bluuebunny/crossref_metadata_2025 huggingface dataset:
Preferential vasoconstriction to cysteinyl leukotrienes in the human saphenous vein compared with the internal mammary artery. Implications for graft performance.
Authors: Allen S P , Chester A H , Dashwood M R , Tadjkarimi S , Piper P J , Yacoub M H
Published: June 2012

BACKGROUND

Platelet aggregation with the release of their vasoactive mediators is an important factor contributing to the patency of coronary bypass grafts. However, the role of leukocyte-derived mediators on graft performance is unclear. Leukotrienes (LTs) are proinflammatory mediators released from a variety of leukocytes that possess both vasoactive and mitogenic properties. We have therefore compared the effects of the cysteinyl LTs (C4, D4, and E4) on the human saphenous vein (SV) and human internal mammary artery (IMA).

METHODS AND RESULTS

Human SVs from 43 patients (mean age, 58 years) and IMAs from 33 patients (mean age, 57 years) were obtained from individuals undergoing coronary artery bypass surgery for coronary artery disease. The samples were set up in organ baths to record changes in vessel wall tension. In undistended SVs the cysteinyl LTs elicited concentration-dependent contractions. The Emax for LTE4 (4.23 +/- 1.0 mN; n = 6) was significantly less than that observed with either LTC4 (25.7 +/- 4.01 mN; n = 7; P < .001) or LTD4 (26.19 +/- 3.16 mN; n = 7; P < .001). In addition, the LTD4 receptor antagonist ICI 198615 (30 nmol/L) significantly inhibited the LTD4 concentration-response curve but not the LTC4 responses. Furthermore, treatment of the SV with acivicin (0.05 mmol/L), a gamma-glutamyl transpeptidase inhibitor, caused a significant rightward displacement of the LTC4 concentration-response curve. In contrast, LTC4 and LTD4 produced a response in IMAs from only 3 of 29 patients. LTC4 and LTD4 produced small contractions, of which the maximum responses were 3.28 +/- 1.92 mN (n = 5) and 3.12 +/- 1.38 mN (n = 5). LTE4 produced no responses in the IMA. Experiments in which the SV was pretreated with L-NG-monomethyl-L-arginine (L-NMMA; 10(-4) mol/L) or indomethacin (10(-5) mol/L) or was denuded of endothelium had no significant effect on the Emax values for LTE4. Also, the IMA remained unresponsive to cysteinyl leukotrienes after treatment with L-NMMA or indomethacin or endothelium removal. In vitro autoradiography localized specific [3H]-LTC4 and [3H]-LTD4 binding sites (putative receptors) to the smooth muscle cells of both SV and IMA, with greater binding to the SV.

CONCLUSIONS

Our data show that there is a preferential contraction to LTs in SV compared with IMA. This difference in smooth muscle cell reactivity to the cysteinyl LTs suggests that endogenous LT production from circulating or infiltrating leukocytes may be an important factor contributing to graft function.
Holding smokers accountable for heart disease costs.
Authors: Kaesemeyer W H
Published: June 2012

This article discusses escalating health care costs in terms of their principal component, cardiovascular diseases. The role of cigarette smoking is highlighted throughout. A Smoker's Accountability Trust is proposed for the prevention of nonfatal myocardial infarction. It is demonstrated that this approach can contain costs by controlling the root causes of their acceleration.
Induction of acidic fibroblast growth factor and full-length platelet-derived growth factor expression in human cardiac allografts. Analysis by PCR, in situ hybridization, and immunohistochemistry.
Authors: Zhao X M , Yeoh T K , Frist W H , Porterfield D L , Miller G G
Published: June 2012

BACKGROUND

Further understanding of cardiac allograft vasculopathy (CAV) is needed to improve long-term survival after cardiac transplantation. The diffuse hyperplasia of coronary intima characteristic of CAV suggests that growth factors may play a role in the development of CAV. Fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) are potent mitogens for smooth muscle cells (SMCs), and PDGF is an important cofactor in the pathogenesis of native coronary atherosclerosis.

METHODS AND RESULTS

Reverse transcriptase/polymerase chain reaction (RT/PCR), in situ hybridization, and immunohistochemistry were used to determine whether transplantation results in increased cardiac expression of acidic (a) FGF, basic (b) FGF, and PDGF-A and -B chains. Sixty-eight myocardial biopsies from 36 heart transplant recipients and 7 normal hearts were analyzed by PCR. aFGF mRNA was present in 54 of 61 allograft biopsies and was not found in any normal heart. In situ hybridization and immunohistochemistry demonstrated diffuse, intense expression of a FGF mRNA and protein in allograft biopsies, predominantly in myocytes and vascular walls. Only scattered aFGF expression was observed in normal hearts. mRNA for the full-length isoform of PDGF-A chain was found in 43 of 61 allograft biopsies and was not detected in any normal heart. In situ hybridization and immunohistochemistry confirmed that full-length PDGF-A chain mRNA and PDGF protein were present in myocytes and vascular walls.

CONCLUSIONS

Expression of aFGF and PDGF-A chain is significantly increased in cardiac allografts. Cardiac myocytes and vascular walls are the predominant sources of aFGF and PDGF. Diffuse expression of these growth factors in cardiac allografts may be important in the pathogenesis of CAV.
Determinants of coronary artery reactivity in premenopausal female cynomolgus monkeys with diet-induced atherosclerosis.
Authors: Williams J K , Shively C A , Clarkson T B
Published: June 2012

BACKGROUND

The purpose of this study was to identify determinants of coronary artery reactivity among premenopausal female monkeys. Estrogen replacement therapy in postmenopausal females modulates reactivity of atherosclerotic coronary arteries. However, no studies have evaluated the factors that modulate coronary artery reactivity among premenopausal females.

