied by a commensurate improvement in ventricular systolic function. This lack of improvement appears to be a result of negative inotropic effects.

This study was designed to more clearly define the relation between various invasive hemodynamic measurements and left ventricular (LV) timing intervals, ejection rate and filling rate derived from the radionuclide angiographic volume curve. Twenty-eight patients were studied with simultaneous intracardiac micromanometer pressure and dP/dt recordings, gated radionuclide angiography and M-mode echocardiography. These techniques permitted multiple variables of systolic and diastolic function to be measured at a constant atrial paced rate of 100 beats/min. There was a strong correlation between peak ejection rate and ejection fraction (r = -0.97) and between peak ejection rate and maximum positive dP/dt (r = -0.85). There also was a strong correlation between peak filling rate and maximum negative dP/dt (r = -0.85). A weaker correlation existed between the time constant of LV relaxation and the peak filling rate (r = -0.49) and between the LV end-diastolic pressure and the peak filling rate (r = -0.62). There was no correlation between the modulus of chamber stiffness and filling rates, and no association was observed between the time to peak filling rate and the hemodynamic variables. Thus, under the conditions studied, the measured peak ejection and filling rate, determined from the radionuclide angiographic volume curve, correlated well with accepted invasive hemodynamic measurements.

Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial catecholamines were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and norepinephrine was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Central hemodynamic variables and regional blood flow and vascular resistances were ascertained in patients with severe congestive heart failure before and after the oral administration of prazosin hydrochloride or hydralazine. Prazosin was administered in doses of 2, 5, and 10 mg and hydralazine, 75 and 100 mg. Although both agents significantly increased cardiac output and decreased vascular resistances, their effects on regional blood flow and vascular resistances were considerably different. Prazosin increased hepatic blood flow and reduced hepatic vascular resistance at lower doses; these changes decreased as prazosin was increased. Hydralazine did not significantly alter mean hepatic blood flow or vascular resistance. Prazosin did not affect renal blood flow or renal vascular resistance. In contrast, hydralazine significantly increased renal blood flow and reduced vascular resistance; the changes were dose related. Both drugs augmented limb blood flow and diminished limb vascular resistance; the magnitude of change was dose dependent.

This report describes a patient who survived rupture of the left ventricular free wall following a myocardial infarction and who then subsequently went on to develop a pseudoaneurysm. The rupture became clinically recognized when the patient developed cardiac tamponade. A large hemopericardium was evacuated by performing a thoracotomy and a pericardiotomy. Although not evident at the time of the initial catheterization, a pseudoaneurysm developed over the ensuing months. The aneurysm was initially recognized by radionuclide angiography and confirmed by left ventricular angiography at a second cardiac catheterization. The aneurysm was successfully resected, and the patient was alive and functioning normally 18 months after rupture and 12 months after aneurysmectomy.

Rest and exercise systemic hemodynamic parameters, coronary blood flow, and myocardial energetics were assessed before and 15 min after the sublingual administration of 20 mg of nifedipine in 10 patients with idiopathic congestive cardiomyopathy. When compared with control, nifedipine increased rest and exercise cardiac index by 37% and 28%, respectively (p less than .001). Peripheral vasodilation was demonstrated with a drop in systemic arterial pressure, exercise pulmonary capillary wedge pressure, and systemic vascular resistance (p less than .05). The calcium-channel blocker did not alter myocardial oxygen consumption; however, coronary blood flow increased by 32% at rest (p less than .01) while coronary vascular resistance diminished both at rest and after exercise compared with control (p less than .05). Nifedipine elicited a decrease in the rest and exercise aortocoronary sinus oxygen difference while the coronary sinus oxygen saturation increased (p less than .01). In this group of patients with idiopathic congestive cardiomyopathy, nifedipine enhanced myocardial performance while increasing coronary blood flow and favorably altering the myocardial oxygen supply-demand balance.

Hydralazine possesses positive inotropic properties in animal model preparations. To determine whether this vasodilator elicits a positive inotropic response in the failing human ventricle, hydralazine, 75 or 100 mg, was administered orally to 14 patients with left ventricular dysfunction and congestive heart failure; the results were compared with those of first-dose prazosin at 5 and 10 mg. The duration of the preejection period and the isovolumic developed pressure/duration of isovolumic contraction (delta P/delta t) were used as indexes of inotropy. Prazosin did not effect a significant response in the duration of the preejection period or in the delta P/delta t. Hydralazine significantly shortened the preejection period and increased the delta P/delta t over 8 hours after administration; these data suggest that hydralazine elicits a positive inotropic response in the failing human ventricle.

