bluuebunny/crossref_metadata_2025 huggingface dataset:
Relative roles of Ca2(+)-dependent and Ca2(+)-independent mechanisms in hypoxic contractile dysfunction.
Authors: Koretsune Y , Marban E
Published: June 2011

Contractile function is known to be impaired during hypoxia or metabolic inhibition, but the relative importance of activator Ca2+ deficiency compared with the accumulation of depressant metabolites remains controversial. To distinguish between these possibilities, we used nuclear magnetic resonance (NMR) spectroscopy to measure the most likely mediators--intracellular [Ca2+] [( Ca2+]i), inorganic phosphate concentration [( Pi]), and pH--before and during hypoxia in perfused ferret hearts. Ca2+ transients were quantified by gated fluorine-19 NMR spectroscopy. Left ventricular developed pressure decreased to steady-state levels approximately 60% of control values after 20 minutes of hypoxic perfusion (induced by equilibrating the perfusate with 10% O2-90% N2). With hypoxia, phosphorus NMR revealed an increase in [Pi] and a mild intracellular acidosis. Both [Pi] and intracellular pH correlate well with the extent of decline of developed pressure in each heart, but multiple regression analysis points to the changes in [Pi] as the dominant influence. In contrast, [Ca2+]i at end diastole was not influenced by hypoxia, whereas the peak systolic values were paradoxically increased. The ratio of Ca2+ transient amplitude in hypoxia to that in control had no correlation with percent of developed pressure. These findings indicate that contractile failure during relatively mild, steady-state hypoxia is not due to a critical failure of any of the mechanisms that regulate cytoplasmic activator Ca2+. Instead, the accumulation of Pi (and to a lesser degree, H+) mediates hypoxic contractile dysfunction.
Myocardial protection with preconditioning.
Authors: Li G C , Vasquez J A , Gallagher K P , Lucchesi B R
Published: June 2011

Myocardial preconditioning with brief coronary artery occlusions before a sustained ischemic period is reported to reduce infarct size. To determine the number of occlusive episodes required to produce the preconditioning effect, we performed single or multiple occlusions of the left circumflex coronary artery (LCx) followed by a sustained occlusion (60 minutes) of the LCx. Anesthetized dogs underwent one (P1), six (P6), or 12 (P12) 5-minute occlusions of the LCx. Each occlusion period was followed by a 10-minute reperfusion period. A 60-minute occlusion of the LCx followed the preconditioning sequences. A control group received a 60-minute occlusion of the LCx without preconditioning. All groups were subjected to 6 hours of reperfusion after which the heart was removed for calculating infarct size (IS), area at risk (AR), and left ventricular mass (LV). The IS/AR ratio for the control group was 29.8 +/- 4.4% (n = 17), which was substantially greater (p less than 0.001) than that of the preconditioned groups: P1, 3.9 +/- 1.3% (n = 14); P6, 0.4 +/- 0.3% (n = 5); and P12, 2.9 +/- 2.8% (n = 5). There were no significant differences in the IS/AR ratio among the three preconditioned groups. The AR/LV ratio was comparable among all groups and did not differ statistically: control, 40.4 +/- 1.3%; P1, 36.2 +/- 1.7%; P6, 36.1 +/- 1.7%; and P12, 37.3 +/- 2.1%. Collateral blood flow to the inner two thirds of the risk region determined with radiolabeled microspheres during ischemia did not differ significantly between the control group (0.03 +/- 0.01 ml/min/g, n = 8) and single occlusion group (0.06 +/- 0.02 ml/min/g, n = 8), indicating that the marked disparity in infarct size could not be attributed to differences in collateral blood flow. The data indicate that preconditioning with one brief ischemic interval is as effective as preconditioning with multiple ischemic periods.
Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. TAMI Study Group.
Authors: Ohman E M , Califf R M , Topol E J , Candela R , Abbottsmith C , Ellis S , Sigmon K N , Kereiakes D , George B , Stack R
Published: June 2011

To determine the clinical consequences of reocclusion of an infarct-related artery after reperfusion therapy, we evaluated 810 patients with acute myocardial infarction. Patients were admitted into four sequential studies with similar entry criteria in which patency of the infarct-related artery was assessed by coronary arteriography 90 minutes after onset of thrombolytic therapy. Successful reperfusion was established acutely in 733 patients. Thrombolytic therapy included tissue-type plasminogen activator (t-PA) in 517, urokinase in 87, and a combination of t-PA and urokinase in 129 patients. All patients received aspirin, intravenous heparin and nitroglycerin, and diltiazem during the recovery phase. A repeat coronary arteriogram was performed in 88% of patients at a median of 7 days after the onset of symptoms. Reocclusion of the infarct-related artery occurred in 91 patients (12.4%), and 58% of these were symptomatic. Angiographic characteristics at 90 minutes after thrombolytic therapy that were associated with reocclusion compared with sustained coronary artery patency were right coronary infarct-related artery (65% versus 44%, respectively) and Thrombolysis in Myocardial Infarction (TIMI) flow 0 or 1 (21% versus 10%, respectively) before further intervention. Median (interquartile value) degree of stenosis in the infarct-related artery at 90 minutes was similar between groups: 99% for reoccluded (value, 90/100%) compared with 95% for patent (value, 80/99%). Patients with reocclusion had similar left ventricular ejection fractions compared with patients with sustained patency at follow-up. However, patients with reocclusion at follow-up had worse infarct-zone function at -2.7 (value, -3.2/-1.8) versus -2.4 (SD/chord) (value, -3.1/-1.3) (p = 0.016). The recovery of both global and infarct-zone function was impaired by reocclusion of the infarct-related artery compared with maintained patency; median delta ejection fraction was -2 compared with 1 (p = 0.006) and median delta infarct-zone wall motion was -0.10 compared with 0.34 SD/chord (p = 0.011), respectively. In addition, patients with reocclusion had more complicated hospital courses and higher in-hospital mortality rates (11.0% versus 4.5%, respectively; p = 0.01). We conclude that reocclusion of the infarct-related artery after successful reperfusion is associated with substantial morbidity and mortality rates. Reocclusion is also detrimental to the functional recovery of both global and infarct-zone regional left ventricular function. Thus, new strategies in the postinfarction period need to be developed to prevent reocclusion of the infarct-related artery.
Left ventricular ejection performance, wall stress, and contractile state in aortic regurgitation before and after aortic valve replacement.
Authors: Taniguchi K , Nakano S , Kawashima Y , Sakai K , Kawamoto T , Sakaki S , Kobayashi J , Morimoto S , Matsuda H
Published: June 2011