METHODS AND RESULTS

Twenty-five adult premenopausal female monkeys were fed an atherogenic diet for 32 months. During this time, monkeys were housed in small social groups and determined to be socially dominant (associated with normal ovarian function) or subordinate (associated with impaired ovarian function). After 32 months, coronary artery vasomotor responses to intracoronary acetylcholine, nitroglycerin, and serotonin were assessed by computer-assisted quantitative coronary angiography. Coronary arteries of dominant monkeys dilated (+9 +/- 2%), whereas those of subordinate monkeys constricted (-6 +/- 2%) in response to acetylcholine (P < .05). There was no effect of social status on vascular response to nitroglycerin or serotonin (P > .10). Vascular responses to acetylcholine were independent of social status effects on plasma lipids, blood pressure, and atherosclerosis extent. The correlation between acetylcholine responses and plasma estradiol concentration measured on the day of angiography was r = .7 (P = < .01). Furthermore, dilation occurred only if plasma estradiol concentrations were greater than 60 pg/mL.

CONCLUSIONS

Psychosocial factors and endogenous estrogen production are important modulators of acetylcholine-mediated dilation of atherosclerotic coronary arteries among premenopausal female monkeys.
Adenovirus-mediated transfer of a gene encoding human apolipoprotein A-I into normal mice increases circulating high-density lipoprotein cholesterol.
Authors: Kopfler W P , Willard M , Betz T , Willard J E , Gerard R D , Meidell R S
Published: June 2012

BACKGROUND

In animal models of atherosclerosis, augmentation of circulating high-density lipoprotein (HDL) cholesterol exerts a protective effect against development of fatty streaks and promotes plaque regression.

METHODS AND RESULTS

To investigate the potential of gene transfer to increase HDL cholesterol, a fusion gene encoding human apolipoprotein A-I (apo A-I) under the control of the human cytomegalovirus (CMV) immediate-early promoter was packaged into a recombinant adenovirus (AdCMV apo A-I). BALB/c mice infected with AdCMV apo A-I by intravenous injection accumulate immunoreactive apo A-I in serum; levels 5 days after infection averaged 168 mg/dL. A 35% increase in HDL cholesterol and a 47% increase in total cholesterol were observed in mice infected with AdCMV apo A-I compared with control viruses. Analysis of size-fractionated lipoproteins revealed that human apo A-I is incorporated into murine HDL particles. Expression of human apo A-I declined to < 10% of maximum after 12 days and mRNA encoding apo A-I, prevalent 5 days after infection, was undetectable in the livers of infected mice after 12 days.

CONCLUSIONS

We conclude that adenovirus-mediated transfer of a gene encoding apo A-I produces transient elevations of circulating HDL cholesterol of a magnitude correlated with important physiological effects. These observations suggest the potential for gene-based therapeutic strategies to reduce cardiovascular risk.
Left ventricular end-systolic elastance is incorrectly estimated by the use of stepwise afterload variations in conscious, unsedated, autonomically intact dogs.
Authors: Crottogini A J , Willshaw P , Barra J G , Pichel R H
Published: June 2012

BACKGROUND

End-systolic elastance (Ees), the slope parameter of the end-systolic pressure (ESP)-volume (ESV) relation (ESPVR), is usually estimated in patients by producing stepwise, steady-state pharmacological afterload variations and collecting one ESP-ESV point from each step. The ESPVR is then constructed by fitting a linear equation to these points. In sedated, autonomically blocked dogs, it has been shown that when one point from control, one point from a state of increased afterload, and one point from a state of decreased afterload are used, the resulting Ees incorrectly estimates true Ees, defined as the slope of the ESPVR obtained by transient vena caval occlusion. We investigated if this was also the case in unsedated, autonomically intact dogs when the points used belonged to steady states of progressively decreasing or progressively increasing afterload pressure.

METHODS AND RESULTS

In 10 conscious dogs instrumented with left ventricular (LV) endocardial sonomicrometers to measure LV volume, a LV pressure transducer, and an inferior vena caval (IVC) occluder, two protocols were carried out on separate days. In each protocol, an ESPVR was generated by IVC occlusion in the control state and in two steady-state levels of afterload change produced by stepwise infusion of nitroprusside (protocol 1, afterload decrease) and angiotensin II (protocol 2, afterload increase). In each protocol, steady-state ESP-ESV data points were averaged from the control state and from each level of afterload variation. Linear equations were fitted to the three steady-state points from each protocol, and the estimated Ees values obtained (EesEST) were compared with the Ees values of the control ESPVRs obtained by IVC occlusion (EesTRUE). In protocol 1, EesEST underestimated EesTRUE by about 16% (EesEST, 6.49 +/- 1.55 mm Hg/mL; EesTRUE, 7.48 +/- 1.29 mm Hg/mL; P < .02). In protocol 2, EesEST overestimated EesTRUE by about 37% (EesEST, 9.99 +/- 3.97 mm Hg/mL; EesTRUE, 6.43 +/- 3.88 mm Hg/mL; P < .007).

CONCLUSIONS

In conscious, autonomically intact dogs, the use of stepwise, steady-state afterload variations to obtain ESP-ESV data points to construct the ESPVR incorrectly estimates Ees. In the case of afterload reduction, EesTRUE is underestimated an average of 16.3%, and in the case of afterload increase, EesTRUE is overestimated an average of 37.1%. These errors should be taken into account when interpreting clinical studies using this methodology.
Cytomegalovirus infection-enhanced allograft arteriosclerosis is prevented by DHPG prophylaxis in the rat.
Authors: Lemström K B , Bruning J H , Bruggeman C A , Koskinen P K , Aho P T , Yilmaz S , Lautenschlager I T , Häyry P J
Published: June 2012

BACKGROUND

Major risk factors for accelerated allograft arteriosclerosis include humoral and cellular immune response, hyperlipidemia, and viral infections. We demonstrated earlier that rat cytomegalovirus (RCMV) infection doubles smooth muscle cell proliferation and intimal thickening of rat aortic allografts. In this study, the effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) on RCMV-enhanced rat allograft arteriosclerosis are investigated.

