bluuebunny/crossref_metadata_2025 huggingface dataset:
Rate-dependent properties of adenosine-induced negative dromotropism in humans.
Authors: Lai W T , Lee C S , Wu S N
Published: June 2012

BACKGROUND

The antiarrhythmic effects of sodium channel and calcium channel blockers are known to be rate dependent. Little is known about the rate-dependent effect of adenosine on human atrioventricular (AV) nodal conduction. The purpose of this study was to determine whether the negative dromotropic effect of adenosine is dependent on heart rate.

METHODS AND RESULTS

Atrial pacing at 20-millisecond increments decreasing stepwise was performed, and the curves that relate the AH interval to the atrial pacing cycle length were analyzed. The change in AV nodal function was evaluated in three protocols: (1) In 8 group 1A and 6 group 1B patients, an intravenous infusion of adenosine at a dose of 140 and 320 micrograms.kg-1.min-1 was given, respectively; (2) a bolus injection of a fixed dose of adenosine was given to 12 group 2A patients without and 6 group 2B patients with propranolol (0.1 mg/kg) treatment; and (3) in 12 group 3 patients, the AV nodal function was evaluated after intravenous propranolol (0.05 mg/kg) and after subsequent intravenous aminophylline (loading dose, 5 mg/kg; maintenance dose, 0.9 mg.kg-1.h-1). No significant depression of AV nodal function could be demonstrated during intravenous infusion of adenosine. The bolus injection of adenosine could prolong the AH interval, which was dependent on heart rate and more significant at a shorter pacing cycle length. Intravenous propranolol significantly depressed the AV nodal conduction and shifted the curves of the AH interval versus the pacing cycle length to the right. Subsequent intravenous aminophylline shortened the AV nodal conduction time, however, in a rate-independent manner.

CONCLUSIONS

The negative dromotropic effects induced by intravenous bolus injection of adenosine became more pronounced at fast atrial pacing rates. These results indicate that adenosine causes rate-dependent prolongation of AV nodal conduction in humans.
Mitogenic effect of serotonin on vascular endothelial cells.
Authors: Pakala R , Willerson J T , Benedict C R
Published: June 2012

BACKGROUND

Recent studies indicate that serotonin (5-HT) has a growth-promoting effect on several different cell types, including smooth muscle cells. After percutaneous transluminal coronary angioplasty, there is damage and denudation of vascular endothelial cells, which promotes platelet aggregation at the site of injury. Aggregating platelets release 5-HT; thus, a high concentration of the amine may be present at sites of endothelial damage, which may act as a mitogen to endothelial cells.

METHODS AND RESULTS

The mitogenic effect of 5-HT was examined on canine and bovine aortic endothelial cells by (1) assessing the increase in [3H]thymidine incorporation into DNA and (2) assessing the increase in the absolute number of cells after stimulation with 5-HT. 5-HT at an added concentration of 200 to 1000 mumol/L in the media induced a significant increase in [3H]thymidine incorporation into endothelial cells and an increase in cell number. This effect was not observed with fibroblasts. As the concentrations of added 5-HT were decreased, the endothelial cells had to be stimulated with 5-HT for longer periods to induce the same degree of cellular proliferation. The precursors and metabolic breakdown products of 5-HT were inactive. The 5-HT-induced endothelial proliferation was reversed by 5-HT2 receptor antagonists and pertussis toxin. These data suggest that the mitogenic effect of 5-HT on endothelial cells is mediated by the 5-HT2 receptor, which is coupled to a G protein.

CONCLUSIONS

5-HT is a mitogen for endothelial cells at concentrations likely to be present at sites of vascular injury. This effect is probably mediated via the 5-HT2 receptor. The growth-promoting effects of 5-HT on endothelial cells may facilitate the healing of intima after vascular damage.
Modulation of expression of monocyte/macrophage plasminogen activator activity and its implications for attenuation of vasculopathy.
Authors: Lundgren C H , Sawa H , Sobel B E , Fujii S
Published: June 2012

BACKGROUND

The binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) on cell surfaces has the potential to influence degradation of extracellular matrix (ECM). Thus, uPA bound to monocyte/macrophages and its interactions with plasminogen activator inhibitors types 1 and 2 (PAI-1 and PAI-2) may modify atherogenesis by altering cell-associated proteolytic activity, degradation of ECM, and neointimal formation at sites of vascular injury.

METHODS AND RESULTS

To determine whether the expression of proteins on the surface of cells involved in fibrinolysis changes in human cells in response to mediators implicated in atherogenesis, we exposed U937 cells (an immortal human monocyte-like cell line) to transforming growth factor-beta (TGF-beta) and to thrombin. Induction of uPAR mRNA occurred with TGF-beta (5 ng/mL) in a time-dependent fashion (P = .05; n = 4). Thrombin (5 National Institutes of Health [NIH] U/mL) increased uPAR mRNA by 2.8-fold above control (n = 4) without altering PAI-1 mRNA or protein synthesis (n = 4). The increase in uPAR gene expression in cells exposed to either TGF-beta or thrombin translated into a functional increase in cell-surface proteolytic activity. Under control conditions, U937 cells expressed PAI-2 but not PAI-1 mRNA. PAI-2 mRNA expression increased (P < .05; n = 4) with thrombin (5 NIH U/mL) but was suppressed by TGF-beta (5 ng/mL). TGF-beta induced PAI-1 mRNA within 6 hours accompanied by a 9-fold increase in PAI-1 protein from 6 hours (2.9 +/- 1.9 ng/mL) to 24 hours (20.0 +/- 9.6 ng/mL, P = .005; n = 3) paralleled by increased synthesis as shown in metabolic labeling experiments with 35S-methionine and immunoprecipitation of labeled PAI-1. PAI-1 mRNA and protein expression were seen in human coronary artery atherectomy specimens as well and were localized to analogous monocyte/macrophages and to smooth muscle cells as judged from results of in situ hybridization and immunocytochemistry studies.

