bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Expression of Tissue Inhibitors of Metalloproteinases in the Failing Human Heart
Authors: Li Yun You , Feldman Arthur M. , Sun Yi , McTiernan Charles F.
Published: June 2012

Background
—Extracellular matrix turnover is regulated by matrix metalloproteinases (MMPs) and a family of tissue inhibitors of metalloproteinases (TIMPs). Together, these proteins may contribute to myocardial remodeling in congestive heart failure. We hypothesized that the expression of MMPs and TIMPs might be differentially regulated in the failing human heart.

Methods and Results
—Northern blot analyses were performed with probes to TIMP-1 to -4 and GAPDH with poly A
+
mRNA from ventricular tissues of patients with ischemic cardiomyopathy (ICM, n=16) or idiopathic dilated cardiomyopathy (DCM, n=15) and nonfailing control hearts (n=15). TIMP-1 to -4 and MMP-9 proteins were quantified by ELISA and/or Western blot, and the total gelatinolytic activity was studied by gelatin zymography. The results showed that cardiac expression of TIMP-1 and -3 transcripts and proteins was significantly reduced in ICM and DCM. No significant difference was observed in TIMP-2 and -4 transcripts. However, TIMP-4 protein was significantly reduced in ICM myocardium. MMP-9 protein content and total gelatinolytic activity were upregulated in the same samples.

Conclusions
—These studies demonstrated a selective downregulation of TIMPs along with upregulation of MMP-9 and gelatinolytic activity in the failing hearts, alterations that favor matrix degradation and turnover. These findings might be of pathophysiological significance and might suggest new therapeutic targets for limiting the ventricular remodeling and dilatation process characteristic of the failing human heart.
Hyperhomocysteinemia After an Oral Methionine Load Acutely Impairs Endothelial Function in Healthy Adults
Authors: Bellamy M.F. , McDowell I.F.W. , Ramsey M.W. , Brownlee M. , Bones C. , Newcombe R.G. , Lewis M.J.
Published: June 2012

Background
—Elevated plasma homocysteine is a risk factor for arteriosclerosis, but a cause-and-effect relationship remains to be fully established. Endothelial dysfunction, an early event in the atherogenic process, has been shown to be associated with hyperhomocysteinemia in experimental and human studies. To further establish a direct relationship between changes in plasma homocysteine and endothelial dysfunction, we investigated whether moderate hyperhomocysteinemia induced by an oral methionine load would acutely impair flow-mediated endothelium-dependent vasodilatation in healthy adults.

Methods and Results
—Twenty-four healthy volunteers completed a randomized crossover study in which an oral methionine load (0.1 g/kg) was administered on 1 of 2 study days, 7 days apart. At each visit, plasma homocysteine and brachial artery endothelium-dependent and -independent dilatation were measured at baseline and at 4 hours. To further elucidate the temporal relationship between methionine, homocysteine, and endothelial function, an oral methionine load was administered in 10 subjects on a separate visit, and the time courses of plasma methionine, homocysteine, and flow-mediated brachial artery dilatation were measured at baseline and after 1, 2, 3, 4, and 8 hours. After oral methionine, plasma homocysteine increased from 7.9±2.0 μmol/L at baseline to 23.1±5.4 μmol/L at 4 hours (
P
<0.0001, n=24) and was associated with a decrease in flow-mediated brachial artery dilatation from 0.12±0.09 to 0.06±0.09 mm (
P
<0.05). The time course of the impairment of flow-mediated vasodilatation mirrored the time course of the increase in homocysteine concentration.

Conclusions
—Oral methionine loading raises plasma homocysteine and impairs flow-mediated endothelium-dependent vasodilatation. This supports the view that homocysteine may promote vascular disease by inducing endothelial dysfunction.
Acute Coronary Syndromes in the GUSTO-IIb Trial
Authors: Armstrong Paul W. , Fu Yuling , Chang Wei-Ching , Topol Eric J. , Granger Christopher B. , Betriu Amadeo , Van de Werf Frans , Lee Kerry L. , Califf Robert M.
Published: June 2012

Background
—Recurrent ischemia after an acute coronary syndrome portends an unfavorable outcome and has major resource-use implications. This issue has not been studied systematically among the spectrum of patients with acute coronary presentations, encompassing those with and without ST-segment elevation.

Methods and Results
—We assessed the 1-year prognosis of the 12 142 patients enrolled in the GUSTO-IIb trial by the presence (n=4125) or absence (n=8001) of ST-segment elevation. This latter group was further categorized into those with baseline myocardial infarction (n=3513) or unstable angina (n=4488). We also assessed the incidence of recurrent ischemia and its impact on outcomes. Recurrent ischemia was significantly rarer in those with ST-segment elevation (23%) than in those without (35%;
P
<0.001). Mortality at 30 days was greater among patients with ST-segment elevation (6.1% versus 3.8%;
P
<0.001) but less so at 6 months; by 1 year, mortality did not differ significantly (9.6% versus 8.8%). Patients with non–ST-segment-elevation infarction had higher rates of reinfarction at 6 months (9.8% versus 6.2%) and higher 6-month (8.8% versus 5.0%) and 1-year mortality rates (11.1% versus 7.0%) than such patients who had unstable angina.