Left ventricular ejection performance, wall stress, and contractile state were evaluated in 35 patients with chronic aortic regurgitation. Cineangiography and pressure measurements were obtained before and a mean of 26 months after aortic valve replacement, and data were compared with those from 30 normal control subjects. The relation between quantitative changes in wall stress and changes in ejection fraction after surgery was determined. Preoperatively, end-systolic stress was elevated in patients with aortic regurgitation (218 +/- 45 vs. 160 +/- 23 kdynes/cm2 [mean +/- SD] for control subjects, p less than 0.01), and ejection fraction was depressed (0.46 +/- 0.11 vs. 0.65 +/- 0.05, p less than 0.01). End-systolic stress decreased postoperatively (151 +/- 41 kdynes/cm2, p less than 0.01) and ejection fraction increased (0.58 +/- 0.11, p less than 0.01). The magnitude of increase in ejection fraction correlated significantly and negatively (r = -0.65) with the quantitative change in end-systolic stress after surgery. Contractile function, as assessed by the ejection phase index-end-systolic stress relation, did not significantly change: 23 of 35 patients preoperatively and 18 of 35 patients postoperatively had values that clearly fell below the 95% confidence limit of the ejection fraction-end-systolic stress relation for controls. After surgery, individual ejection fraction-end-systolic stress relationships demonstrated a shift parallel to the regression curve for the control subjects. Moreover, persistent postoperative left ventricular hypertrophy was significantly associated with persistent contractile dysfunction. Thus, late improvement in left ventricular ejection performance after aortic valve replacement can be attributed to the reduction in end-systolic stress. Contractile function itself was not improved by surgery. Persistent postoperative hypertrophy may be a marker for myocardial contractile dysfunction.
Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension.
Authors: Eisenberg P R , Lucore C , Kaufman L , Sobel B E , Jaffe A S , Rich S
Published: June 2011

Although the mechanisms involved in the pathophysiology of primary pulmonary hypertension have not yet been delineated, thrombosis has been implicated. This study was designed to determine whether thrombin activity as reflected by plasma concentrations of fibrinopeptide A (FPA), a marker of the action of thrombin on fibrinogen, is increased in patients with primary pulmonary hypertension. To evaluate fibrinolytic activity, we measured plasma concentrations of tissue-type plasminogen activator, plasminogen activator inhibitor-1, and cross-linked fibrin degradation products. We studied 31 patients with primary pulmonary hypertension. Plasma FPA concentrations measured by radioimmunoassay, were elevated to 87.4 +/- 36.9 ng/ml (mean +/- SEM). Fifteen minutes after administration of heparin (5,000 U), FPA concentrations decreased to 6.8 +/- 1.4 ng/ml (p less than 0.001 compared with preheparin levels). In 21 of 30 patients (70%), FPA concentrations after heparin administration were less than half the preheparin levels, a response consistent with inhibition of thrombin by heparin and the short half-life of FPA. Despite evidence for marked thrombin activity, plasma concentrations of cross-linked fibrin degradation products were normal in all but four patients. Plasminogen activator inhibitor-1 activity was elevated in 19 of the 27 patients in whom it was measured, potentially limiting the fibrinolytic response. The elevations of FPA indicate that thrombin activity is increased in vivo in patients with primary pulmonary hypertension. Thus, sequential assays of plasma markers of thrombosis and fibrinolysis in vivo may help identify those patients who may benefit from treatment with anticoagulants.
Activation and decreased deformability of neutrophils after intermittent claudication.
Authors: Neumann F J , Waas W , Diehm C , Weiss T , Haupt H M , Zimmermann R , Tillmanns H , Kübler W
Published: June 2011