CONCLUSIONS

The results indicate that there is induction of PAI-1 and uPAR in U937 cells exposed to TGF-beta and thrombin. In atheroma, analogous processes may modulate early migration of luminal monocytes into the subintimal space and proteolysis of ECM. Thus, cell surface, monocyte-directed fibrinolysis may influence atherosclerosis, restenosis, or both.
Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits.
Authors: Ameli S , Hultgardh-Nilsson A , Cercek B , Shah P K , Forrester J S , Ageland H , Nilsson J
Published: June 2012

BACKGROUND

Several epidemiological studies have shown an inverse relation between high-density lipoprotein (HDL) cholesterol levels and coronary heart disease. Recently, observational studies have suggested a similar inverse relation between HDL and restenosis after coronary balloon angioplasty. Despite these observations, it is unclear whether this inverse relation reflects a direct vascular protective effect of HDL or apolipoprotein (apo) A-I, the major apolipoprotein component of HDL. Therefore, to determine whether HDL directly influences neointima formation, we investigated the effect of recombinant apo A-I Milano (apo A-I M), a mutant of human apo A-I with Arg-173 to Cys substitution, on intimal thickening after balloon injury in cholesterol-fed rabbits.

METHODS AND RESULTS

Cholesterol feeding was initiated 18 days before injury and continued until the time of death. Eight rabbits received intravenous injections of 40 mg of apo A-I M linked to a phospholipid carrier on alternate days, beginning 5 days before and continuing for 5 days after balloon injury of femoral and iliac arteries. Eight rabbits received the carrier alone, and four received neither apo A-I M nor the carrier. Three weeks after balloon injury, apo A-I M-treated rabbits had significantly reduced intimal thickness compared with the two control groups (mean +/- SD): 0.49 +/- 0.29 versus 1.14 +/- 0.38 mm2 and 1.69 +/- 0.43 mm2, P < .002 by ANOVA). The intima-to-media ratio was also significantly reduced by apo A-I M (0.7 +/- 0.2 versus 1.5 +/- 0.5 and 2.1 +/- 0.1, P < .002 by ANOVA) compared with the two controls. The fraction of intimal lesion covered by macrophages, as identified by immunohistochemistry using macrophage-specific monoclonal antibody, was significantly less in apo A-I M-treated rabbits compared with carrier-treated animals (25.3 +/- 17% versus 59.4 +/- 12.3%, P < .005). Aortic cholesterol content, measured in an additional 10 rabbits, did not differ significantly between apo A-I M-treated animals (n = 5) and carrier-treated controls (n = 5).

CONCLUSIONS

Apo A-I M significantly reduced intimal thickening and macrophage content after balloon injury in cholesterol-fed rabbits without a change in arterial total cholesterol content. Although the precise mechanism of action remains to be defined, these findings are consistent with a direct vascular effect of apo A-I, which could have potential therapeutic implications.
The renin-angiotensin system and volume overload-induced changes in cardiac collagen and elastin.
Authors: Ruzicka M , Keeley F W , Leenen F H
Published: June 2012

BACKGROUND

Besides cardiac load, the renin-angiotensin system (RAS) and aldosterone may regulate collagen accumulation during maturation or hypertrophic growth. The effect of cardiac volume overload on both left ventricular (LV) and right ventricular (RV) collagen and elastin and the possible role of the RAS in such changes have not yet been assessed.

METHODS AND RESULTS

In the present study we assessed (1) the effects of 4 to 10 weeks of volume overload by an aortocaval shunt or minoxidil on LV and RV collagen and elastin and (2) the potential of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin II receptor blocker losartan to prevent and regress volume overload-induced changes in cardiac collagen and elastin. Cardiac volume overload by aortocaval shunt or minoxidil treatment decreased LV collagen accumulation as compared with control rats. In contrast, RV collagen accumulation was potentiated during the initial weeks but not during chronic aortocaval shunt. Enalapril and losartan prevented the relative decreases in LV collagen content and concentration induced by a shunt. Losartan also reversed the decrease in LV collagen content by aortocaval shunt. Neither blocker significantly affected the enhanced RV collagen accumulation during the initial weeks of shunt, but both blockers further potentiated RV collagen accumulation during chronic volume overload. Aortocaval shunt for 4 weeks but not 10 weeks enhanced LV and RV elastin accumulation. This initial increase in LV and RV elastin content was blocked by both enalapril and losartan.

CONCLUSIONS

Cardiac volume overload, even when accompanied by increased plasma renin activity, decreases LV collagen accumulation, suggesting that in contrast to the stimulatory effect of systolic wall stress, increased diastolic wall stress inhibits collagen accumulation. In support of this concept, enalapril and losartan decreased LV preload and maintained LV collagen accumulation. In contrast to LV collagen, RV collagen accumulation was potentiated during the initial weeks of volume overload, possibly related to acute RV pressure overload shortly after aortocaval shunt and its decrease with chronic shunt. Enalapril and losartan had minimal effect on the enhanced RV collagen during the initial weeks of aortocaval shunt but potentiated RV collagen during chronic shunt, possibly by decreasing RV diastolic pressures. Altogether, these data suggest that during cardiac volume overload, the RAS affects cardiac collagen primarily by its hemodynamic effects. The RAS, however, may potentiate RV and LV elastin accumulation during the initial weeks of volume overload since both enalapril and losartan block this increase.
Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with serum ACE concentration and increased risk for CAD in the Japanese.
Authors: Nakai K , Itoh C , Miura Y , Hotta K , Musha T , Itoh T , Miyakawa T , Iwasaki R , Hiramori K
Published: June 2012

BACKGROUND

The angiotensin I-converting enzyme (ACE) is a key component of the renin-angiotensin system thought to be important in the pathogenesis of hypertension and cardiovascular disease. Deletion polymorphism in the ACE gene may be a risk factor for myocardial infarction in the Caucasian population. However, this finding has not yet been investigated in the Japanese population.