METHODS AND RESULTS

Aortic allografts from the DA to the WF rat strain were used. The recipients were inoculated with 10(5) plaque-forming units of RCMV 1 day after transplantation. Two groups of RCMV-infected rats were treated with DHPG with an initial dose of 20 mg/kg IP and a maintenance dose of 10 mg/kg IP twice a day for a period of 14 days. In the DHPG prophylaxis group (n = 22), the drug administration started 1 day before infection, and in the DHPG treatment group (n = 17), 7 days after infection. One group of infected rats was left untreated (n = 21). The grafts were removed 7 and 14 days and 1, 3, and 6 months after transplantation. In the DHPG prophylaxis group, no virus could be recovered by plaque assays. In the treatment group, 50% of rats were virus-positive at 1 month and 40% at 3 months. DHPG prophylaxis prevented the infiltration of inflammatory cells and their proliferation in the adventitia of RCMV-infected recipients (P < .01), with a 60% reduction in the interleukin-2 receptor expression (P < .05) and a 30% decrease in major histocompatibility complex class II expression (P = NS). DHPG prophylaxis did not significantly alter the levels of insulin-like growth factor-1, epidermal growth factor, platelet-derived growth factor-BB, transforming growth factor-beta 1, acidic fibroblast growth factor, and basic fibroblast growth factor messages in the allograft vascular wall. Early media necrosis was reduced. Arteriosclerotic alterations and proliferation of smooth muscle cells were both reduced 50% to 70% by DHPG prophylaxis (P < .05 at 3 months). The responses in the DHPG treatment group were quite similar but less impressive and statistically nonsignificant.

CONCLUSIONS

We consider it likely that DHPG inhibits arteriosclerotic alterations primarily by reducing the infectious virus and thereby the inflammatory response in the allograft vascular wall; another possibility is a direct antiproliferative effect on smooth muscle cell replication. A dose-dependent inhibitory effect of DHPG on smooth muscle cell replication was recorded in an in vitro study.
Vagal cardiopulmonary reflexes after left ventricular deafferentation.
Authors: Minisi A J , Cersley T L
Published: June 2012

BACKGROUND

Cardiac transplantation and chronic myocardial infarction interrupt vagal afferent nerve fibers, which originate mainly from the ventricles. Marked abnormalities of reflexes mediated by cardiopulmonary receptors with vagal afferent fibers have been demonstrated after both cardiac transplantation and chronic myocardial infarction. The relation between these reflex abnormalities and ventricular deafferentation is not known.

METHODS AND RESULTS

To further assess this relation, we investigated the effects of left ventricular (LV) deafferentation on the control of renal sympathetic nerve activity (RSNA) by the vagal cardiopulmonary reflex in chloralose-anesthetized, mechanically ventilated dogs with sinoaortic denervation. Responses of left atrial pressure (LAP) and RSNA to hemorrhage and volume expansion were measured before and after application of 88% phenol to either the inferoposterior LV (n = 12) or the entire LV (n = 14). In control experiments, measurements were made before and after application of saline to the LV (n = 12). Reflex sensitivity (percent change in RSNA per mm Hg change in LAP) measured during volume expansion was mildly attenuated after both total (prephenol, -9.1 +/- 0.7; postphenol, -6.6 +/- 0.7; P < .05) and inferoposterior (pre, -12.5 +/- 1.8; post, -8.1 +/- 0.6; P = .055) LV deafferentation. Reflex sensitivity measured during hemorrhage was not significantly altered by inferoposterior or total LV deafferentation. Epicardial saline had no significant effect on reflex sensitivity values measured during either volume expansion or hemorrhage. Reflex inhibition of RSNA in response to intracoronary nicotine was abolished after phenol application, indicating adequate ventricular deafferentation. Phenol application had no significant effect on LAP-myocardial segment length relations measured by sonomicrometry (n = 6).

CONCLUSIONS

Interruption of vagal afferent input from the LV has only modest effects on the control of RSNA by the vagal cardiopulmonary reflex. These data indicate that there is considerable redundancy in the vagal cardiopulmonary reflex such that receptors from the lungs and other cardiac chambers can largely compensate for the loss of afferent input from the LV.
Do fish oils prevent restenosis after coronary angioplasty?
Authors: Leaf A , Jorgensen M B , Jacobs A K , Cote G , Schoenfeld D A , Scheer J , Weiner B H , Slack J D , Kellett M A , Raizner A E
Published: June 2012

BACKGROUND

The omega-3 polyunsaturated fatty acids derived from fish oils have been shown to modulate many factors believed to affect the pathogenesis of atherosclerosis. Because certain features of restenosis following angioplasty mimic some of the early changes of atherogenesis, some researchers have suggested that fish oil might prevent restenosis following angioplasty. We report the effects of omega-3 fatty acids on the rate of restenosis following percutaneous intraluminal coronary angioplasty (PTCA).

METHODS AND RESULTS

From August 1989 through September 1992, 551 patients were randomized to start receiving a daily dietary supplement of ten 1.0-g capsules containing 80.6% ethyl esters of omega-3 fatty acids providing 4.1 g eicosapentaenoic acid (EPA) and 2.8 g docosahexaenoic acid (DHA) for 6 months or an equal amount of an ethyl ester of corn oil. Four hundred seventy subjects who were well matched for risk factors completed successful angioplasty of one or multiple lesions in native coronary vessels and constituted the study cohort, of whom 447 were evaluable at 6 months after PTCA. The criteria for restenosis were that the quantitative coronary angiography at 6 months show a > 30% increase in narrowing at the stenosis site or loss of at least half of the gain achieved at the time of PTCA and final restenosis with < 50% luminal diameter remaining. In 93% of the patients, the end point was determined by angiography and in all except 1% of these by quantitative coronary angiography. Compliance with the fish oil supplement was good as judged by incorporation of EPA and DHA in plasma and red blood cell phospholipids. The restenosis rate among analyzable patients was 46% for corn oil and 52% for fish oil (P = .37). The addition of 200 mg alpha-tocopherol for all subjects during the study had no effect on restenosis rates.