This study investigated local alterations in neutrophil activation and deformability after intermittent claudication. In 17 patients with one-sided peripheral arterial occlusive disease, neutrophil count, proportion of activated neutrophils (by nitro blue tetrazolium test), and neutrophil filterability as a measure of passive deformability were assessed in the femoral arterial and venous blood of the diseased leg and in the femoral venous blood of the healthy leg (n = 10). The values were obtained at rest, immediately after claudication, and 10 minutes after claudication induced by repetitive toe stands. Immediately after exercise, the arterial and venous blood differences in the diseased leg were 1) neutrophil count, 9% (95% confidence interval [CI], 5-14%; relative increase in the venous blood compared with arterial blood); 2) the proportion of activated neutrophils, 26% (CI, 10-42%); and 3) the neutrophil filterability, -10% (CI, -4% to -15%). At rest and 10 minutes after exercise, neutrophil parameters did not differ significantly between the femoral arterial and venous blood. Furthermore, no arterial and venous blood differences in the neutrophil parameters were found in the healthy leg. In addition to local changes, systemic changes occurred immediately after exercise. In the femoral arterial blood, the total neutrophil count had risen by 13% (CI, 8-18%), the proportion of activated neutrophils had risen by 41% (CI, 25-58%), and average neutrophil rigidity had risen 17% (CI, 11-22%) compared with the values obtained before exercise. At 10 minutes after exercise, all neutrophil parameters were still elevated. We conclude that even short periods of ischemia, as in intermittent claudication, cause local alterations in neutrophil function and distribution.
Recurrent pericarditis. Relief with colchicine.
Authors: Guindo J , Rodriguez de la Serna A , Ramió J , de Miguel Diaz M A , Subirana M T , Perez Ayuso M J , Cosín J , Bayés de Luna A
Published: June 2011

Recurrence is one of the major complications of pericarditis. Treatment of recurrence is often difficult, and immunosuppressive drugs or surgery may be necessary. We conducted an open-label prospective study of nine patients (seven men and two women; age, 18-64 years; mean age, 41.7 +/- 13.7 years). Patients were treated with colchicine (1 mg/day) to prevent recurrences. All patients had suffered at least three relapses despite treatment with acetylsalicylic acid, indomethacin, prednisone, or a combination. Pericarditis was classified as idiopathic in five patients, postpericardiotomy in two, post-myocardial infarction in one, and associated with disseminated lupus erythematosus in one. For statistical analysis, we conducted a paired comparison design (Student's t test). All patients treated with colchicine responded favorably to therapy. Prednisone was discontinued in all patients after 2-6 weeks (mean, 26.33 +/- 10.9 days), and colchicine alone was continued. After a mean follow-up of 24.3 months (minimum, 10 months; maximum, 54 months), no recurrences were observed in any patient; there was a significant difference between the symptom-free periods before and after treatment with colchicine (p less than 0.002). Our study suggests that colchicine may be useful in avoiding recurrence of pericarditis, although these results need to be confirmed in a larger, double-blind study.
Failed elective percutaneous transluminal coronary angioplasty requiring coronary artery bypass surgery. In-hospital and late clinical outcome at 5 years.
Authors: Talley J D , Weintraub W S , Roubin G S , Douglas J S , Anderson H V , Jones E L , Morris D C , Liberman H A , Craver J M , Guyton R A
Published: June 2011

This study was performed to define the in-hospital and late clinical outcome at 5 years in 430 patients who had a failed elective percutaneous transluminal coronary angioplasty (PTCA) and underwent coronary artery bypass graft (CABG) surgery during their hospitalization. This group comprised 5.9% of 7,246 patients undergoing elective PTCA. CABG surgery was performed in 346 patients with ongoing myocardial ischemia (80.5%) and in 84 patients without ischemia (19.5%). Their mean age was 56 +/- 9 years, and 76.3% were male. One-vessel disease was present in 72.3%, and the mean left ventricular ejection fraction was 59 +/- 11%. Overall, 1.9 +/- 0.9 bypass grafts were placed. There was increased use of the internal thoracic artery in the nonischemic group. A new nonfatal postprocedural Q wave myocardial infarction occurred in 21.2% and occurred more frequently in the ischemic (25.4%) than in the nonischemic (3.6%) group (p less than 0.0001). There were six in-hospital deaths (1.4%), an incidence that did not differ between the two groups. Follow-up was 99.8% complete. There were 25 deaths (93.2 +/- 1.5%, 5-year survival), including 16 of cardiac cause (95.3 +/- 1.3%, 5-year cardiac survival). Q wave myocardial infarction occurred in 111 patients (91 in-hospital), and freedom from cardiac death or nonfatal myocardial infarction at 5 years was 71 +/- 3%. In the group going to CABG surgery with ongoing ischemia, the 5-year cardiac survival was 94.9 +/- 1.6%, and in the group without ischemia, the corresponding survival was 96.2 +/- 2.2%. By multivariate analysis, the presence of preoperative myocardial ischemia, pre-PTCA diameter stenosis less than 90%, and the presence of multiple-vessel disease correlated with the occurrence of cardiac death or nonfatal myocardial infarction at 5 years. At this large-volume center with extensive PTCA operator and surgical experience, the excellent survival and low event rates over 5 years support the concept that despite the failed elective PTCA procedure, there was little effect on long-term survival provided the patient underwent prompt successful surgical revascularization.
Relation between steady-state force and intracellular [Ca2+] in intact human myocardium. Index of myofibrillar responsiveness to Ca2+.
Authors: Gwathmey J K , Hajjar R J
Published: June 2011