METHODS AND RESULTS

A 287-bp insertion/deletion polymorphism in intron 16 of the ACE gene was examined by polymerase chain reaction in a cross-sectional study of 100 healthy subjects and 178 patients with coronary artery disease (CAD) (70 angina pectoris, 108 myocardial infarction), whose serum ACE levels were concomitantly measured. Polymorphism of the ACE gene was characterized by three genotypes: two deletion alleles (genotype DD), two insertion alleles (genotype II), and heterozygous alleles (genotype ID). No differences could be detected among the three genotypes for total cholesterol, HDL cholesterol, and body mass index. Serum ACE levels were 11.4 +/- 2.7, 14.5 +/- 3.5, and 16.6 +/- 4.6 IU/mL for genotypes II, ID, and DD, respectively. In the study population, the genotype DD was more closely associated with CAD than the other two genotypes (ID and II). The frequency of deletion alleles was higher (0.58) in the CAD group than in healthy control subjects (0.42) (P < .05). Furthermore, multivessel disease was more strongly associated with deletion alleles than with insertion alleles (P < .05).

CONCLUSIONS

A deletion polymorphism of the ACE gene is associated with serum ACE activity and increased risk for CAD in the Japanese.
Alterations in muscarinic K+ channel response to acetylcholine and to G protein-mediated activation in atrial myocytes isolated from failing human hearts.
Authors: Koumi S , Arentzen C E , Backer C L , Wasserstrom J A
Published: June 2012

BACKGROUND

A variety of previous studies have demonstrated reduced diastolic potential and electrical activity in atrial specimens from patients with heart disease. Although K+ channels play a major role in determining resting membrane potential and repolarization of the action potential, little is known about the effects of preexisting heart disease on human atrial K+ channel activity.

METHODS AND RESULTS

We characterized the inwardly rectifying K+ channel (IKI) and the muscarinic K+ channel [IK(ACh)] in atrial myocytes isolated from patients with heart failure (HF) and compared electrophysiological characteristics with those from donors (control) by the patch-clamp technique. Resting membrane potentials of isolated atrial myocytes from HF were more depolarized (-51.1 +/- 9.7 mV, mean +/- SD, n = 30 patients) than those from donors (-73.0 +/- 7.2 mV, n = 4 patients, P < .001). The action potential duration in HF was longer than that in donors. Although acetylcholine (ACh) shortened the action potential, reduced the overshoot, and hyperpolarized the atrial cell membrane in HF, these effects were attenuated compared with those observed in donors. The whole-cell membrane current slope conductance in HF was small, the reversal potential was more positive, and the sensitivity to ACh was less compared with donors. In single-channel recordings from cell-attached patches, IK1 channel conductance and gating characteristics were the same in HF and donor atria. When ACh was included in the pipette solution, IK(ACh) was activated in both groups. Single-channel slope conductance of IK(ACh) averaged 42 +/- 3 pS (n = 28) in HF and 44 +/- 2 pS (n = 4) in donors, and mean open lifetime was 1.3 +/- 0.3 milliseconds (n = 24) in HF and 1.5 +/- 0.4 milliseconds (n = 4) in donors. These values were virtually identical in the two groups (not significantly different, NS), although both single IK1 and IK(ACh) channel densities were less in HF. Channel open probability of IK(ACh) was also less in HF (4.0 +/- 1.2%, n = 24) than in donors (6.8 +/- 1.1%, n = 3, P < .01). The concentration of ACh at half-maximal activation was 0.11 mumol/L in HF and 0.03 mumol/L in donors. In excised inside-out patches, IK(ACh) from HF required higher concentrations of GTP and GTP gamma S to activate the channel compared with donors. These results suggest a reduced IK(ACh) channel sensitivity to M2 cholinergic receptor-linked G protein (Gi) in HF compared with donors.

CONCLUSIONS

Atrial myocytes isolated from failing human hearts exhibited a lower resting membrane potential and reduced sensitivity to ACh compared with donor atria. Whole-cell and single-channel measurements suggest that these alterations are caused by reduced IK1 and IK(ACh) channel density and reduced IK(ACh) channel sensitivity to Gi-mediated channel activation in HF.
Hemodynamic and metabolic effects of paced linkage following heterotopic cardiac transplantation.
Authors: Morris-Thurgood J , Cowell R , Paul V , Kalsi K , Seymour A M , Ilsley C , Mitchell A , Khaghani A , Yacoub M
Published: June 2012

BACKGROUND AND PURPOSE

Heterotopic cardiac transplantation is a valuable surgical technique that maximizes the use of donor organs. However, recipient heart function may decline steadily postoperatively with resulting clinical deterioration. Paced linkage has the potential of reducing afterload and enhancing coronary flow of both hearts, thereby improving recipient- and donor-heart function. This may have long-term as well as short-term benefits.