Conclusions
—Refractory ischemia was associated with an approximate doubling of mortality among patients with ST-segment elevation and a near tripling of risk among those without ST elevation. This study highlights not only the substantial increase in late mortality and reinfarction with non–ST-segment-elevation infarction but also the opportunities for better triage and application of therapeutic strategies for patients with recurrent ischemia.
Comparison of
201
Tl,
99m
Tc-Tetrofosmin, and Dobutamine Magnetic Resonance Imaging for Identifying Hibernating Myocardium
Authors: Gunning Mark G. , Anagnostopoulos Constantinos , Knight Charles J. , Pepper John , Burman Elisabeth D. , Davies Glyn , Fox Kim M. , Pennell Dudley J. , Ell Peter J. , Underwood S. Richard
Published: June 2012

Background
—Both radionuclide perfusion tracers and contractile response to dobutamine have been used to identify hibernating myocardium. The aim was to compare
201
Tl (thallium) single photon emission CT (SPECT),
99m
Tc-tetrofosmin (tetrofosmin) SPECT, and dobutamine cine MRI for identifying regions of reversible myocardial dysfunction.

Methods and Results
—Thirty patients with 3-vessel coronary artery disease and impaired left ventricular function (mean LVEF, 24.0%; SD, 8.3%) scheduled for coronary bypass grafting were recruited. All underwent rest/dobutamine stress (5 to 10 μg · kg
−1
· min
−1
) cine MRI, stress/rest tetrofosmin SPECT, and stress/redistribution and separate-day rest/redistribution thallium SPECT before surgery. Stress/redistribution thallium SPECT and resting MRI were repeated after surgery. In a 9-segment model, SPECT images were scored visually for tracer uptake, which was also measured from a polar plot of myocardial counts. MRI was scored visually for endocardial motion, myocardial thickening, and thickness. Five patients died before follow-up, and 2 declined postoperative investigation. In the remaining 23 patients, mean LVEF increased from 24.0% (SD, 8.3%) to 29.7% (SD, 11.1%) (
P
<0.05). Of 207 segments analyzed, 145 had significantly abnormal wall motion before surgery, and 82 of these improved function after revascularization. The criteria for predicting recovery of severely hypokinetic segments on preoperative imaging were tracer uptake graded “moderately reduced” or better, or positive inotropic response on dobutamine MRI. Late-rest thallium images showed the highest sensitivity (76%), compared with stress-redistribution thallium (68%) and rest tetrofosmin (66%) (
P
<0.05). All 3 tracer techniques were nonspecific (44%, 51%, and 49%, respectively). Redistribution of thallium after the resting injection was insensitive (18%) but highly specific (83%). Inotropic response to dobutamine was also insensitive (50%) but specific (81%).

Conclusions
—Radionuclide uptake is a sensitive but nonspecific predictor of myocardial functional recovery, whereas dobutamine MRI is specific but insensitive.
Cellular Basis for the Normal T Wave and the Electrocardiographic Manifestations of the Long-QT Syndrome
Authors: Yan Gan-Xin , Antzelevitch Charles
Published: June 2012

Background
—This study probes the cellular basis for the T wave under baseline and long-QT (LQT) conditions using an arterially perfused canine left ventricular (LV) wedge preparation, which permits direct temporal correlation of cellular transmembrane and ECG events.

Methods and Results
—Floating microelectrodes were used to record transmembrane action potentials (APs) simultaneously from epicardial, M-region, and endocardial sites or subendocardial Purkinje fibers. A transmural ECG was recorded concurrently. Under baseline and LQT conditions, repolarization of the epicardial action potential, the earliest to repolarize, coincided with the peak of the T wave; repolarization of the M cells, the last to repolarize, coincided with the end of the T wave. Thus, the action potential duration (APD) of the longest M cells determine the QT interval and the T
peak
–T
end
interval serves as an index of transmural dispersion of repolarization. Repolarization of Purkinje fibers outlasted that of the M cell but failed to register on the ECG. The morphology of the T wave appeared to be due to currents flowing down voltage gradients on either side of the M region during phase 2 and phase 3 of the ventricular action potential. The interplay between these opposing forces determined the height of the T wave as well as the degree to which the ascending or descending limb of the T wave was interrupted, giving rise to bifurcated T waves and “apparent T-U complexes” under LQT conditions. Spontaneous and stimulation-induced polymorphic ventricular tachycardia with characteristics of torsade de pointes (TdP) developed in the presence of
dl
-sotalol.

Conclusions
—Our results provide the first direct evidence that opposing voltage gradients between epicardium and the M region and endocardium and the M region contribute prominently to the inscription of the ECG T wave under normal conditions and to the widened or bifurcated T wave and long-QT interval observed under LQT conditions. Our data suggest that the “pathophysiological U” wave observed in acquired or congenital LQTS is more likely to be a second component of an interrupted T wave, and argue for use of the term T2 in place of U to describe this event.
Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism
Authors: Staels Bart , Dallongeville Jean , Auwerx Johan , Schoonjans Kristina , Leitersdorf Eran , Fruchart Jean-Charles
Published: June 2012

Abstract
—Treatment with fibrates, a widely used class of lipid-modifying agents, results in a substantial decrease in plasma triglycerides and is usually associated with a moderate decrease in LDL cholesterol and an increase in HDL cholesterol concentrations. Recent investigations indicate that the effects of fibrates are mediated, at least in part, through alterations in transcription of genes encoding for proteins that control lipoprotein metabolism. Fibrates activate specific transcription factors belonging to the nuclear hormone receptor superfamily, termed peroxisome proliferator-activated receptors (PPARs). The PPAR-α form mediates fibrate action on HDL cholesterol levels via transcriptional induction of synthesis of the major HDL apolipoproteins, apoA-I and apoA-II. Fibrates lower hepatic apoC-III production and increase lipoprotein lipase—mediated lipolysis via PPAR. Fibrates stimulate cellular fatty acid uptake, conversion to acyl-CoA derivatives, and catabolism by the β-oxidation pathways, which, combined with a reduction in fatty acid and triglyceride synthesis, results in a decrease in VLDL production. In summary, both enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL underlie the hypotriglyceridemic effect of fibrates, whereas their effect on HDL metabolism is associated with changes in HDL apolipoprotein expression.
Intracoronary Stenting and Risk for Major Adverse Cardiac Events During the First Month
Authors: Schühlen Helmut , Kastrati Adnan , Dirschinger Josef , Hausleiter Jörg , Elezi Shpend , Wehinger Anne , Pache Jürgen , Hadamitzky Martin , Schömig Albert
Published: June 2012

Background
—Our rationale for this study was to analyze the risk for procedural failure of attempted stenting and the risk for major adverse cardiac events (MACE) after success and to develop a risk stratification protocol for successful procedures.