A novel approach was developed allowing the measurement of steady-state force and intracellular calcium concentration ([Ca2+]i) in tetanized human ventricular trabeculae carneae without pharmacological intervention. We compared and contrasted three methods of assessing calcium sensitivity of the myofilaments: 1) force-[Ca2+] relations in skinned fiber preparations, 2) peak twitch force-peak [Ca2+]i relations, and 3) steady-state force-[Ca2+]i relations in intact muscles. Steady-state contractile activation was achieved rapidly by tetanizing intact human trabeculae, loaded with aequorin, a Ca2(+)-sensitive bioluminescent protein, at a stimulation frequency of 15-20 Hz. Steady-state force and [Ca2+]i were measured during tetani, and the force versus [Ca2+]i relation was obtained by varying the extracellular calcium concentration ([Ca2+]o). Force-[Ca2+]i relations obtained from control and myopathic hearts were fitted to the Hill equation: %Force = [Ca2+]inh/([Ca2+]inh50% + [Ca2+]inh), where nh is the Hill coefficient, and [Ca2+]50% is the [Ca2+] required for 50% activation. The curves of tetani had Hill coefficients of 5.21 +/- 0.20 (n = 6) and 5.61 +/- 0.60 (n = 10) and [Ca2+]50% of 0.56 +/- 0.05 microM (n = 6) and 0.54 +/- 0.09 microM (n = 10) in control and myopathic muscles, respectively. We also constructed peak force-peak [Ca2+]i relations using isometric twitches from the same muscles. These curves were shifted toward higher [Ca2+]i compared with the steady-state force-[Ca2+]i curve derived from tetani. Ryanodine (1 microM), which increased the time course of the Ca2+ and force transients, shifted the peak force-peak [Ca2+]i relation to the left, without affecting the steady-state force-[Ca2+]i relation. Exposure to 10 mM caffeine shifted the steady-state force-[Ca2+]i relation to the left, whereas exposure to 3 microM isoproterenol shifted this relation to the right. Experiments using skinned fiber preparations were performed in parallel with experiments on intact muscles from the same hearts. The force-pCa (-log[Ca2+]) relations in saponin-skinned trabeculae from control and myopathic tissue were superimposable. Ryanodine (1 microM) had no effect on the force-pCa relation in skinned fibers. Maximal tension was evoked by the posttetanic twitch, which was larger than the tetanus. This potentiation was abolished in the presence of ryanodine, a sarcoplasmic reticulum inhibitor. We propose that the changes in the steady-state force-[Ca2+]i relations are correlated with alterations in the sensitivity of the myofilaments to Ca2+, whereas changes in the peak force-peak [Ca2+]i relations represent temporal changes in the twitch transient.(ABSTRACT TRUNCATED AT 400 WORDS)
Pathophysiology of silent myocardial ischemia during daily life. Hemodynamic evaluation by simultaneous electrocardiographic and blood pressure monitoring.
Authors: Deedwania P C , Nelson J R
Published: June 2011

The role of myocardial oxygen demand in the genesis of silent myocardial ischemia was evaluated by measuring the heart rate and blood pressure changes preceding the silent ischemic events during daily life in 25 men with proven coronary artery disease. Simultaneous 24-48-hour ambulatory electrocardiographic and blood pressure monitoring were performed during unrestricted daily activities. Of the 92 transient ischemic events recorded during monitoring, 85 (92%) were silent. Sixty-one percent of the silent events were preceded by an increase in the heart rate of 5 beats/min or more. Seventy-three percent of the silent ischemic events showed an average increase of 10 mm Hg in systolic blood pressure within 6 minutes preceding the onset of ST segment depression. The silent ischemic events showed a circadian pattern with a high density (34% of total events) between 6:00 AM and noon. The increase in heart rate and blood pressure paralleled the increase in silent ischemic events during these hours. These results showing significant (p less than 0.001 for both) increases in heart rate and blood pressure preceding a majority of silent ischemic events suggest that increase in myocardial oxygen demand plays a significant role in the genesis of silent ischemia. This pathophysiological mechanism has important therapeutic implications.
Altered myocardial perfusion in patients with angina pectoris or silent ischemia during exercise as assessed by quantitative thallium-201 single-photon emission computed tomography.
Authors: Mahmarian J J , Pratt C M , Cocanougher M K , Verani M S
Published: June 2011

The extent of abnormally perfused myocardium was compared in patients with and without chest pain during treadmill exercise from a large, relatively low-risk consecutive patient population (n = 356) referred for quantitative thallium-201 single-photon emission computed tomography (SPECT). All patients had concurrent coronary angiography. Patients were excluded if they had prior coronary angioplasty or bypass surgery. Tomographic images were assessed visually and from computer-generated polar maps. Chest pain during exercise was as frequent in patients with normal coronary arteries (12%) as in those with significant (greater than 50% stenosis) coronary artery disease (CAD) (14%). In the 219 patients with significant CAD, silent ischemia was fivefold more common than symptomatic ischemia (83% versus 17%, p = 0.0001). However, there were no differences in the extent, severity, or distribution of coronary stenoses in patients with silent or symptomatic ischemia. Our major observation was that the extent of quantified SPECT perfusion defects was nearly identical in patients with (20.9 +/- 15.9%) and without (20.5 +/- 15.6%) exertional chest pain. The sensitivity for detecting the presence of CAD was significantly improved with quantitative SPECT compared with stress electrocardiography (87% versus 65%, p = 0.0001). Although scintigraphic and electrocardiographic evidence of exercise-induced ischemia were comparable in patients with chest pain (67% versus 73%, respectively; p = NS), SPECT was superior to stress electrocardiography for detecting silent myocardial ischemia (52% versus 35%, respectively; p = 0.01). The majority of patients in this study with CAD who developed ischemia during exercise testing were asymptomatic, although they exhibited an angiographic profile and extent of abnormally perfused myocardium similar to those of patients with symptomatic ischemia. The prognostic significance of quantified perfusion defects detected by SPECT remains to be assessed.
Doppler assessment of right ventricular filling in a normal population. Comparison with left ventricular filling dynamics.
Authors: Zoghbi W A , Habib G B , Quinones M A
Published: June 2011