The purpose of this study was to document early structural changes in the human heart after the initial administration of doxorubicin. Endomyocardial biopsies were performed at baseline and at 4 and 24 hours after doxorubicin administration to 13 patients. Morphometric analysis of electron micrographs (x 31,200) quantitated mitochondrial and tubular sizes (sarcoplasmic reticulum and T tubules). The mitochondrial size increased from 0.25 +/- 0.01 mu 2 (mean +/- SE) at baseline to 0.27 +/- 0.03 mu 2 (not significant [NS]) at 4 hours and 0.30 +/- 0.03 mu 2 (NS) at 24 hours. The tubular size increased from 2.24 +/- 0.13 x 10(4) nm2 at baseline to 2.60 +/- 0.26 x 10(4) nm2 (P less than 0.05) at 4 hours and 2.46 +/- 0.29 x 10(4) nm2 (NS) at 24 hours. Micrographs analyzed for nuclear changes showed nucleolar contraction and segregation of granular and fibrillar components. These changes were noted in five of ten patients at 4 hours and in eight of 13 patients at 24 hours. Serial echocardiographic and systolic time interval determinations of left ventricular function demonstrated a significant improvement at both 4 and 24 hours. In conclusion, doxorubicin has its most significant effect on tubular structures. Left ventricular function improved during this time despite these findings.

In order to determine and compare the pharmacodynamic responses to single and multiple dose prazosin therapy in cardiac failure, 14 patients with severe low-output heart failure underwent central and regional hemodynamic measurements after random placement in one of two prazosin dosing schedules. A single 5 mg oral dose of prazosin (Group A, no. = 7) significantly increased the cardiac index and stroke volume index while significantly decreasing systemic, pulmonary and pulmonary capillary wedge pressures and vascular resistances. Hepatic plasma flow and limb blood flow increased after the single dose. Striking attenuation of these hemodynamic effects occurred when the same dose was administered after 24 hours of pretreatment with oral prazosin, 2 mg every 8 hours (Group B, no. = 7). The plasma prazosin levels of the two groups, drawn 2 hours after administration, were 24.5 and 30.5 ng/ml, respectively. Repeated administration of prazosin in patients with congestive heart failure results in rapid attenuation of its beneficial central and regional hemodynamic effects. The usefulness of this vasodilator as a preload- and afterload-reducing agent in the clinical setting of chronic congestive heart failure may be limited by the development of pharmacodynamic tolerance.

The most recent patient in a 13-year experience with 14 patients suffering massive pulmonary thromboembolism requiring pulmonary thromboembolectomy is the focus of this report. This 40-year-old woman not only survived life-threatening acute hypoxemia and right heart failure, but was also found to have developed a unique transudative 700 cc pericardial effusion. Pulmonary artery pressure was 90/30 (mean 50 mmHg), accompanied by 17 mm right ventricular alternans. Systemic alternans and tamponade physiology were absent. This unusual natural model for acute right heart failure illustrates a novel mechanism for pericardial effusion physiology.

Ten nuclei from the endomyocardial biopsies for each of the following 32 patients were examined by electron microscopy: seven patients before and then four and 24 hours after treatment with first-dose doxorubicin; seven patients before and four and 24 hours after treatment with first-dose doxorubicin plus N-acetyl cysteine; nine patients with doxorubicin induced cardiomyopathy; and nine patients with idiopathic congestive cardiomyopathy. Five criteria were used to semiquantitatively compare nuclei and nucleoli from each group. The most dramatic changes in nuclear and nucleolar morphology were seen four hours after doxorubicin administration. Nucleoli were smaller, contracted or segregated and contained fewer fibrillar centers and a collapsed or fragmented nucleolonema. The addition of N-acetylcysteine to treatment did not alter these results. By 24 hours, nuclei had returned to the pre-treatment status. Long-term doxorubicin therapy produced increased chromatin clumping and slightly contracted nucleoli. The idiopathic congestive cardiomyopathic nuclei differed significantly from these doxorubicin cardiomyopathic nuclei in the decreased amount of chromatin clumping and the increase in fibrillar centers and nucleonema pattern. It is concluded from this study that: (1) doxorubicin markedly alters the morphology of the human myocardial nucleus and nucleolus four hours after treatment, but these changes diminish by 24 hours; (2) N-acetylcysteine treatment fails to prevent these changes; and (3) the nuclei and nucleoli of chronic doxorubicin-induced cardiomyopathy differ significantly from other congestive cardiomyopathies, but do resemble changes seen four hours after the first dose of doxorubicin.