Methods and Results
—Stenting was attempted in 2894 procedures during the 5-year study period (success in 98.3% of 3815 lesions). After failure, the MACE rate was 42.6%. The risk for failure was higher for lesions in the left circumflex coronary artery or in venous bypass grafts and after an acute occlusion before stenting; it increased with stenosis length or grade and decreased with vessel size and growing institutional experience in stenting. After success, death occurred in 0.8%, death or myocardial infarction in 2.0%, and any MACE in 3.6%. Independent risk factors for MACE were older age, diabetes, acute myocardial infarction, unstable angina, impaired left ventricular function, residual dissections, stent overlap, longer stented segments, and a postprocedural regimen without ticlopidine. Procedural factors were substantially stronger predictors than operator-independent variables available before procedures. Overall, the risk declined after the first 3 days. Two major factors exhibited time-dependent variations of their influence: while residual dissections were the dominant risk factor within the first 3 days with a reduction after that, no protective effect of ticlopidine could be identified before day 3. From these results, we derived a risk stratification protocol for individual procedures.

Conclusions
—These results underscore the importance of optimal angiographic results and the need for antiplatelet regimens with immediate onset. Our risk stratification protocol may guide individual postprocedural care and allow us to compare risk profiles of different study populations and to devise quality control programs for stenting.
Dopamine Depresses Minute Ventilation in Patients With Heart Failure
Authors: van de Borne Philippe , Oren Ron , Somers Virend K.
Published: June 2012

Background
—Low-dose dopamine is frequently used in patients in the intensive care setting. Dopamine may inhibit chemoreceptor afferents and hence decrease chemoreflex sensitivity to hypoxia.

Methods and Results
—In a double-blind, randomized, crossover study, we determined the effects of dopamine (5 μg · kg
−1
· min
−1
) and placebo infusion on oxygen saturation, minute ventilation, and sympathetic nerve activity during normoxia and 5 minutes of hypoxia in 10 normal young subjects. We further investigated the effects of dopamine and placebo on minute ventilation during normoxic breathing in 8 patients with severe heart failure and in 8 age-matched control subjects. Dopamine did not decrease minute ventilation during normoxia in normal subjects. During hypoxia, minute ventilation was 12.9±1.3 L/min on dopamine and 15.8±1.5 L/min on placebo (
P
<0.0001). Oxygen saturation during hypoxia was lower with dopamine (78±3%) than placebo (84±2%;
P
<0.0001). Sympathetic nerve activity during hypoxia was not enhanced with dopamine despite the lower O
2
saturation. Subjects were able to maintain a voluntary apnea to a lower oxygen saturation on dopamine than on placebo (
P
<0.05). In heart failure patients breathing room air, but not in age-matched control subjects, dopamine decreased minute ventilation despite decreased oxygen saturation and increased P
etco
2
during dopamine (all
P
≤0.02).

Conclusions
—Dopamine inhibits chemoreflex responses during hypoxic breathing in normal humans, preferentially affecting the ventilatory response more than the sympathetic response. Dopamine also depresses ventilation in normoxic heart failure patients breathing room air. Ventilatory inhibition by low-dose dopamine may adversely influence outcome in hypoxic patients, especially in patients with heart failure.
Randomized Evaluation of Anticoagulation Versus Antiplatelet Therapy After Coronary Stent Implantation in High-Risk Patients
Authors: Urban Philip , Macaya Carlos , Rupprecht Hans-Jürgen , Kiemeneij Ferdinand , Emanuelsson Hakan , Fontanelli Alessandro , Pieper Michael , Wesseling Thea , Sagnard Luc
Published: June 2012

Background
—Although the association of ticlopidine and aspirin has been shown to be superior to anti–vitamin K agents and aspirin after coronary stent implantation in low-risk patients, the latter combination has remained an unproven reference regimen for high-risk patients until recently.

Methods and Results
—We randomized 350 high-risk patients within 6 hours after stent implantation to receive during 30 days either aspirin 250 mg and ticlopidine 500 mg/d (A+T group) or aspirin 250 mg/d and oral anticoagulation (A+OAC group) targeted at an international normalized ratio of 2.5 to 3. The primary composite end point was defined as the occurrence of cardiovascular death, myocardial infarction, or repeated revascularization at 30 days. Patients were eligible if (1) the stent(s) were implanted to treat abrupt closure after PTCA; (2) the angiographic result after implantation was suboptimal; (3) a long segment was stented (>45 mm and/or ≥3 stents); or (4) the largest balloon inflated in the stent had a nominal diameter of ≤2.5 mm. The primary cardiac end point was reached for 10 patients (5.6%) in the A+T group and 19 (11%) in the A+OAC group (relative risk [RR], 1.9; 95% CI, 0.9 to 4.1;
P
=0.07). Major vascular and bleeding complications were less frequent in the A+T group (3 patients, 1.7%) than in the A+OAC group (12 patients, 6.9%) (RR, 4.1; 95% CI, 1.2 to 14.3;
P
=0.02).