To examine whether alterations in right ventricular filling dynamics occur with increasing age and to compare right and left ventricular filling in normal subjects, pulsed Doppler echocardiographic studies were performed at the tricuspid and mitral anuli in 50 normal volunteers (23 males and 27 females) with an age range of 5-66 years. An age-related decrease in peak early filling velocity, increase in peak late velocity, and augmentation in the late/early ratio of peak velocities at the tricuspid anulus were observed (r = -0.68, 0.63, and 0.84, respectively). Significant correlations were also found between age and first third, first half, and atrial filling fractions (r = -0.60, -0.72, and 0.69, respectively). Weaker relations were observed between heart rate and Doppler-derived diastolic parameters (r = 0.18-0.54). Right ventricular filling indexes related significantly to those of the left ventricle (r = 0.58-0.88), the best being for the late/early ratio of peak velocities. With inspiration, an increase in early and late right ventricular filling occurred, whereas a reduction in filling occurred in the left ventricle. Thus, careful consideration for age, heart rate, and respiration is necessary in examining the effect of disease states or therapeutics on the filling dynamics of either the right or left ventricle.
Determination of transmural location of onset of activation from cardiac surface electrograms.
Authors: Burgess M J , Lux R L , Ershler P R , Menlove R
Published: June 2011

Methods of estimating depth of origin of ventricular activation from cardiac surface electrograms were evaluated in experiments on eight dogs. The ventricles were paced via multielectrode needle arrays placed transmurally in from four to six locations in the wall of the left ventricle. A multiplexed data-recording system was used to simultaneously record from 64 unipolar cardiac surface electrodes during pacing at each multielectrode needle site. The four indexes evaluated were the maximum and average gradients of activation isochrones around the site of earliest epicardial activation, the QRS area at the site of earliest epicardial activation, the interval between the QRS onset computed from all 64 epicardial surface electrograms, and the time of the minimum dV/dt in the electrogram displaying the earliest epicardial activation time (t(ee)-t(rmso) interval). Correlation coefficients between depth of stimulation and average and maximum gradients of isochrones, QRS area at the site of earliest epicardial activation, and t(ee)-t(rmso) interval were 0.985 or higher. These methods, particularly those involving gradients of isochrones, should be useful for evaluating electromaps of patients undergoing surgery for ablation of tachyarrhythmias.
Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD).
Authors: Francis G S , Benedict C , Johnstone D E , Kirlin P C , Nicklas J , Liang C S , Kubo S H , Rudin-Toretsky E , Yusuf S
Published: June 2011

Neuroendocrine activation is known to occur in patients with congestive heart failure, but there is uncertainty as to whether this occurs before or after the presence of overt symptoms. In the Studies of Left Ventricular Dysfunction (SOLVD), a multicenter study of patients with ejection fractions of 35% or less, we compared baseline plasma norepinephrine, plasma renin activity, plasma atrial natriuretic factor, and plasma arginine vasopressin in 56 control subjects, 151 patients with left ventricular dysfunction (no overt heart failure), and 81 patients with overt heart failure before randomization. Median values for plasma norepinephrine (p = 0.0001), plasma atrial natriuretic factor (p less than 0.0001), plasma arginine vasopressin (p = 0.006), and plasma renin activity (p = 0.03) were significantly higher in patients with left ventricular dysfunction than in normal control subjects. Neuroendocrine values were highest in patients with overt heart failure. Plasma renin activity was normal in patients with left ventricular dysfunction without heart failure who were not receiving diuretics and was significantly increased (p less than 0.05) in patients on diuretic therapy. We conclude that neuroendocrine activation occurs in patients with left ventricular dysfunction and no heart failure. Neuroendocrine activation is further increased as overt heart failure ensues and diuretics are added to therapy.
Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group.
Authors: Swedberg K , Eneroth P , Kjekshus J , Wilhelmsen L
Published: June 2011

There is a varying hormonal activation in heart failure. To be able to evaluate this activation and relate it to prognosis, we took blood samples at baseline and after 6 weeks from 239 patients with severe heart failure (all in New York Heart Association class IV) randomized to additional treatment with enalapril or placebo. In this study (CONSENSUS), which has previously been reported, there was a significant reduction in mortality among patients treated with enalapril. The present data show in the placebo group a significant positive relation between mortality and levels of angiotensin II (p less than 0.05), aldosterone (p = 0.003), noradrenaline (p less than 0.001), adrenaline (p = 0.001), and atrial natriuretic factor (p = 0.003). A similar relation was not observed among the patients treated with enalapril. Significant reductions in mortality in the groups of patients treated with enalapril were consistently found among patients with baseline hormone levels above median values. There were significant reductions in hormone levels from baseline to 6 weeks in the group of patients treated with enalapril for all hormones except adrenaline. There were no correlations between these changes in hormone levels. Summarily, there is a pronounced but variable neurohormonal activation in heart failure even in patients with similar clinical findings. This activation is reduced by enalapril therapy. The results suggest that the effect of enalapril on mortality is related to hormonal activation in general and the renin-angiotensin system in particular.
Excretion of thromboxane A2 and prostacyclin metabolites before and after exercise testing in patients with and without signs of ischemic heart disease.
Authors: Wennmalm A , Nowak J , Bjurö T
Published: June 2011