CONCLUSIONS

This was the largest of such trials to date, and a supplement of 8 g/d of omega-3 fatty acids failed to prevent the usual high rate of restenosis after PTCA. No adverse effects were attributable to this large daily supplement of omega-3 fatty acids.
Adjunctive intracoronary infusion of antithrombin III during percutaneous transluminal coronary angioplasty. Results of a prospective, randomized trial.
Authors: Schächinger V , Allert M , Kasper W , Just H , Vach W , Zeiher A M
Published: June 2012

BACKGROUND

Heparin needs the plasma protein antithrombin III to function as an inhibitor of thrombin, and local antithrombin III deficiency might therefore limit the antithrombotic effectiveness of heparin during percutaneous transluminal coronary angioplasty.

METHODS AND RESULTS

In the present double-blind study, 615 consecutive patients undergoing percutaneous transluminal coronary angioplasty (PTCA), of a total of 713 stenoses, were prospectively randomized to receive a bolus injection of 15,000 U heparin followed by a continuous intracoronary infusion via the guiding catheter of either 250 U heparin per minute or 250 U heparin plus 25 U antithrombin III per minute during the procedure. Four clinical variables, 19 lesion-specific characteristics, and 16 procedure-related variables were evaluated. Procedural success was assessed by quantitative angiography; procedure-related ischemic complications were analyzed during in-hospital follow-up. Procedural success rates (< 50% final diameter stenosis and no major ischemic complication) were similar, with 85% in the heparin group (n = 324 patients) and 83% in the heparin+antithrombin III group (n = 291 patients). Percent diameter stenosis after PTCA was 39 +/- 18% in the heparin group and 40 +/- 20% in the heparin+antithrombin III group (NS). There were no differences between the two groups with respect to PTCA-related acute vessel occlusion, angiographic evidence of intracoronary thrombus formation, post-procedure creatine kinase increase, Q-wave myocardial infarction, or emergency coronary artery bypass surgery. High-risk subgroup analysis revealed no beneficial effect of adjunctive intracoronary antithrombin III in any of the analyzed subgroups. In addition, although risk stratification according to the criteria of the American College of Cardiology/American Heart Association Task Force classification proved to be very useful for the entire study population, no beneficial effect of intracoronary antithrombin III infusion was observed in any of the different risk groups.

CONCLUSIONS

Compared with heparin alone, adjunctive intracoronary antithrombin III therapy does not appear to have any beneficial effect on procedural outcome as well as type and frequency of acute complications during PTCA even in subgroups of patients with a high risk for thrombotic complications. Thus, a local deficiency of antithrombin III does not play a major role for the failure of heparin to abolish thrombotic complications during PTCA.
Role of nitric oxide in reactive hyperemia in human forearm vessels.
Authors: Tagawa T , Imaizumi T , Endo T , Shiramoto M , Harasawa Y , Takeshita A
Published: June 2012

BACKGROUND

The role of nitric oxide (NO) in reactive hyperemia (RH) is not well known. We investigated whether NO plays a role in RH in human forearm vessels by examining the effects of NG-monomethyl-L-arginine (L-NMMA), a blocker of NO synthesis, on reactive hyperemic flow.

METHODS AND RESULTS

Forearm blood flow (FBF) was measured by strain-gauge plethysmography with a venous occlusion technique. The left brachial artery was cannulated for drug infusion and direct measurement of arterial pressure. To produce RH, blood flow to the forearm was prevented by inflation of a cuff on the upper arm to suprasystolic pressure for intervals of 3 and 10 minutes. After the release of arterial occlusion (AO), FBF was measured every 15 seconds for 3 minutes. Resting FBF was 4.3 +/- 0.3 mL.min-1.100 mL-1 before 3 minutes of AO and 4.1 +/- 0.6 mL.min-1.100 mL-1 before 10 minutes of AO. FBF increased to 32.3 +/- 1.9 and 38.2 +/- 3.1 mL.min-1.100 mL-1 immediately after 3 and 10 minutes of AO, respectively, and gradually decayed (n = 13). Intra-arterial infusion of L-NMMA (4 mumol/min for 5 minutes) decreased baseline FBF (P < .01) without changes in arterial pressure. L-NMMA did not affect the peak reactive hyperemic FBF after 3 and 10 minutes of AO. L-NMMA significantly decreased total reactive hyperemic flow (flow debt repayment) by 20% to 30% after 3 and 10 minutes of AO. Simultaneous infusion of L-arginine (a precursor of NO) with L-NMMA reversed the effects of L-NMMA.

CONCLUSIONS

Our results suggest that NO plays a minimal role in vasodilation at peak RH but plays a modest yet significant role in maintaining vasodilation after peak vasodilation. Our results also suggest that reactive hyperemia in human forearms is caused largely by mechanisms other than NO.
17 beta-Estradiol inhibits flow- and acute hypoxia-induced prostacyclin release from perfused endocardial endothelial cells.
Authors: Redmond E M , Cherian M N , Wetzel R C
Published: June 2012

BACKGROUND

Because of the marked difference in the incidence and severity of cardiovascular diseases between men and premenopausal women, several groups have studied the effect of sex steroids, particularly estrogen, on vascular endothelial prostacyclin (PGI2) release. No previous studies have addressed the effect of estrogen on endocardial endothelial cells (EECs), which are involved in the modulation of the myocardium and potentially in downstream pulmonary and systemic vascular tone. Furthermore, all previous studies of estrogen effects on cultured endothelial cell function have used cells grown under standard static cell culture conditions, thereby ignoring the contribution of flow, the ubiquitous environmental endothelial stimulus.