Doxorubicin induced acute as well as chronic myocardial morphologic alterations. Twenty patients with normal cardiovascular function were randomized to 2 groups based on age and dose of doxorubicin. Group I received placebo 1 hour before doxorubicin administration; group II received acetylcysteine (N-acetyl-L-cysteine) (Nac) 1 hour before doxorubicin. Endomyocardial biopsies were performed at base line at 4 and 24 hours after doxorubicin administration. Biopsy tissue was viewed by electron microscopy, and stereoscopic techniques were used to determine tubular and mitochondrial area. The change of the tubular area was similar in the 2 groups, was maximum at 4 hours, and was proportionately spread throughout the cell. The mitochondrial swelling was also similar in the 2 groups and proportionate throughout the cell but was maximum at 24 hours. This study demonstrated that the acute doxorubicin-induced damage was diffuse and not prevented by Nac.

Two patients presented with severe left heart failure and large secundum atrial septal defects without severe pulmonary hypertension. The acute hemodynamic effects of two commonly used vasodilator agents, isosorbide dinitrate and hydralazine, are described. Although isosorbide dinitrate improved systemic forward cardiac output, it also increased left-to-right intracardiac shunting in both patients. On the other hand, hydralazine dramatically improved systemic toward output and concomitantly diminished left-to-right shunt flow in each patient (43 and 21 percent). The complexities of combined severe left ventricular failure and a large atrial septal defect with left-to-right shunting, and the importance of extensive hemodynamic monitoring at the time of pharmacologic intervention, are discussed.

Platelet function and prostaglandin activity were evaluated in nine patients with coronary artery disease undergoing percutaneous left anterior descending coronary artery angioplasty (PTCA) and compared to nine normal controls. Transcoronary measurements (arterial-coronary sinus) of platelet counts, mean platelet volume, platelet factor 4 (PF4), beta thromboglobulin, thromboxane (B2), and 6-keto-PGF 1 alpha were made. When compared to normal controls, the patients with coronary artery disease had higher circulating baseline levels of PF4 in the coronary sinus. There was no transcardiac production of any factor at baseline or immediately after infusion of nitroglycerin or performance of PTCA. These results suggest that PTCA does not grossly alter arachidonic acid metabolism or platelet activity.

The adenine nucleotide content of the human myocardium in the distribution of the left anterior descending coronary artery (LAD) was measured before and after saphenous vein bypass grafting. The purpose of the study were twofold: (1) to relate the level of adenosine triphosphate (ATP) before bypass grafting to the percent stenoses of the LAD and (2) to determine the benefit or lack of benefit of bypass grafting on ATP content. Eighteen patients with angiographically determined LAD lesions of 40% to 100% underwent bypass grafting with standard cardiopulmonary bypass and cardioplegia. Transmural needle biopsy specimens were obtained from the center of the area perfused by the LAD immediately before cross-clamping of the aorta and 30 minutes after reperfusion of the myocardium via the native LAD and the graft. The tissue was divided into thirds: The endocardial and epicardial thirds were analyzed for ATP by high-pressure liquid chromatography and the middle third was viewed by light microscopy. The percent narrowing of the LAD correlated well (r = -0.71) with the ratio of ATP to total adenine nucleotides (TAN) in the endocardium. Epicardial ATP did not correlate with the percent stenoses of the LAD. The endocardial ATP/TAN ratio increased in the group as a whole from 0.51 +/- 0.27 (mean +/- SD) to 0.64 +/- 0.26 (p less than 0.01) after bypass grafting, and this was most impressive in those eight patients with LAD lesions greater than 90% (0.32 +/- 0.20 before grafting to 0.60 +/- 0.29 after grafting, p less than 0.005). However, the epicardial ATP/TAN ratio decreased from 0.75 +/- 0.15 before grafting to 0.64 +/- 0.17 after grafting (p less than 0.05), and this decrease occurred regardless of the percent narrowing of the LAD. There was no difference in vacuolization between the pre-grafting and post-grafting biopsy specimens, and intramyocardial hemorrhage was not observed. This study has demonstrated a close relationship between the degree of LAD stenosis and endocardial ATP content. Also, the endocardium supplied by arteries with greater than 90% lesions had significantly increased ATP while the epicardium had decreased ATP content after bypass grafting.