We addressed the hypothesis that platelets are not activated in association with effort-induced myocardial ischemia in stable coronary disease. Seventy-two patients undergoing a diagnostic bicycle exercise test were stratified according to the development of chest pain (yes/no, 33/39) and of exercise-induced ST-segment depression of at least 200 microV in the electrocardiogram (yes/no, 12/60). Noninvasive indexes of platelet activation and of platelet/vessel wall interaction (urinary excretion of the 2,3-dinor-metabolites of thromboxane A2 [Tx-M] and prostacyclin [PGI-M], respectively) were analyzed in samples collected in the basal state and after the test. Basal Tx-M and PGI-M did not differ in patients with (236 +/- 35 and 131 +/- 22 pg/mg creatinine, respectively) and without (185 +/- 16 and 101 +/- 13 pg/mg creatinine, respectively) chest pain, or in those with (178 +/- 45 and 162 +/- 41 pg/mg, respectively) and without (216 +/- 22 and 104 +/- 11 pg/mg, respectively) ST-segment depression during the test. Patients without chest pain or without ST-segment depression moderately increased (p less than 0.05) their urinary Tx-M (by 21% and 13%, respectively) and PGI-M (by 28% and 23%, respectively) after exercise. No significant increases were observed in those developing chest pain or ST depression during exercise. These data indicate that effort-induced myocardial ischemia is not associated with an increase in platelet activation or platelet/vessel wall interaction in patients with stable coronary disease.
Optimizing the exercise test for pharmacological investigations.
Authors: Myers J , Froelicher V F
Published: June 2011

Exercise trials in cardiology are often hindered by inconsistent approaches to exercise testing. These inconsistencies include the choice of exercise protocol, exercise end points, points of analysis, and absence or misuse of gas exchange data. Gas exchange techniques greatly enhance the accuracy with which cardiopulmonary function is assessed by exercise. Commonly used protocols are not always appropriate for all patients or all studies. Both cardiovascular disease and the exercise protocol can have an important impact on the relation between changes in work rate and oxygen uptake. Ramp protocols appear to offer the greatest promise for assessing cardiopulmonary function. Analyzing hemodynamic and gas exchange responses at several points submaximally, in addition to those at peak exercise, can add important information concerning the efficacy of a drug. A great deal of confusion continues to hinder the application of the gas exchange anaerobic threshold, and many of the commonly used testing end points are not reliable.
Comparison of propranolol, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential effects on ambulatory ischemia, exercise performance, and anginal symptoms. The ASIS Study Group.
Authors: Stone P H , Gibson R S , Glasser S P , DeWood M A , Parker J D , Kawanishi D T , Crawford M H , Messineo F C , Shook T L , Raby K
Published: June 2011

Episodes of transient myocardial ischemia during ambulatory activities are common in patients with stable coronary artery disease and who are often asymptomatic. Selection of therapy for episodes of asymptomatic ischemia is limited by a lack of direct comparative studies. To determine the most effective monotherapy for patients with stable angina and a high frequency of asymptomatic ischemic episodes, propranolol-LA (mean daily dose, 293 mg), diltiazem-SR (mean daily dose, 350 mg), nifedipine (mean daily dose, 79 mg) were each compared with placebo, each for 2 weeks, in a randomized, double-blinded, crossover trial. Entry criteria were a positive exercise treadmill test during placebo therapy characterized by 1.0 mm or more ST segment depression and angina pectoris, and six or more episodes of transient ST segment depression of 1.0 mm or more on a 48-hour ambulatory electrocardiogram. One hundred ninety-four patients were screened, 63 were eligible and received randomized therapy, of which 56 patients completed at least two of the four treatment periods and were included in an intent-to-treat analysis. Fifty patients completed all four treatment phases and were included in the protocol-completed analysis. Anti-ischemia efficacy was assessed by 48-hour ambulatory electrocardiographic monitoring, exercise treadmill tests, and anginal diaries. Ninety-four percent of all episodes of ambulatory ischemia were asymptomatic. Compared with placebo, only propranolol was associated with a marked reduction in all manifestations of asymptomatic ischemia during ambulatory electrocardiographic monitoring (2.3 versus 1.0 episodes/24 hr; mean duration of ischemia per 24 hours, 43.6 versus 5.7 minutes; both p less than 0.0001). Diltiazem's reduction of the frequency of episodes compared with placebo (2.3 versus 1.9 episodes/24 hr) was associated with a trend (p = 0.08) in the protocol-completed analysis and with a significant reduction in the intent-to-treat analysis (p = 0.03). Nifedipine had no significant effect on any measured variable of ambulatory ischemia. The dosages of medication used may have been excessive for some patients, and a more beneficial effect may have been evident at a lower dose. In contrast to the marked effects of the active agents on ambulatory asymptomatic ischemia, the effects on exercise performance and angina pectoris were slight. The active agents modestly improved treadmill exercise duration time until 1 mm ST segment depression (3%), and only propranolol and diltiazem had significant effects. Only diltiazem significantly prolonged the total exercise time. Anginal frequency was significantly decreased by both propranolol and diltiazem.(ABSTRACT TRUNCATED AT 400 WORDS)
Beta-adrenergic receptors in lymphocyte subsets after exercise. Alterations in normal individuals and patients with congestive heart failure.
Authors: Maisel A S , Harris T , Rearden C A , Michel M C
Published: June 2011