METHODS AND RESULTS

The effect of 17 beta-estradiol pretreatment (100 ng/mL, 72 hours) on cultured sheep EEC PGI2 release in response to multiple physiologically relevant stimuli was studied. EECs were grown in six-well plates (static conditions) or on microcarrier beads and perfused at a constant flow with normoxic (PO2 = 150 mm Hg, PCO2 = 35 mm Hg) or hypoxic (PO2 = 35 mm Hg, PCO2 = 35 mm Hg) Krebs solution. The stable metabolite of PGI2, 6-keto-PGF1 alpha, was determined in samples from both static and perfusion experiments by direct radioimmunoassay. 17 beta-Estradiol pretreatment did not alter basal or stimulated (arachidonic acid, 1 mumol/L, 10 mumol/L; A23187, 10 mumol/L; and bradykinin, 1 mumol/L) PGI2 release in static conditions. Untreated and acutely treated (100 ng/mL added to perfusate) EECs responded to flow with a time-dependent increase in PGI2 release that plateaued between 60 and 100 minutes. In contrast, 17 beta-estradiol-pretreated, perfused EECs did not increase PGI2 release over time. During perfusion, acute hypoxia increased PGI2 release: 140 +/- 65 (normoxia) to 296 +/- 113 pg (hypoxia) 6-keto-PGF1 alpha/mg per minute. 17 beta-Estradiol inhibited hypoxia-induced PGI2 release: 296 +/- 113 pg (untreated EECs, hypoxia) versus 159 +/- 60 pg (17 beta-estradiol pretreated, hypoxia) 6-keto-PGF1 alpha/mg per minute.

CONCLUSIONS

This study demonstrates for the first time an inhibitory effect of 17 beta-estradiol on flow- and acute hypoxia-induced increase in PGI2 release from perfused EECs in the absence of any effect on pharmacologically stimulated PGI2 release from static cultures. These effects of 17 beta-estradiol may explain in part the well-recognized gender and estrogen effects in cardiovascular diseases and highlight the importance of flow in studies of endothelial cell function.
Correlation between decreased myocardial glucose phosphorylation and the DNA mutation size in myotonic dystrophy.
Authors: Annane D , Duboc D , Mazoyer B , Merlet P , Fiorelli M , Eymard B , Radvanyi H , Junien C , Fardeau M , Gajdos P
Published: June 2012

BACKGROUND

Myotonic dystrophy, the most common form of adult dystrophy, has been shown to be caused by amplification of CTG triplet repeat in the 3' untranslated region of a protein kinase gene located on chromosome 19. Impaired glucose metabolism has been suggested as a possible explanation of brain and skeletal muscle involvement in this multisystem disease. We investigated whether myocardial glucose metabolism is impaired in myotonic dystrophy and whether this impairment is related to the size of the mutation.

METHODS AND RESULTS

The myocardial metabolic rate for glucose (MMRGlu, mumol.min-1.g-1), K1 (blood-to-tissue transfer constant), k2 (tissue-to-blood transfer constant), and k3 (phosphorylation rate constant) were determined in 7 control subjects and 12 patients with myotonic dystrophy by using parametric images generated from dynamic cardiac positron emission tomography (PET) and 18F-fluoro-2-deoxy-glucose studies. The expansion of the CTG triplet repeats was analyzed in patients with the probe cDNA25 after EcoRI digestion. Nonparametric tests were used to compare quantitative variables between control subjects and patients. The correlations between the size of the mutation and PET parameters were studied by linear regression. MMRGlu and k3 were significantly decreased in patients compared with control subjects (0.39 +/- 0.20 versus 0.64 +/- 0.25, P = .03, and 0.09 +/- 0.07 versus 0.24 +/- 0.21, P = .03, respectively), whereas K1 and k2 were not statistically different between control subjects and patients. MMRGlu and k3 correlate inversely with the length of the CTG triplet repeat (r = -.65 and P = .03 for MMRGlu, and r = -.85 and P = .001 for k3, respectively).

CONCLUSIONS

In myotonic dystrophy, the observed reductions in MMRGlu and phosphorylation are inversely linked to the length of the mutation. This observation suggests that impaired modulation of a protein kinase involved in myocardial hexokinase activation may give a pathophysiological schema to relate the molecular defect and the abnormal myocardial metabolism in myotonic dystrophy.
Evidence of genetic heterogeneity in Romano-Ward long QT syndrome. Analysis of 23 families.
Authors: Towbin J A , Li H , Taggart R T , Lehmann M H , Schwartz P J , Satler C A , Ayyagari R , Robinson J L , Moss A , Hejtmancik J F
Published: June 2012

BACKGROUND

The Romano-Ward long-QT Syndrome (LQTS) is an autosomal dominant inherited trait characterized by prolonged QT interval on ECG, life-threatening arrhythmias, syncope, and sudden death in affected individuals. A gene responsible for this disorder has been shown to be linked to the Harvey ras-1 locus (H-ras-1) DNA marker on the short arm of chromosome 11 (11p) in 7 families. The purpose of this study was to determine, by analyzing 23 families with LQTS for linkage to chromosome 11p, whether evidence exists for more than one gene causing LQTS (ie, locus heterogeneity).