METHODS AND RESULTS

The study was performed on 11 heterotopic transplant recipients. The two hearts were linked with a pacemaker (paced linkage) to produce recipient heart systole during different periods of donor-heart diastole. The recipient ventricular contraction was timed to occur during early, mid, and late diastole of the donor heart. Hemodynamic baseline measurements were compared with the optimal counterpulsated data. Paced linkage produced significant improvements in total cardiac output, 5.0 +/- 0.9 compared with baseline 4.5 +/- 0.8 L/min (P = .021); recipient coronary sinus flow, 278 +/- 145 versus 186 +/- 108 mL/min (P = .022); and aortic systolic pressure, 135 +/- 27 versus 123 +/- 27 mm Hg (P = .005). There was an overall improvement in systolic ventricular performance in the recipient heart when pace linked, as evidenced by a significant increase in left ventricular systolic pressure of 118 +/- 36 compared with the baseline value of 108 +/- 33 mm Hg (P = .016), an increase in ejection period from 174 +/- 30 versus 203 +/- 48 (P = .046), and a decrease in the pre-ejection period of 147 +/- 37 when paced versus 181 +/- 39 milliseconds (P = .013). The metabolic studies showed a significant decrease in hypoxanthine release from a baseline level of 0.4 mumol/L to a paced value of -0.06 mumol/L (P = .002); these very low values would suggest that there is no evidence of ischemia. Hemodynamic changes in the donor heart included a significant reduction in the left ventricular end-diastolic pressure from 6.8 +/- 4.4 versus baseline of 10.5 +/- 5.8 mm Hg (P = .029) and in maximum -dP/dT from 3.2 +/- 1.7 versus baseline of 2.1 +/- 1.1.

CONCLUSIONS

Paced linkage after heterotopic cardiac transplant produces significant functional improvements in both hearts. Permanent pacemaker implantation may sustain these acute benefits and prevent the premature deterioration of the recipient heart.
Nonuniform course of left ventricular pressure fall and its regulation by load and contractile state.
Authors: Leite-Moreira A F , Gillebert T C
Published: June 2012

BACKGROUND

Effects of systolic left ventricular pressure (LVP) on rates of pressure fall remain incompletely understood. This study analyzed phase-plane dP/dt versus LVP plots to differentiate between accelerating and decelerating effects and to investigate the variability in reported load effects on rates of LVP fall.

METHODS AND RESULTS

Abrupt aortic occlusions were performed by inflating a balloon positioned in the ascending aorta of anesthetized open-chest dogs (n = 17). The occlusions resulted in clamp elevations of systolic LVP. In protocol A, the elevations of systolic LVP induced by total aortic occlusions were timed at early, mid, and late ejection. The magnitude of the elevations was 36.0 +/- 3.6 mm Hg for early, 11.6 +/- 0.6 mm Hg for mid, and negligible for late occlusions. The course of LVP fall appeared to be more complex than previously appreciated. Pressure fall might be subdivided in an initial accelerative phase, an intermediate decelerative phase, and a terminal decelerative phase. The initial phase accelerated with mid and late occlusions. The intermediate phase slowed down with early and to a lesser extent with mid occlusions. The terminal phase was never affected by aortic clamp occlusions. In protocol B, early elevations of systolic LVP were obtained with multiple graded aortic occlusions. The effects of matched LVP elevations of 12 mm Hg on rate of LVP fall were evaluated with the time constant of LVP fall (tau) and showed an interanimal variability ranging from acceleration and a 20% decrease in tau to deceleration and a 35% increase in tau. Changes in tau were moderately correlated with commonly used indexes of contractility (peak +dP/dt, r = -.78; regional fractional shortening, r = -.63). These changes in tau showed a close correlation with the systolic LVP of the test beat, expressed as a percentage of the peak isovolumetric LVP, obtained with total aortic occlusion (r = .984). This suggested that the contraction-relaxation coupling should be analyzed in terms of peak force development rather than contraction velocity or ejection fraction.

CONCLUSIONS

LVP fall could be subdivided into an initial accelerative phase, an intermediate decelerative phase, and a terminal decelerative phase. Effects of elevations in systolic LVP on rate of LVP fall could be predicted by knowing peak isovolumetric LVP. Nonuniformity of LVP fall and adequate interpretation of load effects should be taken into account when clinical situations or pharmacological interventions are considered. In congestive heart failure, slow LVP fall could mainly reflect working conditions close to isovolumetric rather than relaxation disturbances.
Sudden cardiac death in heart failure. The role of abnormal repolarization.
Authors: Tomaselli G F , Beuckelmann D J , Calkins H G , Berger R D , Kessler P D , Lawrence J H , Kass D , Feldman A M , Marban E
Published: June 2012

Congestive heart failure is a common, highly lethal cardiovascular disorder claiming over 200,000 lives a year in the United States alone. Some 50% of the deaths in heart failure patients are sudden, and most of these are probably the result of ventricular tachyarrhythmias. Methods designed to identify patients at risk have been remarkably unrewarding, as have attempts to intervene and prevent sudden death in these patients. The failure to impact favorably on the incidence of sudden death in heart failure patients stems largely from a lack of understanding of the underlying mechanisms of arrhythmogenesis. This article explores the role of abnormalities of ventricular repolarization in heart failure patients. We will examine evidence for the hypothesis that alteration of repolarizing K+ channel expression in failing myocardium predisposes to abnormalities in repolarization that are arrhythmogenic. The possible utility of novel electrophysiological and ECG measures of altered ventricular repolarization will be explored. Understanding the mechanism of sudden death in heart failure may lead to effective therapy and more accurate identification of patients at greatest risk.
Mortality within 24 hours of thrombolysis for myocardial infarction. The importance of early reperfusion. The GUSTO Investigators, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.
Authors: Kleiman N S , White H D , Ohman E M , Ross A M , Woodlief L H , Califf R M , Holmes D R , Bates E , Pfisterer M , Vahanian A
Published: June 2012

BACKGROUND

A paradoxical increased risk of death has been reported during the first 24 hours after thrombolysis for myocardial infarction. The mechanism of this phenomenon is not known, nor is its relation to the success or failure of reperfusion. The present study was a prospectively designed analysis of deaths occurring within the first 24 hours in the GUSTO trial.