This study assesses the effect of aging on human myocardial morphology. Fifteen patients, ranging in age from 28 to 75 with normal cardiac history, physical examination and noninvasive tests of left ventricular function, underwent right ventricular endomyocardial biopsy prior to cancer chemotherapy. Cell diameter, nuclear area and fibrosis were quantified by light microscopy. Semiquantitative methods of electron microscopy were used to grade lipofuscin deposition, tubular dilation, myofibrillar loss, folding of discs and lipid deposition. The results demonstrated that myocardial cell diameter correlated directly with age (r = 0.73, p less than 0.01) and systolic blood pressure (r = 0.51, p less than 0.05). Nuclear area (r = 0.76, p less than 0.01) and folded discs (r = 0.53, p less than 0.05), two signs of increased protein production also correlated with age. Lipid deposition (r = 0.40), tubular dilation (r = 0.31) and lipofuscin deposition (r = 0.20) increased with, but did not correlate significantly with age. Lipid deposition (r = 0.56, p less than 0.05) and tubular dilation (r = 0.43, p less than 0.05) did correlate with cell diameter. Thus, the aging myocardium is characterized by increased cell size and some degenerative changes.

Our purpose was to determine the effect of vasoactive intestinal polypeptide (VIP) on the cardiovascular system with special emphasis on coronary vascular effects. In section I, VIP was infused into six healthy and six cobalt-cardiomyopathic dogs at two infusion rates (0.02 and 0.05 micrograms/kg/min). Left ventricular end diastolic pressure and mean systemic pressure fell significantly in both groups. Heart rate rose in both, and maximum systolic dP/dt increased in the myopathic group. Cardiac output and regional blood flows were determined by serial left atrial injections of radioactive 15 +/- 3 mum (mean +/- SD) microspheres. In both groups, blood flow increased significantly to the esophagus, pancreas, atria, and ventricles and to the endocardial and epicardial regions of the left ventricular free wall. Blood flow to the brain decreased. In section II, VIP was infused intravenously at 0.1 micrograms/kg/min into six anesthetized dogs with coronary sinus flow, pulmonary artery, and systemic artery catheters inserted. Cardiac index rose from baseline (3.1 +/- 0.5 to 4.8 +/- 1.3 L/min/m2, P less than 0.005), as did coronary blood flow (90 +/- 25 to 159 +/- 54 ml/min, P less than 0.005) during the VIP infusion. Myocardial oxygen consumption rose from 14.1 +/- 3.9 to 19.8 +/- 5.4 ml/min (P less than 0.001), but the aorta-to-coronary sinus O2 difference decreased from 157 +/- 19 ml/L to 132 +/- 42 ml/L (P less than 0.05), and the percent O2 extracted from coronary blood also decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Dobutamine was given intravenously for three days to 38 patients with congestive cardiomyopathy. The patients were followed by serial determinations of functional class and by non-invasive measurements of left ventricular function-systolic time intervals (PEP/LVET) and echocardiogram (% delta D). The average PEP/LVET declined significantly (p < 0.001) at three days, four and nine weeks, and at 10 months after the discontinuation of dobutamine infusion. Also, 67% (20 of 30) of patients had improvement of the PEP/LVET by greater than -0.04 at seven days. Even two and six months after dobutamine, 58% (15 of 26) and 39% (seven of 18) were improved. Similarly, the % delta D was improved by at least 2% in 60% (18 of 30) at seven days and 55% (16 of 29) at four weeks. At two and six months, 50% (14 of 28) and 42% (10 of 24) were improved. Those patients who did not improve their FC were more likely (five of nine) to have left ventricular free wall thickness (by echocardiogram) less than 0.5 cm./M2. Those who responded usually (22 of 29) had a ventricular wall thickness greater than 0.5 cm./M2. Although the mechanism of the prolonged improvement after a three day infusion of dobutamine is not understood, this study suggests that dobutamine has a role in the therapy of chronic congestive heart failure.