Dynamic exercise increases the number of beta-adrenergic receptors in mixed lymphocytes by a mechanism that is incompletely understood. In a set of in vivo studies, we have investigated the effects of dynamic exercise on the subset distribution of circulating lymphocytes and on the number of beta-adrenergic receptors in each of these subsets in two groups of patients. In healthy subjects, exercise increased plasma norepinephrine and epinephrine and caused lymphocytosis. Whereas the number of Thelper cells increased only modestly, the number of Tsuppressor/cytotoxic and natural killer cells more than tripled. The number of beta-adrenergic receptors varied among subsets but was not significantly altered by dynamic exercise in any subset except natural killer cells (35% increase, p = 0.0302). In a group of patients with congestive heart failure, dynamic exercise increased plasma norepinephrine but did not alter plasma epinephrine and did not cause significant lymphocytosis. We did not detect any significant alterations of circulating leukocyte subsets or beta-adrenergic receptors in any of these subsets after exercise. A combined analysis of healthy patients and heart failure patients revealed a significant correlation between increases in plasma epinephrine and increases in circulating lymphocytes. We conclude that the exercise-induced increase in beta-adrenergic receptors of mixed lymphocytes is predominantly caused by a redistribution of circulating cell subsets that differ in their beta-adrenergic receptor number. This appears to be mediated by epinephrine rather than norepinephrine.
Adaptation to ischemia during percutaneous transluminal coronary angioplasty. Clinical, hemodynamic, and metabolic features.
Authors: Deutsch E , Berger M , Kussmaul W G , Hirshfeld J W , Herrmann H C , Laskey W K
Published: June 2011

The clinical, electrocardiographic, and coronary hemodynamic responses to sequential 90-second occlusions of the left anterior descending coronary artery in 12 patients undergoing elective percutaneous transluminal coronary angioplasty were examined. Transmyocardial lactate metabolism was examined in an additional group of seven patients with clinical and hemodynamic features similar to the first group. We noted that in comparison with the initial balloon occlusion the second occlusion was characterized by less subjective anginal discomfort, less ST segment shift (0.44 +/- 0.13 versus 0.21 +/- 0.07 mV, p = 0.01), and lower mean pulmonary artery pressure (25 +/- 1.0 versus 20 +/- 1.7 mm Hg, p = 0.005). In addition, for the same heart rate-blood pressure product, cardiac vein flow during the second inflation was significantly lower than that recorded during the first inflation (96 +/- 1.4 versus 83 +/- 2.4 ml/min, p = 0.005). Finally, there was significantly less myocardial lactate production during the second inflation (lactate extraction ratio: first inflation, -0.11 +/- 0.03; second inflation, -0.03 +/- 0.02; p = 0.04). We conclude that the lessened clinical, electrocardiographic, hemodynamic, and metabolic evidence of myocardial ischemia during the second of two periods of coronary artery occlusion during percutaneous transluminal coronary angioplasty supports the concept of adaptation to myocardial ischemia (ischemic preconditioning).
Intracoronary urokinase for intracoronary thrombus accumulation complicating percutaneous transluminal coronary angioplasty in acute ischemic syndromes.
Authors: Schieman G , Cohen B M , Kozina J , Erickson J S , Podolin R A , Peterson K L , Ross J , Buchbinder M
Published: June 2011

Intracoronary urokinase was used to treat flow-limiting intracoronary thrombus accumulation that complicated successful percutaneous transluminal coronary angioplasty (PTCA) during acute ischemic syndromes in 48 patients who were followed up through the acute phase of their illness. The study group comprised 10 patients with unstable angina pectoris, 18 patients with an evolving acute myocardial infarction, and 20 patients with postinfarction angina. The initial mean percent coronary diameter stenosis for the entire population was 95 +/- 7% and decreased with initial PTCA to 41 +/- 20% (p less than 0.001), with improved corresponding coronary flow by Thrombolysis in Myocardial Infarction trial (TIMI) grade. However, thrombus accumulation then resulted in a significant increase in percent diameter stenosis to 83 +/- 17% (p less than 0.001); a corresponding significant reduction in coronary flow also occurred by TIMI grade. After administration of intracoronary urokinase (mean dose, 141,000 units; range, 100,000-250,000 units during an average period of 34 minutes), with additional PTCA, mean percent diameter stenosis significantly decreased to 34 +/- 17% (p less than 0.001); a correspondingly significant improvement in mean coronary flow by TIMI grade occurred to 2.9 +/- 0.2. Overall, the angiographic success rate was 90%. There were no ischemic events requiring repeat PTCA and no procedure-related myocardial infarctions or deaths before hospital discharge. One patient was referred for urgent coronary artery bypass graft surgery after a successful PTCA. Plasma fibrinogen levels were obtained in 15 patients, and in no patient was the level below normal for our laboratory.(ABSTRACT TRUNCATED AT 250 WORDS)
Expression of recombinant genes in myocardium in vivo after direct injection of DNA.
Authors: Lin H , Parmacek M S , Morle G , Bolling S , Leiden J M
Published: June 2011