METHODS AND RESULTS

There were 41,021 patients enrolled in GUSTO, a randomized comparison of streptokinase with intravenous or subcutaneous heparin, accelerated tissue-type plasminogen activator (TPA), and combination of streptokinase and TPA. An angiographic mechanistic substudy examined reperfusion (using the TIMI flow grading criteria) 90 minutes after the assigned thrombolytic regimen was begun in 1567 patients. There were 1125 deaths (2.8%) within 24 hours ("early deaths") and 1726 additional deaths (4.2%) after 24 hours but within 30 days ("later deaths"). At the time of presentation, the most potent predictors of early death were hypotension and sinus tachycardia. In a multiple logistic regression model, lower systolic blood pressure, shorter height, higher heart rate, and the absence of prior smoking distinguished early death from later death. Reinfarction occurred in 26 patients (2.4%), shock in 572 patients (52%), atrioventricular block in 308 patients (28%), and tamponade in 106 patients (10%) dying early compared with 262 (15%), 788 (46%), 396 (23%), and 74 (4%) respective patients dying later. There were no differences in early mortality among the thrombolytic regimens for the first 6 hours after randomization. By 24 hours, however, mortality was 2.89% for streptokinase recipients, 2.84% for combination therapy recipients, and 2.36% for accelerated TPA recipients (P = .005). There was little difference among patients with differing flow grades in the infarct artery during the first 4 hours, although mortality was 2.35% for patients with flow grade 0 or 1, 2.92% for patients with flow grade 2, and 0.89% for patients with flow grade 3.

CONCLUSIONS

Even with aggressive management regimens, mortality within the first 24 hours accounted for a large proportion of postthrombolytic deaths. Patients dying early were more likely to present with pump failure than were those dying later and were more likely to diet of events related to left ventricular dysfunction, although cardiac tamponade also accounted for a significant minority of these deaths. Thus, the severity of the clinical presentation rather than the underlying risk factors predicts early mortality. Based on the angiographic substudy data, it appears that rather than hastening early mortality, successful restoration of complete antegrade flow in the infarct-related artery protects against early death.
Activation of complement and kinin systems after thrombolytic therapy in patients with acute myocardial infarction. A comparison between streptokinase and recombinant tissue-type plasminogen activator.
Authors: Agostoni A , Gardinali M , Frangi D , Cafaro C , Conciato L , Sponzilli C , Salvioni A , Cugno M , Cicardi M
Published: June 2012

BACKGROUND

We have previously shown that treatment with streptokinase induces abrupt complement activation and transient neutropenia in patients with acute myocardial infarction (AMI). The purpose of this study was to compare the effects of two different thrombolytic agents--streptokinase (SK) and recombinant tissue-type plasminogen activator (rTPA)--on activation of the complement and kinin systems in plasma of patients with AMI.

METHODS AND RESULTS

Forty-one patients with AMI who were eligible for thrombolytic therapy were studied. Twenty-three patients were treated with streptokinase (1.5 million IU IV over 60 minutes) and 18 were treated with rTPA (8 with bolus of 10 mg IV, followed by 50 mg infused over 60 minutes and then 40 mg infused over 120 minutes; 10 patients were administered rTPA and heparin according to the accelerated infusion protocol indicated by the GUSTO study). C4a and C3a were measured by radioimmunoassay, soluble terminal complement components (SC5b-9) and anti-SK IgG antibodies were measured by ELISA. Cleaved high molecular weight kininogen (HK) was quantitated in plasma by SDS-PAGE and immunoblotting analysis. C4a levels were significantly and similarly increased in both groups, whereas the levels of C3a and SC5b-9 after rTPA infusion were only slightly elevated and were significantly lower than after SK. No differences were observed between patients treated with slow or accelerated rTPA regimens. The titer of antibodies to SK was highly correlated with the levels of C3a and SC5b-9, whereas a lesser correlation was observed with C4a. Treatment with rTPA did not induce the transient neutropenia observed after SK infusion. The cleavage products of HK were significantly greater after SK than after rTPA infusion.

CONCLUSIONS

Our results show that both thrombolytic agents activate the classic complement pathway and that plasmin could be the common trigger for this phenomenon. A significant activation of the complement common pathway (from C3 to terminal components) was observed only with SK infusion and is attributable to the rapid formation of immunocomplexes between SK and anti-SK antibodies present in plasma as a consequence of previous streptococcal infections. The minimal activation of C5 component of the common pathway explains the absence of leukopenia in patients treated with rTPA. Cleavage of HK, larger after SK than after rTPA infusion, represents a condition enhancing the generation of bradykinin by kallikrein. The recent experimental data that indicate a damaging effect of complement activation on the infarcted zone and the contrasting favorable effect consequent to bradykinin formation raise some questions about the clinical importance of the different biological consequences of SK versus rTPA.
Fibrin formation and degradation in patients with arteriosclerotic disease.
Authors: Herren T , Stricker H , Haeberli A , Do D D , Straub P W
Published: June 2012

BACKGROUND

The blood coagulation cascade was reported to be activated in patients with arteriosclerotic disease of the lower limbs (peripheral arterial disease, PAD). There is more thrombin and fibrin formation compared with healthy control subjects. In many studies, however, the presence of arteriosclerotic disease had not been thoroughly ruled out in the control group. Therefore, markers of the activation of the blood coagulation cascade were measured in patients with PAD and in a carefully defined control group, both groups being subjected to an exercise test.