We studied 30 patients with moderate-to-severe congestive heart failure in a double-blind, randomized, placebo-controlled trial to determine the acute and long-term effects of isosorbide dinitrate on clinical status and on resting and exercise hemodynamics. Seventeen patients received placebo and 13 isosorbide dinitrate. First-dose isosorbide dinitrate (40 mg orally) decreased resting and exercise pulmonary capillary wedge pressure, pulmonic and systemic arterial pressures and pulmonic and systemic vascular resistances without augmenting exercise capacity. Compared with placebo, chronic therapy with isosorbide dinitrate (40 mg orally every 6 hours for 12 weeks) significantly improved clinical status and exercise capacity. Resting and exercise systemic blood pressure and systemic vascular resistance returned to baseline values during chronic isosorbide dinitrate therapy, but pulmonary capillary wedge pressure, pulmonary artery pressure and pulmonary vascular resistance remained improved. In patients with congestive heart failure, 12 weeks of oral isosorbide dinitrate therapy improves resting and exercise hemodynamics, exercise capacity, and clinical status; tolerance develops to the systemic arterial vascular effects without attenuation of the venous and pulmonary vascular effects.

The purpose of this study was to identify the histologic characteristics of human myocardium in congestive heart failure (CHF) by cellular hypertrophy, nuclear area, endocardial thickness, and percentage of fibrosis and to correlate histologic findings to cause, severity, and duration of disease. Right ventricular endomyocardial biopsies from 109 patients were quantitatively analyzed. Ten patients with normal cardiac history, physical examination results, and cardiac function served as the control group. The remaining patients were divided into the following groups: those treated with doxorubicin (n = 18), and those with chest pain with normal coronary arteries (n = 8), familial CHF (n = 3), CHF associated with myotonic dystrophy (n = 3), peripartal CHF (n = 2), valvular CHF (n = 9), alcohol-induced CHF (n = 13), postviral CHF (n = 6), or idiopathic CHF (n = 36). Linear regression analyses showed a strong correlation between cell diameter and nuclear area (r = .70, p less than .001) and weaker correlations between amount of fibrosis and cell diameter (r = .30, p less than .005) and fibrosis and nuclear area (r = .29, p less than .005). Results of function studies and histologic measurements (e.g., echocardiographically measured change in the minor-axis dimension of the left ventricle with systole and cell diameter) correlated poorly (r = -.33, p less than .005). Duration of dyspnea did not correlate with any histologic factor. Within the normal group there was a direct correlation of cell diameter with age (r = .67, p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study is to investigate the validity of performing biochemical analyses on human endomyocardial biopsies. One problem of such analyses is the decay of metabolites between the time of biopsy and the analyses. This was addressed by varying the time delay from biopsy to submersion in liquid nitrogen (-200 degree C). Neither cyclic AMP or cyclic GMP changed significantly up to 90 seconds after biopsy. The reproducibility of the assays in human heart biopsies was determined by submitting paired samples from each procedure. The ATP content was determined by a fluorescent technique and was related to the protein and creatine content. The average ATP of 25 paired samples was 12.3 nm per mg protein; the average difference between the paired samples was -0.6, and the 95% confidence interval was 5.6 nm/mg protein. The average ATP-to-creatine ratio was 0.25; the 95% confidence interval was 0.12. The cyclic AMP and cyclic GMP were found to average 3.3 and 0.25 femtomoles/mcg protein, respectively. The 95% confidence intervals were 1.8 and 0.12 fmoles/mcg protein. The problems of sampling error and blood and connective tissue contamination decrease the reliability of the biochemical analyses. Reproducibility is adequate, however, to acquire meaningful biochemical information on the human heart.

Central and regional hemodynamic parameters were evaluated at baseline and following three months of placebo or hydralazine therapy (100 mg orally every eight hours) in 20 patients with idiopathic dilated cardiomyopathy. Both control (placebo) and hydralazine groups were comparable with respect to functional classification (New York Heart Association classes III and IV) and baseline hemodynamic variables. In the hydralazine group, cardiac index increased 25 percent (2.4 +/- 0.4 to 3.0 +/- 0.5 liters/minute/m2), renal blood flow increased 26 percent (648 +/- 199 to 815 +/- 229 ml/minute), and limb blood flow was augmented by 35 percent (6.8 +/- 3.0 to 9.2 +/- 4.6 ml/dl/minute) with long-term therapy. These changes were significant (all p less than 0.05) when compared with both baseline values and values in the control group. Both central and regional hemodynamic parameters remained unaltered in the control group. Long-term hydralazine therapy (three months) elicited a favorable circulatory response in this group of patients with chronic congestive heart failure. Central or regional hemodynamic tolerance to oral hydralazine failed to develop in the majority of patients.