METHODS AND RESULTS

Twenty-three families (262 family members) were clinically evaluated using medical histories, ECGs, and Holter recordings. Each corrected QT interval (QTc) were determined using Bazett's formula. Blood for DNA extraction and cell line immortalization was obtained after informed consent. Southern blotting and polymerase chain reaction were performed, and linkage analysis carried out using the LINKAGE computer program (v 5.03). Genetic heterogeneity was determined using the HOMOG 2 (v 2.51) computer program. Twenty-three families were studied for evidence of linkage to chromosome 11p using the H-ras-1 locus probe pTBB-2 and multiple flanking markers, including tyrosine hydroxylase (TH). Two-point linkage analysis using pTBB-2 and TH markers was consistent with linkage in 15 of 23 families, with the maximum single-family LOD score of +3.038 occurring at theta = 0. However, 8 of 23 families had negative LOD scores, with the values in 4 families being less than -2 at theta = 0, consistent with exclusion of linkage. Analysis with the HOMOG program was consistent with genetic heterogeneity (P < .0001). Multipoint linkage data using pTBB-2 and TH were also examined for evidence of heterogeneity. HOMOG analysis of multipoint LOD scores from 100 cM surrounding the H-ras-1 locus also supported heterogeneity (P < .001).

CONCLUSIONS

In the 23 families with LQTS analyzed for linkage to the H-ras-1 locus on chromosome 11p15.5, 15 of 23 families had LOD scores consistent with linkage. The remaining 8 of 23 families had negative LOD scores, 4 of which were definitively excluded from linkage. Thus, genetic heterogeneity is definitively (P < .001) demonstrated for this disorder.
Long-term survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry.
Authors: Emond M , Mock M B , Davis K B , Fisher L D , Holmes D R , Chaitman B R , Kaiser G C , Alderman E , Killip T
Published: June 2012

BACKGROUND

This study describes the impact of clinical, angiographic, and demographic characteristics on the long-term survival of Coronary Artery Surgery Study (CASS) patients while they were under medical treatment. Revascularization rates for the population are also provided.

METHODS AND RESULTS

All CASS patients who had not received heart surgery before enrollment (23,467 patients) were included in this survival analysis while they were under medical treatment or surveillance. Follow-up time ranged from 0 to 17 years (median, 12 years). Long-term vital status is known for 95.8% of these patients. Log-rank tests, Kaplan-Meier survival curves, and Cox proportional-hazards regression are used to describe and assess the impact of patient characteristics on survival. Characteristics that had a significant impact on survival, in order of observed explanatory power, are age, number of diseased vessels, congestive heart failure score, smoking history, ejection fraction, sex, presence of left main coronary artery disease, presence of diabetes, left ventricular wall motion score, presence of other illnesses, history of myocardial infarction, and presence of left main equivalent disease. Overall, 12-year survival for patients with zero-, one-, two- and three-vessel disease is 88%, 74%, 59%, and 40%, respectively. Twelve-year survival for patients with at least one diseased vessel and ejection fractions in the ranges of 50% to 100%, 35% to 49%, and 0% to 34% is 73%, 54%, and 21%, respectively. High myocardial jeopardy, high anginal class, and two or three proximal diseased vessels characterize the profile of patients most likely to have received surgical treatment during follow-up.

CONCLUSIONS

These results contribute to the understanding of the natural history of coronary artery disease and are also of historical interest. The poor survival of patients with three-vessel disease and low ejection fractions continues to emphasize the importance of considering revascularization for these patients.
Relation between physical training and ambulatory blood pressure in stage I hypertensive subjects. Results of the HARVEST Trial. Hypertension and Ambulatory Recording Venetia Study.
Authors: Palatini P , Graniero G R , Mormino P , Nicolosi L , Mos L , Visentin P , Pessina A C
Published: June 2012

BACKGROUND

This study was undertaken to assess whether ambulatory blood pressure (BP) in a population of stage I hypertensive individuals was lower in the subjects performing regular exercise training.

METHODS AND RESULTS

The study was carried out in 796 young hypertensive patients (592 men) who had never been treated who took part in the HARVEST trial. The diagnosis of stage I hypertension was made on the basis of six office BP measurements. Subjects underwent noninvasive 24-hour ambulatory BP monitoring, 24-hour urine collection for catecholamine assessment, and echocardiography (n = 457). They were classified as exercisers if they reported at least one session of aerobic sports per week and as nonexercisers if they did not engage regularly in sports activities. Age (P < .0001), body mass index (P = .002), 24-hour heart rate (P < .0001), alcohol intake (P = .02), smoking (P = .02), and norepinephrine output (P = .04) were lower in the active (n = 153) than the inactive (n = 439) men. Physically active men exhibited a lower 24-hour and daytime diastolic BP than the inactive men, while there were no group differences in office BP or in nighttime diastolic BP and in ambulatory systolic BP. The between-group ambulatory diastolic BP difference remained statistically significant after adjustment for age, body mass index, alcohol intake, and smoking (P < .0001). Of the nonexercisers, 46.2% were confirmed hypertensives, compared with only 26.8% of the exercisers (P < .0001), on the basis of daytime diastolic BP. Echocardiographic left ventricular dimensional and functional indexes were similar in the two groups of men. Similar findings were shown by the 16 women who engaged in aerobic sports.

CONCLUSIONS

These data suggest that participation in aerobic sports may attenuate the risk of hypertension in young subjects whose office BP is in the stage I hypertensive range at office measurement.
Impact of Acute Pulmonary Rejection on Cardiac Function
Authors: McLarty Allison J. , McGregor Christopher G. A. , Shu N. H. , Miller Virginia M. , Ritman Erik L.
Published: June 2012

Background
Experiments were designed to define cardiac function in dogs with single lung allografts during acute rejection of the allografted lung.