Conclusions
—High-risk patients should be treated with A+T rather than A+OAC after coronary stenting because the bleeding and vascular complications are significantly reduced and there is a marked trend suggesting a decrease in cardiac events.
Influence of the Novel Inotropic Agent Levosimendan on Isometric Tension and Calcium Cycling in Failing Human Myocardium
Authors: Hasenfuss Gerd , Pieske Burkert , Castell Maria , Kretschmann Bodo , Maier Lars S. , Just Hanjörg
Published: June 2012

Background
—Levosimendan was shown to increase calcium sensitivity by a novel mechanism and to inhibit phosphodiesterase III activity in animal myocardium.

Methods and Results
—We investigated the influence of levosimendan on isometric contractions and calcium transients (aequorin method) in muscle strips from human hearts with end-stage failing dilated or ischemic cardiomyopathy (n=27). Data were compared with the effects of the phosphodiesterase inhibitor milrinone (n=9). The average maximum increase in twitch tension was 47±14% (range, 6% to 150%) at a levosimendan concentration of 0.8±0.3 μmol/L (
P
<0.01). This was associated with significant increases in maximum rates of tension rise and fall and decreases in times to peak tension, to 50% relaxation, and to 95% relaxation. In aequorin-loaded muscles, levosimendan 10
−6
mol/L increased average tension by 50% (
P
<0.02), associated with a nonsignificant increase in aequorin light (16%). With milrinone 10
−5
mol/L, average tension increased by 58% and aequorin light by 49% (
P
<0.05). In those muscle strips with pronounced inotropic effects (>50% increase in tension), there was a comparable and pronounced increase in aequorin light with both agents. However, in muscle strips with weak inotropic responses (<50% increase in tension), the increase in light was significantly higher with milrinone than with levosimendan.

Conclusions
—Levosimendan has inotropic and lusitropic actions in failing human myocardium. Comparison with the phosphodiesterase inhibitor milrinone indicates that in case of pronounced inotropic stimulation, the modes of action of the two agents may be similar (phosphodiesterase inhibition), whereas small inotropic effects of levosimendan may result predominantly from calcium sensitization.
Adenovirus-Mediated Gene Transfer of the Human Tissue Inhibitor of Metalloproteinase-2 Blocks Vascular Smooth Muscle Cell Invasiveness In Vitro and Modulates Neointimal Development In Vivo
Authors: Cheng Linda , Mantile Giuditta , Pauly Rebecca , Nater Cynthia , Felici Angelina , Monticone Robert , Bilato Claudio , Gluzband Yehezkiel A. , Crow Michael T. , Stetler-Stevenson William , Capogrossi Maurizio C.
Published: June 2012

Background
—Endovascular injury induced by balloon withdrawal leads to the increased activation of matrix metalloproteinases (MMPs) in the vascular wall, allowing smooth muscle cells (SMCs) to digest the surrounding extracellular matrix (ECM) and migrate from the media into the intima. The objective of this study was to examine the effects of a replication-deficient adenovirus carrying the cDNA for human tissue inhibitor of metalloproteinase-2 (AdCMV.hTIMP-2) on SMC function in vitro and neointimal development in the injured rat carotid artery.

Methods and Results
—Infection of cultured rat aortic SMCs at a multiplicity of infection of 100 with AdCMV.hTIMP-2 resulted in high-level expression of hTIMP-2 mRNA and protein secretion into the medium. Conditioned media (CM) from AdCMV.hTIMP-2–infected but not control virus (AdCMV.null or AdCMV.βgal)–infected SMCs inhibited MMP-2 activity on gelatin zymograms as well as the chemoattractant-directed migration of SMCs across reconstituted basement membrane proteins in the Boyden chamber assay. In contrast, AdCMV.hTIMP-2 CM had no effect on chemoattractant-directed migration of SMCs occurring in the absence of an ECM barrier or on the proliferation of cultured neointimal SMCs. Delivery of AdCMV.hTIMP-2 (2.5×10
9
pfu) to the carotid artery wall at the time of balloon withdrawal injury inhibited SMC migration into the intima by 36% (
P
<0.05) at 4 days and neointimal area by 53% (
P
<0.01) at 8 days and by 12% (
P
=NS) at 21 days after injury. AdCMV.hTIMP-2 had no effect on medial area.

Conclusions
—Adenovirus-mediated hTIMP-2 gene transfer inhibits SMC invasiveness in vitro and in vivo and delays neointimal development after carotid injury.
Hemodynamic and Coronary Effects of the Endothelin Antagonist Bosentan in Patients With Coronary Artery Disease
Authors: Wenzel René R. , Fleisch Martin , Shaw Sidney , Noll Georg , Kaufmann Urs , Schmitt Rita , Jones C. Richard , Clozel Martine , Meier Bernhard , Lüscher Thomas F.
Published: June 2012

Background
—Endothelin is a potent endothelium-derived vasoconstrictor peptide with proliferative properties. Elevated levels of the peptide occur in coronary artery disease; however, its pathophysiological role as a regulator of coronary tone and structure is uncertain. Endothelin-receptor antagonists are specific tools to clarify this issue and might be useful in the treatment of coronary artery disease.

Methods and Results
—In a double-blind, placebo-controlled randomized study, we investigated the effects of the ET
A
/ET
B
endothelin-receptor antagonist bosentan or placebo on systemic and coronary hemodynamics in 28 patients with angiographically documented stable coronary artery disease by quantitative coronary angiography and an intracoronary Doppler guidewire. Bosentan 200 mg IV decreased systolic blood pressure (
P
<0.05), whereas heart rate increased slightly (
P
<0.05). Coronary diameter increased, particularly in vessels with no or mild angiographic changes (
P
<0.01). Glycerol trinitrate did not further dilate these segments, whereas coronary diameter increased significantly after nitrate in the placebo group. The increase in coronary diameter after bosentan correlated inversely with plasma LDL-cholesterol levels (
P
<0.01) in both stenotic and angiographically normal coronary segments. Coronary flow velocity did not change. Bosentan was well tolerated.