METHODS AND RESULTS

Twenty-two patients with angiographically documented PAD of grade II (Fontaine classification) and 13 control subjects in whom the presence of arteriosclerotic lesions was ruled out by noninvasive means in the carotid arteries, abdominal aorta, leg arteries, and coronary arteries took part in the study. Before and immediately after a treadmill stress test, the concentrations of prothrombin fragment F1 + 2 (F1 + 2), thrombin-antithrombin III complexes (TAT), fibrinopeptide A (FPA; this peptide was measured in spot urine also), and D-dimers were measured. Before exercise, the concentrations of F1 + 2 (1.0 +/- 0.6 versus 0.7 +/- 0.3 nmol/L), TAT (2.9 +/- 2.1 versus 1.9 +/- 0.8 micrograms/L), and D-dimers (318.2 +/- 270.1 versus 150.0 +/- 91.4 micrograms/L) were significantly higher in the patients with PAD compared with the healthy control subjects. FPA concentrations in plasma (1.9 +/- 1.0 versus 1.4 +/- 0.6 micrograms/L) and spot urine were not different, however. F1 + 2, FPA, and D-dimer concentrations correlated with the severity of the PAD as assessed by the ankle systolic blood pressure index (ABPI). The symptom-limited stress test did not lead to further activation of the blood coagulation cascade. However, concentrations of F1 + 2 (P < .001) and TAT (P < .01) after exercise correlated with the presence of ischemic changes in the stress-test ECG.

CONCLUSIONS

There is evidence of enhanced thrombin formation in patients with PAD compared with an age- and sex-matched control group without clinical and sonographic evidence of arteriosclerosis. The thrombin formed, however, appears to be almost completely neutralized by antithrombin III. No direct evidence of fibrin formation was obtained, since the FPA concentrations were not different. In the patients with PAD, the higher concentrations of D-dimers are indicative of in vivo fibrinolysis. Thus, some fibrin formation must be postulated to occur in patients with arteriosclerosis.
Reduced peak aerobic capacity in asymptomatic left ventricular systolic dysfunction. A substudy of the studies of left ventricular dysfunction (SOLVD). SOLVD Investigator. Studies of Left Ventricular Dysfunction.
Authors: LeJemtel T H , Liang C S , Stewart D K , Kirlin P C , McIntyre K M , Robertson T H , Moore A , Cahill L , Galvao M , Wellington K L
Published: June 2012

BACKGROUND

Peak oxygen consumption is reduced in patients with symptomatic congestive heart failure, but functional capacity of patients with asymptomatic left ventricular systolic dysfunction has not been assessed by measurement of peak oxygen consumption attained during graded exercise testing.

METHODS AND RESULTS

Peak oxygen consumption, that is, aerobic capacity (VO2, mL/kg per minute), was determined during graded treadmill exercise using the modified Naughton protocol in 40 patients with left ventricular systolic dysfunction (mean ejection fraction ranging from 14% to 35%; mean, 29%) who, while not receiving any cardiac medications, were totally asymptomatic, and in 41 age-matched normal subjects. Peak exercise duration and VO2 were significantly lower in patients with asymptomatic left ventricular systolic dysfunction than in normal subjects (948 +/- 273 versus 1239 +/- 372 seconds, P < .001, and 22.1 +/- 5.9 versus 29.8 +/- 7.7 mL/kg per minute, respectively, P < .001), while asymptomatic patients and normal subjects reached similar respiratory equivalents (1.14 +/- 0.11 versus 1.11 +/- 0.11 [NS]) and level of perceived exertion, using the modified Borg scale (7.4 +/- 2.6 versus 8.1 +/- 1.5 [NS]). Heart rate, systemic blood pressure, and oxygen pulse response to peak exercise were significantly lower in asymptomatic patients than in normal subjects.

CONCLUSIONS

Although patients with left ventricular systolic dysfunction can be totally asymptomatic in their daily activities, they have experienced a substantial reduction in peak aerobic capacity when compared with normal subjects of similar age.
Intracardiac angiotensin-converting enzyme inhibition improves diastolic function in patients with left ventricular hypertrophy due to aortic stenosis.
Authors: Friedrich S P , Lorell B H , Rousseau M F , Hayashida W , Hess O M , Douglas P S , Gordon S , Keighley C S , Benedict C , Krayenbuehl H P
Published: June 2012

BACKGROUND

Cardiac hypertrophy is associated with elevated intracardiac angiotensin-converting enzyme activity, which may contribute to diastolic dysfunction.