Amrinone, 100 mg orally every 8 hours, was administered to 13 patients with moderate-to-severe congestive heart failure (CHF) for 1 month on an outpatient basis to determine the beneficial and undesirable effects of this new cardioactive agent in this clinical setting. These subjects received conventional CHF medications during the course of study. Ten patients who received conventional CHF medications alone served as a control group. Changes in functional classification were not significantly different between the 2 treatment groups. Amrinone augmented exercise capacity 37% above baseline compared with a 12% improvement for the control group. Noninvasive indexes of resting left ventricular function (echocardiography and systolic time intervals) did not change significantly for either group, nor was there a significant change in the exercise ejection fraction. All patients treated with amrinone had greater than or equal to 1 symptom-related or laboratory-detected adverse effect. An increase in the frequency of ventricular ectopic beats was noted at rest in 4 and with exercise in 6 patients (salvos of nonsustained ventricular tachycardia in 2). Six subjects treated with amrinone had gastrointestinal symptoms and 8 developed a viral-like illness. Other adverse effects noted in the amrinone-treated group included near-syncope, headaches, marked anxiety, chest pain, palpitations, maculopapular rash, hypokalemia, and elevation of serum transaminase levels. The control patients had significantly fewer adverse effects. Although individual patients with CHF may benefit from long-term amrinone therapy, the low benefit-to-risk-adverse effect ratio does not warrant widespread application of this drug in the outpatient management of CHF and requires caution when prescribing.

Forty-nine patients with idiopathic dilated cardiomyopathy (IDC) were evaluated to determine the hemodynamic and morphologic effects of vasodilator therapy. Hydralazine (225 mg/day, H), isosorbide dinitrate (160 mg/day, I), and combination H + I therapy were compared with placebo (P) at baseline and after 3 months of continuous therapy. Thirty-three randomly assigned patients completed the study. Hemodynamic parameters included the echocardiographic percent change of left ventricular diameter (% delta D), the systolic time intervals ratio of preejection period to left ventricular ejection time (PEP/LVET), the pulmonary capillary wedge pressure, mean pulmonary artery pressure, cardiac index, systemic vascular resistance, and pulmonary vascular resistance. An endomyocardial biopsy was performed at baseline and after 3 months; the myocardial cell diameter of 50 cells per biopsy was measured. During the 3-month study 5 patients died; there was not a significant difference among the groups in the number of deaths. The % delta D and PEP/LVET did not change in the P or I groups but did improve significantly from baseline in the H and H + I groups. The pulmonary capillary wedge and mean pulmonary artery pressures and the pulmonary vascular resistance did not change in the P or H groups but did decrease significantly in the I and H + I groups. The P and I groups did not have improvement in systemic vascular resistance or cardiac index, whereas the H group had a decrease in systemic vascular resistance and an increase in cardiac index from 2.5 +/- 0.4 to 3.1 +/- 0.4 liters/min/m2 (p less than 0.05). The H + I group also had a decrease in systemic vascular resistance; the cardiac index increased from 2.3 +/- 0.4 to 3.1 +/- 0.4 liters/min/m2 (p less than 0.01). Myocardial cell diameter did not change in the P or I group. Cell diameter of the H group decreased from 25.4 +/- 3.1 microns at baseline to 23.1 +/- 3.8 microns (p less than 0.05) after 3 months of continuous therapy. The H + I group decreased its cell diameter from 23.9 +/- 3.7 to 22.2 +/- 2.2 microns (p less than 0.05). Compared with P and H, patients treated with I alone or H + I had a significant reduction of preload. In contrast to P and I, H alone and H + I elicited improvement in parameters of inotropy and afterload, and this improvement was accompanied by a reduction in cell diameter. Chronic therapy of heart failure with H and H + I effects a persistent augmentation of cardiac function and improvement of myocardial cellular morphology.

Seven patients with severe congestive heart failure received amrinone i.v. (continuous infusions of 10, 20 and 40 micrograms/kg/min) and orally (1.5, 3.0 and 4.5 mg/kg) in order to determine the comprehensive acute hemodynamic response of this agent. Standard hemodynamic, echocardiographic and systolic time interval measurements were made before and sequentially after amrinone administration. Intravenous amrinone significantly increased cardiac index and stroke volume index, did not alter heart rate and significantly decreased pulmonary capillary wedge pressure, mean systemic blood pressure and systemic and pulmonary vascular resistances. The determinants of left ventricular inotropy, delta P/delta t, pre-ejection period index and velocity of circumferential fiber shortening were not affected by amrinone; dobutamine (5 and 10 micrograms/kg/min), used as an internal standard for inotropy, significantly improved these determinants. Except for a significant reduction in pulmonary capillary wedge pressure, first-dose oral amrinone effected little change in central hemodynamic variables and indices of ventricular inotropy; no additional changes occurred after the fifth dose. In the setting of severe chronic congestive heart failure, short-term iv infusions and oral administration of amrinone elicit only mild to moderate hemodynamic changes. Furthermore, these changes are a result of vasodilation (preload and afterload reduction) rather than positive inotropy.