Conclusions
—Endogenous endothelin exerts a vasoconstrictor tone in epicardial coronary arteries of patients with coronary artery disease, as evidenced by the vasodilation exerted by the combined ET
A
/ET
B
endothelin-receptor antagonist bosentan under acute conditions. Bosentan can safely be given to these patients. Hence, further long-term studies are necessary to determine the therapeutic potential of endothelin-receptor antagonists in patients with coronary artery disease.
α-Tocopherol Enrichment of Monocytes Decreases Agonist-Induced Adhesion to Human Endothelial Cells
Authors: Islam Kazi Nazrul , Devaraj Sridevi , Jialal Ishwarlal
Published: June 2012

Background
—Monocyte-endothelium adhesion is a crucial early event in atherogenesis. Several reports indicate that α-tocopherol (AT) is a potent antioxidant in plasma and LDL and also has intracellular effects that are antiatherogenic. Recently, it has been shown that AT supplementation results in decreased monocyte–endothelial cell adhesion. However, there is a paucity of data on the mechanisms by which AT inhibits adhesion of monocytes. We studied the effect of AT enrichment of a human monocytic cell line, U937, on adhesion to human umbilical vein endothelial cells (HUVECs).

Methods and Results
—Both lipopolysaccharide (LPS)– and
N
-formyl-methionyl-leucyl-phenylalanine (FMLP)–stimulated U937 adhesion to HUVECs were studied. AT (50 and 100 μmol/L) significantly decreased adhesion of both LPS- and FMLP-stimulated U937 cells to HUVECs (LPS-treated cells,
P
<0.0125; FMLP-treated cells,
P
<0.05). Expression of the adhesion molecules CD11a, CD11b, CD11c, very late antigen-4 (VLA-4), and L-selectin, as assessed by flow cytometry, was increased in the stimulated U937 cells, and AT resulted in significant reduction in the expression of CD11b and VLA-4. In addition, activation of the transcription factor nuclear factor-κB (NF-κB), as assessed by gel shift assays, was inhibited by pretreatment with AT in LPS-treated U937 cells.

Conclusions
—AT significantly decreases adhesion of activated monocytes to endothelial cells by decreasing expression of CD11b and VLA-4 on monocytes, possibly by inhibiting the activation of NF-κB.
Evidence of Carotid Artery Wall Hypertrophy in Homozygous Homocystinuria
Authors: Megnien Jean-Louis , Gariepy Jérôme , Saudubray Jean-Marie , Nuoffer Jean-Marc , Denarie Nicolas , Levenson Jaime , Simon Alain
Published: June 2012

Background
—We aimed to determine whether intima-media thickness (IMT) was increased in the carotid artery of subjects with homocystinuria to better understand the in vivo contribution of homocysteine to early atherogenesis.

Methods and Results
—We investigated ultrasonographically the right common carotid artery in 14 subjects with homozygous homocystinuria aged 3 to 34 years (mean, 13 years) and in 15 of their heterozygous parents aged 32 to 47 years (mean, 41 years) by comparison with 2 control groups of 15 healthy subjects of the same age. Far-wall IMT and lumen diameter were measured with a computerized program, and the cross-sectional area of the intima-media complex (CSA-IMC) was calculated from IMT and diameter. Comparison with their respective controls, adjusted for body surface area or height, showed that homozygotes had greater IMT (
P
<0.001) and CSA-IMC (
P
<0.05) and smaller diameter (
P
<0.05), whereas heterozygotes had values similar to their controls. Multivariate analysis of the arterial parameters with age, body surface area (or height), and plasma total homocysteine in the homozygous and heterozygous groups combined showed that IMT was related to age (
P
<0.05) and homocysteine (
P
<0.01), diameter was related to body surface area (
P
<0.001) or height (
P
<0.05), and CSA-IMC was related to age (
P
<0.05), body surface area (
P
<0.05) (but not height), and homocysteine (
P
<0.05).

Conclusions
—Homozygous homocystinuria was associated with common carotid wall hypertrophy, whereas heterozygous disease was not. Such hypertrophy may reflect a smooth muscle proliferation induced by hyperhomocysteinemia and represent a promising target for testing vascular effects of therapeutic measures to lower homocysteine.
Congestive Heart Failure in the Community
Authors: Senni Michele , Tribouilloy Christophe M. , Rodeheffer Richard J. , Jacobsen Steven J. , Evans Jonathan M. , Bailey Kent R. , Redfield Margaret M.
Published: June 2012

Background
—Data are limited regarding the classification and prognosis of patients with congestive heart failure (CHF) in the community.

Methods and Results
—Using the resources of the Rochester Epidemiology Project, we evaluated all patients receiving a first diagnosis of CHF in Olmsted County, Minnesota, in 1991 (n=216). Among these patients, 88% were ≥65 years and 49% were ≥80 years of age. The prognosis of patients with a new diagnosis of CHF was poor; survival was 86±2% at 3 months, 76±3% at 1 year, and 35±3% at 5 years. Of the 216 patients, 137 (63%) had an assessment of ejection fraction. In these patients, systolic function was preserved (ejection fraction ≥50%) in 59 (43%) and reduced (ejection fraction <50%) in 78 (57%). Survival adjusted for age, sex, NYHA class, and coronary artery disease was not significantly different between patients with preserved and those with reduced systolic function (relative risk, 0.80;
P
=0.369). ACE inhibitors were used in only 44% of the total population with CHF.