METHODS AND RESULTS

We infused enalaprilat (0.05 mg/min) for 15 minutes into the left coronary arteries of 20 adult patients with left ventricular (LV) hypertrophy due to aortic stenosis (mean aortic valve area, 0.7 +/- 0.2 cm2) and 10 patients with dilated cardiomyopathy (mean ejection fraction, 35 +/- 4%) and assessed (1) simultaneous changes in LV micromanometer pressure and dimensions, (2) LV regional wall motion analyzed by the area method, and (3) Doppler flow-velocity profiles. Systemic neurohormonal activation did not occur with the selective left coronary artery infusion; there were no changes in plasma renin activity, angiotensin-converting enzyme activity, or atrial natriuretic peptide. In patients with aortic stenosis, LV end-diastolic pressure declined from 25 +/- 2 to 20 +/- 2 mm Hg (P < .05). LV pressure-volume and LV pressure-dimension relations showed downward shifts by ventriculography and echocardiography, respectively, indicating improved diastolic distensibility. Regional area change during isovolumic relaxation increased in the anterior segments perfused with enalaprilat but decreased in the inferior segments, indicating acceleration of isovolumic relaxation in the anterior segments and reciprocal shortening in the inferior segments. Regional peak filling rate increased in the anterior segments but not in the inferior segments, and the regional area stiffness constant decreased in the anterior segments but not in the inferior segments. There were no changes in heart rate, cardiac output, or right atrial pressure, excluding alterations in right ventricular/pericardial constraint. In contrast, in the patients with dilated cardiomyopathy the decrease in LV end-diastolic pressure from 22 +/- 2 to 18 +/- 2 mm Hg (P < .05) was accompanied by a significant fall in right atrial pressure (9 +/- 1 to 6 +/- 1 mm Hg), implicating alterations in pericardial constraint. The patients with dilated cardiomyopathy showed no improvement in regional diastolic relaxation, filling, or distensibility.

CONCLUSIONS

Intracoronary enalaprilat at a dosage that did not cause systemic neurohormonal activation improved LV diastolic chamber distensibility and regional relaxation and filling in patients with LV hypertrophy due to aortic stenosis. In contrast, these effects of intracoronary enalaprilat on diastolic function were not observed in patients with dilated cardiomyopathy who did not have concentric hypertrophy. These observations support the hypothesis that the cardiac renin-angiotensin system is activated in patients with concentric pressure-overload hypertrophy and that this activation may contribute to impaired diastolic function.
Interaction of baseline characteristics with the hazard of encainide, flecainide, and moricizine therapy in patients with myocardial infarction. A possible explanation for increased mortality in the Cardiac Arrhythmia Suppression Trial (CAST).
Authors: Anderson J L , Platia E V , Hallstrom A , Henthorn R W , Buckingham T A , Carlson M D , Carson P E
Published: June 2012

BACKGROUND

The Cardiac Arrhythmia Suppression Trial (CAST) was designed to test the hypothesis that suppression of ventricular ectopy with antiarrhythmic drugs after a myocardial infarction reduces the incidence of sudden arrhythmic death. Patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The encainide and flecainide arms of the study were discontinued in 1989 (CAST-I) and the moricizine arm in 1991 (CAST-II) because of excess mortality. To explore the mechanisms of these adverse outcomes, we examined the interaction of baseline characteristics with the hazard of therapy with encainide, flecainide, or moricizine compared with their respective placebos.

METHODS AND RESULTS

CAST-I comprised 755 patients assigned to flecainide or encainide and 743 patients assigned to placebo, whereas in CAST-II, 502 patients received moricizine and 491 patients received placebo. Clinical and laboratory baseline variables of patients receiving active drug and those receiving placebo were similar. In CAST-I patients, there was a significant interaction of active therapy with both all-cause death/cardiac arrest and arrhythmic death/cardiac arrest for non-Q-wave myocardial infarction (total mortality hazard ratios, 1.8 versus 7.9 for Q-wave versus non-Q-wave infarction, P = .03). Ventricular premature depolarization (VPD) frequency > or = 50/h and heart rate > or = 74 beats per minute each interacted significantly with total mortality/cardiac arrest only. In the sicker CAST-II patients (ejection fraction < or = 40%), only diuretic use at baseline interacted significantly with moricizine use for both all-cause death/cardiac arrest and arrhythmic death/cardiac arrest (total mortality hazard ratios, 1.9 versus 0.7 for diuretic use versus no use, P = .01).

CONCLUSIONS

Although active treatment in CAST-I was associated with greater mortality than placebo with respect to almost all baseline variables, the therapeutic hazard was more than expected in patients with non-Q-wave myocardial infarction and (for total mortality) frequent premature VPDs and higher heart rates, suggesting that the adverse effect of encainide or flecainide therapy is greater when ischemic and electrical instability are present. The relative hazard of therapy with moricizine in the sicker CAST-II population was greater in those using diuretics. Thus, although these drugs have the common ability to suppress ventricular ectopy after myocardial infarction, their detrimental effects on survival may be mediated by different mechanisms in different populations, emphasizing the complex, poorly understood hazards associated with antiarrhythmic drug treatment.
Surgery for aortic stenosis in elderly patients. A study of surgical risk and predictive factors.
Authors: Logeais Y , Langanay T , Roussin R , Leguerrier A , Rioux C , Chaperon J , de Place C , Mabo P , Pony J C , Daubert J C
Published: June 2012

BACKGROUND

Aortic stenosis is the most common valvular lesion occurring among elderly patients and has become extremely frequent because of changing demographics in industrialized countries. Surgical risk after the age of 70 has increased. The increasing older age of patients having surgery justifies an analysis of mortality predictive factors.

METHODS AND RESULTS

Between 1976 and February 1993, we performed 2871 operations for aortic stenosis. This study concerns 675 patients (278 men and 397 women) who were > or = 75 years old. Mean age was 78.5 +/- 3 years. Associated lesions were found in 226 patients. A bioprosthesis was implanted in 632 patients (93.6%). Concomitant surgical procedures were performed in 133 patients. Surgical mortality was 12.4% (84 deaths). A longitudinal analysis has been carried out over four successive time periods to evaluate population evolution during these 17 years. Statistical analysis was performed on 46 variables. Multivariate analysis found age (P < .0001), left ventricular failure (P < .0001), lack of sinus rhythm (P < .01), and emergency status (P < .02) to be presurgical independent predictive factors of mortality.