16 normal subjects, ranging in age from 24 to 79 years, underwent simultaneous central and regional (renal, hepatic and limb) hemodynamic measurements; the purpose of this investigation was to determine the relationship between these measurements and age. Cardiac index was inversely related to age, with a correlation coefficient of -0.53 (p less than 0.05). Renal blood flow correlated inversely with age at an r value of -0.52 (p less than 0.05). Although the correlation coefficients did not achieve statistical significance, several trends were noted with increasing age: systemic vascular resistance, renal, hepatic and limb vascular resistances, and mean systemic blood pressure increase and hepatic and limb flows decrease. In normal human subjects, certain central and regional hemodynamic parameters change with age; these changes may ultimately influence function and perhaps, drug disposition (liver and kidney) as well.

Ten women with primary pulmonary hypertension had resting hemodynamic measurements taken before and after the nonparenteral administration of various vasodilators and prostaglandin inhibitors. Only sublingual isoproterenol, alone or combined with sublingual isosorbide dinitrate, effected a substantial (greater than 20%) drop in pulmonary vascular resistance; this decrease was accompanied by little change in pulmonary artery pressure. Isosorbide dinitrate was the only drug that elicited any reduction in pulmonary artery pressure; pulmonary vascular resistance decreased modestly. The oral administration of diazoxide, hydralazine, phentolamine, and tolazoline elicited little change in pulmonary artery pressure or resistance. Except for tolazoline, all these agents significantly decreased systemic blood pressure and resistance. Prostaglandin inhibition by indomethacin (acute and chronic dosing) increased pulmonary and systemic vascular resistances and reduced cardiac output. Aspirin combined with dipyridamole elicited no changes. The vasodilators and prostaglandin inhibitors studied evoked little improvement in resting pulmonary hemodynamic abnormalities in primary pulmonary hypertension.

Thirty patients with congestive heart failure underwent a double-blind study after randomization into either isosorbide dinitrate or placebo. The initial dose (40 mg orally) of isosorbide dinitrate reduced resting and exercise pulmonary artery, pulmonary capillary wedge, and systemic blood pressure and pulmonary and systemic vascular resistance without improving exercise tolerance. Chronic dosing (40 mg orally every 6 h for 3 months) increased exercise tolerance and maintained a reduction in resting and exercise pulmonary artery and pulmonary capillary wedge pressures and pulmonary resistance, while systemic pressure and resistance returned to baseline. Chronic oral isosorbide dinitrate (40 mg every 6 h) improves exercise capacity over a 3-month period with disparate tolerance effects on systemic arterial, systemic venous, and pulmonary vasculature.

The purpose of this study was to define the reproducibility of serial echocardiographic measurements of left ventricular size and function. Fourteen patients in stable condition after heart failure (Group I) had five weekly outpatient echocardiograms performed by a single technician with blinded interpretation. The average end-diastolic diameter (EDD) of all patients was 68 mm, with a mean standard deviation of 4 mm and a 95% confidence interval of 8 mm. The average end-systolic diameter (ESD) was 58 mm; the 95% confidence interval was 5.6%. A group of four patients with heart failure (Group II) had daily echocardiograms while undergoing continuous hemodynamic monitoring. Pulmonary capillary blood pressure and thermodilution cardiac outputs were stable throughout the 4-day study period. Daily morning echographic measurements were constant, with 95% confidence interval of the EDD being only 4 mm. The ESD and % delta D had 95% confidence intervals of 2 mm and 3.2%, respectively. The narrow range of measurements (narrow confidence intervals) demonstrates the excellent reproducibility of these echocardiographic parameters.