Conclusions
—The present study reports the clinical characteristics and natural history of CHF as it presents in the community in the vasodilator era. CHF is a disease of the “very elderly,” frequently occurs in the setting of normal ejection fraction, and has a poor prognosis, regardless of the level of systolic function. Diagnostic and therapeutic methods are underused in the community.
Orthostatic Hypotension Predicts Mortality in Elderly Men
Authors: Masaki Kamal H. , Schatz Irwin J. , Burchfiel Cecil M. , Sharp Dan S. , Chiu Darryl , Foley Daniel , Curb J. David
Published: June 2012

Background
—Population-based data are unavailable concerning the predictive value of orthostatic hypotension on mortality in ambulatory elderly patients, particularly minority groups.

Methods and Results
—With the use of data from the Honolulu Heart Program’s fourth examination (1991 to 1993), orthostatic hypotension was assessed in relation to subsequent 4-year all-cause mortality among a cohort of 3522 Japanese American men 71 to 93 years old. Blood pressure was measured in the supine position and after 3 minutes of standing, with the use of standardized methods. Orthostatic hypotension was defined as a drop in systolic blood pressure (SBP) of ≥20 mm Hg or in diastolic blood pressure of ≥10 mm Hg. Overall prevalence of orthostatic hypotension was 6.9% and increased with age. There was a total of 473 deaths in the cohort over 4 years; of those who died, 52 had orthostatic hypotension. Four-year age-adjusted mortality rates in those with and without orthostatic hypotension were 56.6 and 38.6 per 1000 person-years, respectively. With the use of Cox proportional hazards models, after adjustment for age, smoking, diabetes mellitus, body mass index, physical activity, seated systolic blood pressure, antihypertensive medications, hematocrit, alcohol intake, and prevalent stroke, coronary heart disease and cancer, orthostatic hypotension was a significant independent predictor of 4-year all-cause mortality (relative risk 1.64, 95% CI 1.19 to 2.26). There was a significant linear association between change in systolic blood pressure from supine position to standing and 4-year mortality rates (test for linear trend,
P
<0.001), suggesting a dose-response relation.

Conclusions
—Orthostatic hypotension is relatively uncommon, may be a marker for physical frailty, and is a significant independent predictor of 4-year all-cause mortality in this cohort of elderly ambulatory men.
Transatrial Access to the Normal Pericardial Space
Authors: Verrier Richard L. , Waxman Sergio , Lovett Eric G. , Moreno Ricardo
Published: June 2012

Background
—A nonsurgical means to access the normal pericardial space could provide opportunities for diagnostic sampling and therapeutic interventions. Because there are currently no approved nonsurgical methods to accomplish this, we tested a new approach in large animals.

Methods and Results
—A catheter system was employed in a percutaneous approach from a femoral vein to pierce the right atrial appendage. Pericardial access was confirmed by placement of a radiopaque guidewire visible under fluoroscopy (6 dogs, 13 pigs). In 7 of the pigs, pericardial tamponade, produced by injection of saline or heparinized blood into the pericardial space through this route, was confirmed by fluoroscopy and hemodynamic evidence. The feasibility and safety of this access route were tested with multiple repetitions in all 19 animals. At the end of each of the 17 acute experiments, direct inspection after thoracotomy revealed no hemopericardium, laceration, or bleeding on catheter withdrawal. In 24-hour survival studies performed in 2 of the 6 dogs, the animals exhibited no behavioral signs of discomfort or untoward consequences on recovery from anesthesia. Histology revealed only a small (≈1-mm) fibrinous plug at the site of puncture.

Conclusions
—The percutaneous approach via the right atrial appendage provides a rapid, safe route to access the normal pericardial space for diagnostic sampling and to alleviate high-volume and low-volume (<200 mL) pericardial effusions. The access route is potentially useful for selective administration of therapeutic agents, growth factors, gene vectors, and cardioactive and vasoactive agents to the heart.
Effect of Dietary Patterns on Measures of Lipid Peroxidation
Authors: Miller Edgar R. , Appel Lawrence J. , Risby Terence H.
Published: June 2012

Background
—Free radical–mediated oxidative damage to lipids is thought to be an important process in the pathogenesis of atherosclerosis. Although previous studies have demonstrated a beneficial impact of antioxidant vitamin supplements on lipid peroxidation, the effect of dietary patterns on lipid peroxidation is unknown.

Methods and Results
—During the 3-week run-in period of a randomized trial, 123 healthy individuals were fed a control diet, low in fruits, vegetables, and dairy products, with 37% of calories from fat. Participants were then randomized to consume for 8 weeks: (1) the control diet, (2) a diet rich in fruits and vegetables but otherwise similar to the control diet, and (3) a combination diet rich in fruits, vegetables, and low-fat dairy products and reduced in fat. Serum oxygen radical–absorbing capacity, malondialdehyde (an in vitro measure of lipid peroxidation), and breath ethane (an in vivo measure of lipid peroxidation) were measured at the end of run-in and intervention periods. Between run-in and intervention, mean (95% CI) change in oxygen radical–absorbing capacity (U/mL) was −35 (−93, 13) in the control diet, 26 (−15, 67) in the fruits and vegetables diet (
P
=0.06 compared with control), and 19 (−22, 54) in the combination diet (
P
=0.10 compared with control). Median (interquartile range) change in ethane was 0.84 (0.10, 1.59) in the control diet, 0.02 (−0.61, 0.83) in the fruits and vegetables diet (
P
=0.04 compared with control), and −1.00 (−1.97, 0.25) in the combination diet (
P
=0.005 compared with control). Change in malondialdehyde did not differ between diets.