The ability to program recombinant gene expression in cardiac myocytes in vivo holds promise for the treatment of many inherited and acquired cardiovascular diseases. In this report, we demonstrate that a recombinant beta-galactosidase gene under the control of the Rous sarcoma virus promoter can be introduced into and expressed in adult rat cardiac myocytes in vivo by the injection of purified plasmid DNA directly into the left ventricular wall. Cardiac myocytes expressing recombinant beta-galactosidase were detected histochemically in rat hearts for at least 4 weeks after injection of the beta-galactosidase gene. These results demonstrate the potential of this method of somatic gene therapy for the treatment of cardiovascular disease.
Discrepancies in Recorded Results from Duplicate Neurological History and Examination in Patients Studied for Prognosis in Cerebrovascular Disease
Authors: SISK CHARLES , ZIEGLER DEWEY K. , ZILELI TURGUT
Published: June 2011

Histories were taken and neurological examinations performed according to a carefully standardized protocol by two neurologists on 28 patients with histories of probable transient cerebrovascular insufficiency. Duplicate examinations were performed within a short interval of the initial examinations. Comparison of the findings on the two examinations showed extreme discrepancies in recording of presence or absence of specific symptoms and of signs on the neurological examination, including signs considered "objective"— for example, reflex asymmetry. Discussion between the examiners followed by another set of duplicate examinations reduced the discrepancies on the findings of neurological examination, but did very little to the discrepancies in the history. The necessity of realizing the variability of the history and examination in evaluating the course of, and therapy for, transient cerebrovascular ischemic attacks is emphasized.
Effect of Pa

CO
CO2

on Blood Flow and Microvasculature of Ischemic and Nonischemic Cerebral Cortex
Authors: WALTZ ARTHUR G.
Published: June 2011

The right middle cerebral artery (MCA) was occluded in cats; after subsequent craniectomy cortical blood flow (CBF) was measured bilaterally with
85
Kr, and photographs of the superficial microvasculature were made. Ventilation was controlled, and Pa

CO
CO2

was altered by changing the concentration of CO
2
in the inspired air. In nonischemic cortex CBF varied as an exponential function of Pa

CO
CO2

, and the caliber of superficial arterial vessels (50 to 200µ in diameter) increased with increasing Pa

CO
CO2

. In ischemic cortex, changes of Pa

CO
CO2

produced no change of CBF in six of ten animals studied within one day of occlusion; in four of these six, there was no change in the caliber of arterial vessels. In the four other animals of this group, there was a paradoxical response (an increase of Pa

CO
CO2

produced a decrease of CBF of ischemic cortex), and in two of these four animals, there also was a paradoxical response of the caliber of arterial vessels. In eight animals allowed to survive 5 to 12 days after MCA occlusion, the arterial vessels of ischemic cortex regained some reactivity: a normal response of CBF to changes of Pa

CO
CO2

was found in four, and appropriate changes of vessel caliber were found in all eight. The ischemia-induced impairment of the reactivity of cortical vessels to changes of Pa

CO
CO2

casts doubt on the usefulness of CO
2
inhalation for the treatment of strokes of humans.
Transorbital Approach to the Middle Cerebral Artery of the Squirrel Monkey: A Technique for Experimental Cerebral Infarction Applicable to Ultrastructural Studies
Authors: HUDGINS W. R. , GARCIA JULIO H.
Published: June 2011

An appropriate surgical technique for the production of cerebral infarction must fulfill, among others, the following criteria in order to be suitable for electron microscopy (EM) studies: (1) the method of arterial occlusion should yield a high percentage of infarcts with predictable average size; (2) there must be avoidance of surgical manipulation (i.e., retraction) of the cerebral tissues or exposure of the same to the atmosphere; and (3) the method for occluding the artery must be one that permits fixation by perfusion of the ischemic and nonischemic brain.

Modifications to a previously devised method for induction of cerebral infarct are herein described. This new surgical approach has made it possible to conduct detailed and sequential ultrastructural analysis of experimental cerebral infarctions.
Metabolic Changes in Response to Acute Cerebral Ischemia Following Bilateral Carotid Artery Ligation in Arteriosclerotic Versus Nonarteriosclerotic Rats
Authors: WEXLER BERNARD C.
Published: June 2011

Both the left and right carotid arteries of arteriosclerotic and nonarteriosclerotic male and female rats were surgically ligated to induce a state of sudden and severe cerebral ischemia. The animals promptly developed signs of cerebral impairment and were sacrificed 2, 4, 6, 8, 10, 12, 24 and 48 hours later. A similar group of animals was subjected to the same regimen of carotid artery ligation except that a week's time elapsed between the ligation of each carotid artery.

As with unilateral carotid artery ligation, the bilaterally ligated animals manifested fatty metamorphosis of the liver, myocardial infarction and cerebral edema and necrosis, but the severity of these pathological changes was greatly exacerbated with the more severe ischemia.

Serum creatine phosphokinase, glutamic oxalacetic transaminase, triglycerides, free fatty acids, cholesterol, glucose and corticosterone all rose dramatically and in concert with the pathological changes, e.g., fatty liver. Animals with preexisting arterial disease exhibited much greater excursions of these pathophysiological parameters during the cerebral ischemia than did animals with normal arteries. The entire response pattern indicates that cerebral ischemia is a severe stress and is capable of eliciting highly characteristic pathophysiological changes which could be used to assess the severity or course of cerebral ischemia.