A 51 year old woman sustained ventricular fibrillation while receiving perphenazine and protriptyline. After successful resuscitation and clinical stabilization, cardiac electrophysiologic studies were performed before and after the administration of each of these medications. Perphenazine widened the ventricular echo zone and facilitated induction of short salvoes of ventricular tachycardia (repetitive ventricular response). Protriptyline also widened the ventricular echo zone and allowed easy induction of long runs of ventricular tachycardia. Both psychotropic agents increased the incidence of ventricular dysrhythmias in this patient. The electrophysiologic study is a useful technique in determining the interaction between psychotropic drugs and life-threatening arrhythmias; it may provide a means of identifying the patients with cardiac disease in whom administration of these agents may be fatal.

Central and regional hemodynamic studies were performed before and after the oral administration of 75 mg of hydralazine and/or 20 mg of isosorbide dinitrate in 15 patients with low-output congestive heart failure. Hydralazine increased mean cardiac output 17-25%, mean renal blood flow 19%, and limb blood flow 17% (all p < 0.05). Mean hepatic blood flow did not change significantly with hydralazine. Except for a small increase in cardiac output (6%, p < 0.05) at 30 minutes, isosorbide dinitrate did not significantly alter central, renal, hepatic or limb blood flow. Combining isosorbide dinitrate and hydralazine effected similar increases in cardiac output (17-24%, p < 0.05), renal (17%, p < 0.05) and limb (20%, p < 0.05) blood flow as those elicited by hydralazine alone. The combination did not significantly alter mean hepatic blood flow. Hydralazine, alone or combined with isosorbide dinitrate, increases renal and limb blood flow in congestive heart failure in proportion to the augmented cardiac output; isosorbide dinitrate alone does not alter blood flow to these regions. Neither drug (or combination) changes hepatic blood flow in this clinical setting.

This study was designed to validate the use of combined invasive and noninvasive methods in assessing serial pressure-volume relations in man. Ten patients undergoing cardiac catheterization were studied with simultaneous intracardiac micromanometer pressure recordings, gated radionuclide angiography and echocardiography. Systolic and diastolic function were measured at rest, during right atrial pacing rates of 100 and 120 beats/min and after nitroglycerin administration. Right atrial pacing studies (rate of 100 beats/min) were performed in duplicate to determine the reproducibility of the method. At the conclusion of each study, the model was validated with contrast angiography. Good reproducibility was evident when measuring the maximum and average filling and ejection rates, time to peak filling rate, ejection fraction, the modulus of chamber stiffness, the time course of left ventricular relaxation, global average stress and ventricular work indexes using the model described above. These data were not significantly different (p greater than 0.05) from comparable data obtained from contrast angiography. Right atrial pacing and nitroglycerin administration resulted in predictable alterations in the pressure-volume loop and in the systolic and diastolic measurements. The maximum and average filling rates, ejection rates and time to peak filling rate appeared to be heart rate-dependent variables. By combining available invasive and noninvasive methods, accurate pressure-volume relationships can be determined. Because the method we tested provides accurate volumetric and timing measurements for cardiac events and does not alter hemodynamics, it may be useful for obtaining serial assessments of the pressure-volume relationship in man.

Dobutamine is a new inotropic agent that may induce prolonged clinical improvement in patients with congestive cardiomyopathy. Sixteen patients with severe heart failure but without obstructive coronary disease were studied by serial functional class determinations and by noninvasive measurements of left ventricular function before and after bedrest control period and then after a 3-day infusion of dobutamine. An endomyocardial biopsy procedure was performed on 11 patients before and after the bedrest and on all 16 patients before and after dobutamine. Quantitative ultrastructural analysis of the biopsies was performed on electron micrographs (31,200 X) by a grid technique. The number of electron dense particles per 100 mitochondria did not change after bedrest but there was a significant decrease from 84 +/- 14 to 65 +/- 12 (P < .005) in the pre- to postdobutamine biopsies. The cristae to matrix ratio of the mitochondria did not change with bedrest but improved from 0.37 +/- 0.04 to 0.47 +/- 0.05 (P < .02) after dobutamine. The average mitochondrial size did not change significantly in the bedrest control nor in the dobutamine biopsy samples. However, when the 16 patients were divided into those who had a good clinical response (by functional class and noninvasive measurements of left ventricular function) and those who had no or little response, the 10 responders did decrease their average mitochondria size from 0.26 +/- 0.03 mu 2 to 0.23 +/- 0.02 mu 2 (P < .02). The mechanism by which a 3-day infusion of dobutamine induces a prolonged clinical improvement is not well understood. The use of quantitative ultrastructural technique in this study has demonstrated that there is a morphologic basis to the improvement.