Conclusions
—This study demonstrates that modification of diet can favorably affect serum antioxidant capacity and protect against lipid peroxidation.
Mechanisms Underlying Spontaneous and Induced Ventricular Arrhythmias in Patients With Idiopathic Dilated Cardiomyopathy
Authors: Pogwizd Steven M. , McKenzie John P. , Cain Michael E.
Published: June 2012

Background
—To define the electrophysiological mechanism(s) of inducible and spontaneously occurring ventricular arrhythmias associated with nonischemic cardiomyopathy, 3-dimensional intraoperative mapping from 156 intramural sites was performed in 6 patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation.

Methods and Results
—Electrode density was sufficient to determine the mechanism for 52 of 74 beats of nonsustained ventricular tachycardia (VT) induced by programmed stimulation and 9 of 11 beats of spontaneous ventricular arrhythmias. The first, second, and third extrastimuli (S
2
through S
4
) conducted with progressively greater degrees of conduction delay (total activation times [TAs] of 144±5, 166±5, and 194±5 ms, respectively) owing to slow conduction and on occasion intramural block. The first beats of induced VT arose from subendocardial or subepicardial sites distant from areas of marked conduction delay by a focal mechanism on the basis of the absence of intervening electrical activity between the termination of the last extrastimulus and the initiation of VT (123±31 ms). Subsequent beats arose by a focal mechanism and conducted with a TA of 127±6 ms (
P
=NS versus initiating beats of VT [118±9 ms]). Spontaneous ventricular arrhythmias initiated in the subendocardium by a focal mechanism and conducted with a TA of 138±5 ms. Tissue analysis demonstrated a variable degree of interstitial fibrosis at sites of focal activation. Sites of conduction delay or block typically exhibited marked interstitial and/or replacement fibrosis but were spatially distant from sites initiating VT.

Conclusions
—Spontaneous and induced ventricular arrhythmias in patients with end-stage idiopathic cardiomyopathy can arise in the subendocardium or subepicardium by a focal mechanism.
Differential Distribution of Inward Rectifier Potassium Channel Transcripts in Human Atrium Versus Ventricle
Authors: Wang Zhiguo , Yue Lixia , White Michel , Pelletier Guy , Nattel Stanley
Published: June 2012

Background
—The inward rectifier K
+
current (I
K1
) plays an important role in governing cardiac electrical activity and is well known to have different properties in the atrium compared with the ventricle. Several inward rectifier K
+
channel (IRK) subunits (hIRK, HH-IRK1, HIR, and TWIK-1) with different properties have been cloned from human tissues, but their relative expression in cardiac tissues has not been quantified. The present study was designed to define the relative levels of mRNA for various IRKs in human atrium and in failing and nonfailing ventricle.

Methods and Results
—Competitive reverse transcription–polymerase chain reaction was used to quantify in human atrium and ventricle the mRNA levels of hIRK, HH-IRK1, HIR, and TWIK-1. The absence of important noncardiac contamination was confirmed by demonstrating a lack of detectable mRNA markers for neuronal (acetylcholine receptor) and vascular (maxi-K channel) tissue. mRNA of HIR was more abundant in normal atrium (7.1±1.3 amol/μg total RNA) than ventricle (0.6±0.1 amol/μg,
P
<0.05), whereas TWIK-1 mRNA was more concentrated in ventricle (18.1±4.3 amol/μg) than atrium (1.4±0.3 amol/μg,
P
<0.05). Concentrations of hIRK (42.7±6.7 amol/μg in atrium vs 57.1±9.2 amol/μg in ventricle) and HH-IRK1 (2.0±0.5 amol/μg in atrium vs 1.5±0.5 amol/μg in ventricle) were comparable. No significant differences in IRK subunit transcript concentrations were found between normal and failing ventricles.

Conclusions
—mRNAs for all 4 IRKs are detected in human atrium and ventricle, but the mRNA copy number of a low-conductance subunit (HIR) is larger in atrium and the copy number of a weakly rectifying subunit (TWIK-1) is larger in ventricle. These differences in relative message levels may provide a potential molecular basis for different properties of I
K1
in human atrium compared with ventricle.
Agonistic Anti-β
1
-Adrenergic Receptor Autoantibodies From Cardiomyopathy Patients Reduce the β
1
-Adrenergic Receptor Expression in Neonatal Rat Cardiomyocytes
Authors: Podlowski Svenia , Luther Hans Peter , Morwinski Rosemarie , Müller Johannes , Wallukat Gerd
Published: June 2012

Background
—Autoantibodies directed against the β
1
-adrenergic receptor have been described in patients with dilated cardiomyopathy. These autoantibodies exert an agonistic, chronotropic effect on spontaneously beating cultured neonatal rat cardiomyocytes. We studied the effect of such antibodies on β
1
-adrenergic receptor expression.

Methods and Results
—Cardiomyocytes were incubated with either the β-adrenergic agonist isoproterenol or autoantibodies for 72 hours. β-Adrenergic receptor expression was studied on the mRNA level with semiquantitative reverse transcription–polymerase chain reaction and on the protein level with immunoblotting. Isoproterenol downregulated both mRNA and β
1
- and β
2
-adrenergic receptor protein subtypes, whereas the anti–β
1
-adrenergic receptor autoantibodies decreased only the β
1
-adrenergic receptor mRNA and protein. Long-term incubation of cultured cardiomyocytes with isoproterenol or the anti–β
1
-adrenergic receptor autoantibodies reduced the acute stimulatory effect of isoproterenol on the myocytes. These effects were prevented by incubating the cells with isoproterenol in the presence of propranolol or with anti–β
1
-adrenergic receptor autoantibodies in the presence of bisoprolol. Bisoprolol also abolished the reduction of the β
1
-adrenergic receptor expression caused by longer-term incubation with isoproterenol and the autoantibodies.