Methods and Results
Left lungs were either autotransplanted (n=4) or allotransplanted (n=8) in adult male mongrel dogs. All allotransplanted animals were maintained on triple-drug immunosuppression (cyclosporine, azathioprine, and steroids) for 5 days after the operation. In 4 allotransplanted animals, treatment was discontinued, allowing the animals to reject (usually after a further 3 days; rejecting group); 4 other allotransplanted animals were maintained on immunosuppression for an additional 3 days (immunosuppressed group). Another group of dogs were not operated on but were maintained on the same immunosuppression as the rejecting group (controls). All experimental animals underwent fast computed tomographic scanning with measurement of left ventricular pressure and calculation of ventricular chamber volumes, cross-sectional areas of coronary arteries, myocardial perfusion, and intramyocardial blood volume. Neither cardiac output, left ventricular mass, left ventricular pressure, nor myocardial oxygen consumption was altered during acute rejection of lung allografts. However, left ventricular contractility (systolic elastance, E
max
) and ejection fraction were depressed to approximately one half (
P
<.05) in acutely rejecting animals compared with other groups. The cross-sectional area of the coronary arteries was less in autotransplanted and allotransplanted treated animals than in animals that were not operated on. Cross-sectional area of the coronary arteries was decreased by an additional 30% in the rejecting group (
P
<.05).

Conclusions
The results of this study indicate that acute rejection of a single lung allograft decreases cardiac performance and reduces diameter of coronary arteries in the recipient. Alterations of circulating humoral factors and activated leukocytes may contribute to these changes.
Long-term Reproducibility of Ventricular Tachycardia Induction in Patients With Implantable Cardioverter/Defibrillators
Authors: Gillis Anne M. , Sheldon Robert S. , Wyse D. George , Leitch James W. , Yee Raymond , Klein George J. , Duff Henry J. , Mitchell L. Brent
Published: June 2012

Background
Noninvasive electrophysiological studies (EPSs) can be performed in current implantable antitachycardia pacemaker/cardioverter/defibrillators (ICDs). Thus, these devices may be used as tools to study changes in the electrophysiological substrate and ventricular tachycardia characteristics over time.

Methods and Results
Fifty-five patients receiving an ICD for treatment of sustained ventricular tachyarrhythmias underwent serial EPSs after implantation of the ICD. Studies were performed before hospital discharge and 1, 3, 5, 9, 12, 18, 24, and 36 months after ICD implantation. Sustained monomorphic ventricular tachycardia (VT) was induced in 37 patients (group 1) at the predischarge EPS, whereas no sustained arrhythmia could be induced in 18 patients (group 2) at baseline. Group 1 patients underwent 165 noninvasive EPSs after discharge. Sustained monomorphic VT was induced during 72% of the follow-up EPSs, ventricular fibrillation (VF) was induced during 11% of follow-up EPSs, and no sustained VT or VF was induced during 17% of follow-up visits. Sustained VT was induced at every follow-up EPS in 23 patients (62%), whereas no sustained VT/VF could be induced at least once during follow-up in 14 patients (38%). Clinical or electrophysiological variables did not predict noninducibility during follow-up. However, the probability that a patient would experience spontaneous VT decreased significantly over time in patients in whom VT was not inducible during at least 1 follow-up EPS (
P
=.05). Group 2 patients underwent 86 noninvasive EPSs after discharge. Sustained monomorphic VT was induced during 22% of follow-up EPSs, VF was induced during 19% of follow-up EPSs, and no sustained VT/VF could be induced during 68% of follow-up EPSs. No sustained VT/VF could be induced during every follow-up EPS in 9 patients (50%), whereas sustained monomorphic VT was induced at least once during follow-up in 7 patients (34%). Persistent noninducibility of VT during follow-up was associated with low probability of occurrence of spontaneous VT (11%), whereas inducibility of VT at least once during follow-up was associated with the occurrence of spontaneous VT (89%,
P
=.003).

Conclusions
Considerable variability of VT induction is observed over a lengthy period in patients presenting with sustained VT/VF. Persistent noninducibility of VT is associated with a reduced probability of spontaneous VT. These observations suggest that the substrates for inducible and spontaneous VT change in parallel over time.
Modification of the Fontan Procedure
Authors: Laks Hillel , Ardehali Abbas , Grant Peter W. , Permut Lester , Aharon Alon , Kuhn Micheal , Isabel-Jones Josephine , Galindo Alvaro
Published: June 2012

Background
A modification of the Fontan procedure with unidirectional cavopulmonary connection is described in which the superior vena cava (SVC) is connected to the left pulmonary artery (PA) and the inferior vena cava (IVC) is connected to the right PA via a lateral tunnel with a snare-controlled, adjustable atrial septal defect (ASD). This allows matching of the SVC and IVC flows with the lung of appropriate size. The obligatory left Glenn shunt provides an adequate arterial oxygen saturation, and the elevation in SVC pressure is well tolerated. The adjustable ASD allows selective decompression of the IVC that maintains cardiac output and reduces fluid accumulation in the serous cavities.

Methods and Results
Since March 1992, we have performed this procedure in 18 patients. There were 17 children and 1 adult. Median age was 3 years and 9 months (range, 13 months to 36 years). Six patients had been staged with a previous bidirectional Glenn shunt. Preoperative cardiac catheterization revealed a PA pressure of 13±2 mm Hg and a transpulmonary gradient of 5±3 mm Hg. Ventricular function was satisfactory in all patients. At the completion of bypass, the pressures in the SVC and IVC were 16±4 mm Hg and 10±3 mm Hg, respectively (
P
<.01). The left atrial pressure was 6.0±3.0 mm Hg and the arterial O
2
saturation on 100% oxygen was 93±3%. There was one death as a result of intractable atrial arrhythmias. The remaining 17 patients had a mean hospital stay of 9.7 days (6 to 18 days). The length of pleural drainage was 7±3 days. The ASD was adjusted in 11 patients before discharge. Oxygen saturation at discharge was 85.4±4%. Nine patients had repeat catheterization. The ASD was completely closed in 6 patients, an average of 2.5 months after surgery (range, 3 weeks to 5 months). After ASD closure, the arterial oxygen saturation was 96±3%, and the SVC and IVC pressures were both 13±3 mm Hg.