CONCLUSIONS

Risk-reducing strategy should both favor relatively early surgery to avoid cardiac failure and emergency situations and pay careful attention to the use of myocardial protection and cardiopulmonary bypass. Indications for surgery should remain broad since analysis failed to determine specific high-risk groups to be eliminated, and surgery remains the only treatment for aortic stenosis.
End-systolic volume and long-term survival after coronary artery bypass graft surgery in patients with impaired left ventricular function.
Authors: Hamer A W , Takayama M , Abraham K A , Roche A H , Kerr A R , Williams B F , Ramage M C , White H D
Published: June 2012

BACKGROUND

Left ventricular function is the main predictor of long-term survival in patients with coronary artery disease. In patients with impaired left ventricular function after myocardial infarction, end-systolic volume is a better predictor than the global ejection fraction. We analyzed long-term follow-up of patients with impaired left ventricular function undergoing coronary artery bypass graft surgery to evaluate preoperative predictors of survival.

METHODS AND RESULTS

Consecutive patients with ejection fractions < or = 40% (n = 193) who had undergone surgical revascularization were followed to assess the predictive value of preoperative baseline characteristics and catheterization findings for long-term survival. Patients were followed for 133 +/- 30.7 months. At the time of surgery, patient age was 56 +/- 7.9 years and 169 patients (87.6%) had a history of previous myocardial infarction. Thirty-one patients (16%) were female. The ejection fraction was 32 +/- 7%, and the end-systolic volume was 147.4 +/- 52.6 mL. One hundred sixty-four patients (84.9%) had three-vessel disease, and 44 (22.8%) had a left main stenosis with > 50% diameter loss. Follow-up was complete in 99%. Fourteen patients died (7.3%) within the first 30 days after surgery. Twelve-month actuarial survival was 86%, 4-year survival was 80%, and 10-year survival was 40%. Predictors of poor long-term survival on multivariate analysis were end-systolic volume index (chi 2 = 14.02, P = .002), number of previous myocardial infarctions (chi 2 = 6.47, P = .001), preoperative stenosis score (chi 2 = 4.97, P = .02), and age at the time of surgery (chi 2 = 4.45, P = .03).

CONCLUSIONS

End-systolic volume index is the major predictor of survival after coronary artery bypass graft surgery in patients with impaired left ventricular function. Strategies to prevent ventricular dilatation, such as angiotensin-converting enzyme inhibitors, may improve the long-term outcome in these patients.
Reduction in reperfusion-induced myocardial necrosis in dogs by RheothRx injection (poloxamer 188 N.F.), a hemorheological agent that alters neutrophil function.
Authors: Schaer G L , Hursey T L , Abrahams S L , Buddemeier K , Ennis B , Rodriguez E R , Hubbell J P , Moy J , Parrillo J E
Published: June 2012

BACKGROUND

Reperfusion after prolonged coronary artery occlusion may be followed by additional myocardial necrosis persisting for hours to days. Potential mechanisms include neutrophil-mediated injury and compromised flow within the microcirculation of the reperfused myocardium. Poloxamer 188 is a nonionic surfactant with beneficial hemorheological and neutrophil-inhibitory properties. The purpose of the present study was to determine if poloxamer 188 is capable of reducing the myocardial injury associated with sustained reperfusion and to examine the effect of treatment duration.

METHODS AND RESULTS

Three groups of closed-chest dogs underwent 90 minutes of left anterior descending coronary artery occlusion (angioplasty balloon) and 72 hours of reperfusion. Poloxamer 188, formulated as RheothRx Injection (Burroughs Wellcome Co), was given as a 75 mg/kg IV bolus 15 minutes before reperfusion followed by a 150 mg.kg-1.h-1 continuous IV infusion for 4 hours (n = 13) or 48 hours (n = 13); control dogs (n = 12) received saline for 48 hours. The 48-hour infusion of poloxamer 188 resulted in a 42% reduction in infarct size (as a percent of the area at risk) compared with the control group (25.0 +/- 4.2% versus 43.3 +/- 4.3%, P D .01), whereas the 4-hour group demonstrated a 25% reduction in infarct size compared with the control group (32.4 +/- 4.3%, P = .08). ANCOVA demonstrated that the 48-hour infusion of poloxamer 188 reduced myocardial infarct size independent of differences in collateral blood flow (P = .002 versus control). A trend toward infarct size reduction was observed in the 4-hour infusion group (P = .098 versus control by ANCOVA). Plasma creatine phosphokinase concentration was lower in both poloxamer 188-treated groups (P < .05 versus control). Global left ventricular ejection fraction at 72 hours of reperfusion was improved in the 48-hour infusion group compared with the control group (43 +/- 3.1% versus 33 +/- 2.0%, P < .05), whereas ejection fraction in the 4-hour group was 37 +/- 1.3% (P = NS versus control). Regional ventricular function was also significantly better in the 48-hour infusion group compared with the control group. In vitro studies demonstrated that at concentrations comparable to those achieved in vivo, poloxamer 188 inhibited neutrophil chemotaxis. This finding may represent a beneficial mechanism of action.

CONCLUSIONS

A 48-hour infusion of poloxamer 188 reduced myocardial infarct size and improved left ventricular function in this dog model of 90 minutes of coronary artery occlusion and 72 hours of reperfusion. The finding that the 4-hour infusion of poloxamer 188 did not result in similar benefits suggests that additional reperfusion injury occurred between 4 and 48 hours.