Conclusions
—We conclude that after longer-term treatment with the anti–β
1
-adrenergic receptor autoantibodies, the rat cardiomyocytes showed a β-adrenergic receptor expression similar to that observed in failing hearts from patients with dilated cardiomyopathy.
Cellular Distribution of Ca
2+
Pumps and Ca
2+
Release Channels in Rat Cardiac Hypertrophy Induced by Aortic Stenosis
Authors: Anger Marielle , Lompré Anne-Marie , Vallot Olivier , Marotte Françoise , Rappaport Lydie , MD Jane-Lise Samuel
Published: June 2012

Background
—The response of ventricular myocytes to pressure overload is heterogeneous and not spatially coordinated. We investigated whether or not the alterations in SERCA and RyR gene expression are homogeneous within the myocardium.

Methods and Results
—The cellular distribution of mRNAs and proteins encoding the 2 sarco(endo)plasmic reticulum Ca
2+
-ATPase (SERCA) isoforms (SERCA 2a and 2b) and 2 Ca
2+
release channels (the ryanodine receptor, RyR, and the IP
3
receptor, IP
3
R) were analyzed by in situ hybridization and immunofluorescence, respectively. Analyses were performed during early (1 and 5 days) and late (1 month) stages of cardiac hypertrophy induced in rat by thoracic aortic stenosis (AS). The results indicated that 1 and 5 days after AS, the cellular distribution of SERCA 2a and RyR2 mRNAs in right ventricle and atrium was similar to controls but the mRNA levels appeared to decrease in some areas of the left ventricle (LV). One month after AS, the distribution of SERCA 2a mRNA and protein became heterogeneous throughout the LV, whereas RyR2 mRNA and protein levels were decreased in a homogeneous manner. SERCA 2b, poorly expressed in both cardiomyocytes and vessels of controls, was increased 4-fold 1 month after AS in coronary arteries only. In both sham (Sh) and AS, SERCA 3 and IP
3
R mRNAs were mainly found in the vessels.

Conclusions
—In severe hypertrophy, decreased accumulation of SERCA 2a was heterogeneous and not compensated by an induction of SERCA 2b in the cardiomyocytes. Decrease in RyR2 expression was more homogeneous and not compensated by an increased IP
3
R expression.
Common Methylenetetrahydrofolate Reductase Gene Mutation Leads to Hyperhomocysteinemia but Not to Vascular Disease
Authors: Brattström Lars , Wilcken David E. L. , Öhrvik John , Brudin Lars
Published: June 2012

Background
—The results of retrospective and prospective case-control studies have clearly established that mild elevations of the plasma homocysteine level are associated with increased risk of coronary, cerebral, and peripheral vascular disease. Recently, a mutation (677C→T) was identified in the methylenetetrahydrofolate reductase (MTHFR) gene that results in reduced folate-dependent enzyme activity and reduced remethylation of homocysteine to methionine. Mutant homozygotes (TT genotype) constitute ≈12% of the white population and frequently have mildly elevated circulating homocysteine. Therefore, it seems likely that they would also be at increased risk of vascular disease. A number of studies have investigated this during the past 3 years, and the present article evaluates the results in a meta-analysis.

Methods and Results
—We identified 13 studies in which there were measurements of plasma homocysteine in relation to the 3 genotypes (TT, CT, and CC) and 23 case-control studies comprising 5869 genotyped cardiovascular disease patients (mostly coronary artery disease) and 6644 genotyped control subjects. Those bearing the TT genotype had plasma homocysteine concentrations 2.6 μmol/L (25%) higher than those with the CC genotype. However, there was no difference between patients and control subjects either in the frequency of mutant alleles (T) (34.3% versus 33.8%) or the TT genotype (11.9% versus 11.7%). In the analysis of the 23 studies, the relative risk (OR) of vascular disease associated with the TT genotype was 1.12 (95% CI, 0.92 to 1.37).

Conclusions
—We conclude that although the C677T/MTHFR mutation is a major cause of mild hyperhomocysteinemia, the mutation does not increase cardiovascular risk. Our findings suggest that the mild hyperhomocysteinemia found frequently in vascular disease patients is not causally related to the pathogenesis of the vascular disease.
Novel, Ultraslow Inactivating Sodium Current in Human Ventricular Cardiomyocytes
Authors: Maltsev Victor A. , Sabbah Hani N. , Higgins Robert S. D. , Silverman Norman , Lesch Michael , Undrovinas Albertas I.
Published: June 2012

Background
—Alterations in K
+
channel expression and gating are thought to be the major cause of action potential remodeling in heart failure (HF). We previously reported the existence of a late Na
+
current (I
NaL
) in cardiomyocytes of dogs with chronic HF, which suggested the importance of the Na
+
channel in this remodeling process. The present study examined whether this I
NaL
exists in cardiomyocytes isolated from normal and failing human hearts.

Methods and Results
—A whole-cell patch-clamp technique was used to measure ion currents in cardiomyocytes isolated from the left ventricle of explanted hearts from 10 patients with end-stage HF and from 3 normal hearts. We found I
NaL
was activated at a membrane potential of −60 mV with maximum density (0.34±0.05 pA/pF) at −30 mV in cardiomyocytes of both normal and failing hearts. The steady-state availability was sigmoidal, with an averaged midpoint potential of −94±2 mV and a slope factor of 6.9±0.1 mV. The current was reversibly blocked by the Na
+
channel blockers tetrodotoxin (IC
50
=1.5 μmol/L) and saxitoxin (IC
50
=98 nmol/L) in a dose-dependent manner. Both inactivation and reactivation of I
NaL
had an ultraslow time course (τ≈0.6 seconds) and were independent of voltage. The amplitude of I
NaL
was independent of the peak transient Na
+
current.

Conclusions
—Cardiomyocytes isolated from normal and explanted failing human hearts express I
NaL
characterized by an ultraslow voltage-independent inactivation and reactivation.