Conclusions
The Fontan procedure with unidirectional cavopulmonary connection and adjustable ASD has several advantages that may reduce mortality and morbidity for the high-risk Fontan candidate.
Use of Intravascular Stents in Systemic Venous and Systemic Venous Baffle Obstructions
Authors: Ward Cameron J.B. , Mullins Charles E. , Nihill Michael R. , Grifka Ronald G. , Vick G. Wesley
Published: June 2012

Background
Balloon-expandable intravascular stents are well accepted in the management of arterial obstructions. This study was undertaken to detail the immediate and short-term results of intravascular stent implantation in systemic venous and systemic venous baffle obstructions in children.

Methods and Results
Between September 1991 and June 1994, 12 patients had 21 stents implanted in 13 systemic venous obstructions, 1 patient having stents placed in 2 separate obstructions. In the baffle group, 4 of 13 obstructions were at the superior vena cava/right atrial junction after atrial baffling for transposition of the great arteries. One of 4 patients had complete obstruction requiring transseptal needle perforation before stent implantation. There was an immediate gradient reduction from 12±8.4 mm Hg (range, 4 to 20 mm Hg) to 1.3±1.9 mm Hg (range, 0 to 4 mm Hg,
P
=.05). The obstructed segment diameter increased from 3.5±3.9 mm (range, 0 to 8.5 mm) to 16±2.7 mm (range, 14 to 20 mm,
P
=.002). In the central vein group, 9 of 13 obstructions were in large central veins. Three of 9 patients had complete obstruction requiring transseptal needle perforation before stent implantation. There was an immediate gradient reduction from 10.3±8.5 mm Hg (range, 0 to 20 mm Hg) to 0.8±1.1 mm Hg (range, 0 to 3 mm Hg,
P
=.005). The obstructed segment diameter increased from 1.3±1.1 mm (range, 0 to 2.8 mm) to 9.4±1.7 mm (range, 7.6 to 12 mm,
P
<.001). There were no acute complications in either group. In the follow-up group, patients were scheduled for clinical follow-up at 3, 6, and 12 months with echocardiography or magnetic resonance imaging (MRI) at 3 or 6 months and for repeat cardiac catheterization at 12 months. All stents were patent by echocardiography or MRI when studied at follow-up. Cardiac catheterization in 6 of 12 patients, 2 to 13 months after stent, demonstrated that all stents remained patent without compression or fracture. Follow-up and immediate poststent gradients were not significantly different (1±1.6 versus 0.7±1.2 mm Hg,
P
=NS). Neointimal hyperplasia (5 of 6 patients) reduced the stent lumen only from 12.5±4.7 mm (range, 8 to 20 mm) to 10.6±4.7 mm (range, 4.5 to 17.7 mm,
P
=NS). No stents required redilation. One of 18 stents placed in series had “unlocked” and rotated in the venous lumen but remained fully patent to flow.

Conclusions
Balloon-expandable intravascular stents can be safely and effectively used to relieve systemic venous and systemic venous baffle obstructions, even when obstruction is complete. Short-term follow-up suggests excellent continued patency, but further follow-up is required to observe for progression of neointimal hyperplasia. We postulate that balloon-expandable intravascular stents will become the treatment of choice for the relief of selected systemic venous and venous baffle obstructions in the pediatric population.
Effect of Cocaine on Left Ventricular Function
Authors: Mehta Prabodh M. , Grainger Terry A. , Lust Robert M. , Movahed Assad , Terry Jarrett , Gilliland M.G.F. , Jolly Stanley R.
Published: June 2012

Background
To determine whether alterations in left ventricular (LV) function after a cocaine infusion are due to reduced myocardial contractility or changes in loading conditions, we examined LV function in 30 morphine-sedated, closed-chest dogs. We also wanted to determine the time course of the effects of cocaine on LV function after the infusion was stopped.

Methods and Results
Two-dimensional echocardiography and hemodynamics provided LV fractional shortening and end-systolic wall stress data. Radionuclide ventriculography was also performed. Four groups of dogs received saline or cocaine infusions of 10, 30, or 100 μg · kg
−1
· min
−1
. Cocaine was infused for 90 minutes with ECG and arterial pressure monitoring. Animals were monitored for an additional 120 minutes after the infusion ended. Arterial pressure rose over the course of the experiment in all four groups, but saline and cocaine 10 μg · kg
−1
· min
−1
did not significantly change ejection fraction. Cocaine 30 and 100 μg · kg
−1
· min
−1
acutely increased arterial pressure and heart rate but decreased ejection fraction from 0.64±0.06 to 0.45±0.08 and from 0.65±0.10 to 0.46±0.11, respectively. Additionally, cocaine 100 μg · kg
−1
· min
−1
decreased fractional shortening from 36±9% to 23±12%. However, cocaine 30 and 100 μg · kg
−1
· min
−1
also increased wall stress from 42±15 to 65±11 g/cm
2
and from 37±15 to 90±33 g/cm
2
, respectively. These results were analyzed by use of the relation between wall stress and fractional shortening as an index of contractility. Fractional shortening after cocaine infusion was displaced downward as a result of increased wall stress rather than changes in contractility. In addition, alteration of afterload with phenylephrine (6 μg/kg) and sodium nitroprusside (10 μg/kg) before and during infusion of cocaine 100 μg · kg
−1
· min
−1
showed similar regression lines for wall stress to fractional shortening.

Conclusions
Ejection-phase indexes of LV function were reduced by cocaine in this model of conscious, sedated dogs, but effects were attributable to increased wall stress rather than to reduced myocardial contractility. These effects persisted for at least 2 hours after the infusion was stopped.