bluuebunny/crossref_metadata_2025 huggingface dataset:
Dyslipidemia and an Unfavorable Fatty Acid Profile Predict Left Ventricular Hypertrophy 20 Years Later
Authors: Sundström Johan , Lind Lars , Vessby Bengt , Andrén Bertil , Aro Antti , Lithell Hans O.
Published: June 2012

Background
—Left ventricular hypertrophy (LVH) is a common risk factor for cardiovascular mortality. Causes other than hypertension have not previously been investigated longitudinally. The aim of the present study was to determine hemodynamic, metabolic, and psychosocial predictors at 50 years of age for the prevalence of echocardiographic LVH and geometric subtypes at age 70 by use of a large sample of men from the general population followed up for 20 years.

Methods and Results
—In 1970 to 1973, all men born from 1920 to 1924 and residing in Uppsala County, Sweden, were invited to participate in a health survey aimed at identifying risk factors for cardiovascular disease. At a reinvestigation 20 years later, echocardiographic left ventricular mass index was determined in 475 subjects. A 1-SD increase in body mass index, systolic or diastolic blood pressure, fasting LDL/HDL cholesterol, serum triglycerides, or the serum cholesterol ester proportion of several saturated fatty acids or oleic acid at age 50 significantly increased the odds of having LVH at age 70 by 27% to 41%, whereas an increase in linoleic acid proportion was protective. Almost all metabolic predictors were independent of ischemic heart disease, valvular disease, and use of antihypertensive medication at age 70.

Conclusions
—Dyslipidemia and indices of a low dietary intake of linoleic acid and high intake of saturated and monounsaturated fats, as well as hypertension and obesity, at age 50 predicted the prevalence of LVH 20 years later in this prospective longitudinal cohort study, thereby suggesting that lipids may be important in the origin of LVH.
Genetic Variation in Angiotensin-Converting Enzyme Does Not Prevent Development of Cardiac Hypertrophy or Upregulation of Angiotensin II in Response to Aortocaval Fistula
Authors: Perry Gilbert J. , Mori Tatsuhiko , Wei Chih-Chang , Xu Xiao Yan , Chen Yiu-Fai , Oparil Suzanne , Lucchesi Pamela , Dell’Italia Louis J.
Published: June 2012

Background
—Experimental and clinical evidence suggests that angiotensin II may be an important mediator of cardiac hypertrophy in response to hemodynamic stress. We investigated the effect of genetic variation in angiotensin-converting enzyme (ACE) on the development of cardiac hypertrophy and left ventricular (LV) dysfunction in response to volume overload.

Methods and Results
—Male heterozygous ACE knockout (1/0) and wild-type (1/1) mice were studied 4 weeks after the creation of an aortocaval fistula (ACF). The LV weight/body weight ratio increased 74% in ACF versus sham-operated control mice but did not differ between genotypes. Echocardiographic circumferential stress versus rate-corrected velocity of circumferential shortening curves demonstrated depressed LV function in ACF versus sham-operated mice but no difference between genotypes. LV ACE activity was higher in 1/1 versus 1/0 mice and in ACF versus sham-operated mice, and it increased significantly more in the 1/1 versus the 1/0 mice after ACF (
P
<0.001 for effect of genotype, ACF/sham operation, and interaction term). LV angiotensin II was higher in ACF versus sham-operated mice but did not differ between genotypes, despite 3-fold higher LV ACE activity in ACF 1/1 versus ACF 1/0 mice.

Conclusions
—ACE underexpression does not prevent cardiac hypertrophy or LV dysfunction in response to volume overload. LV angiotensin II is unaffected by ACE genotype, both at baseline and after volume overload, indicating that the heart can maintain angiotensin II levels across a broad range of genetic ACE variation under both physiological and pathophysiological conditions.
Enhanced Ventilatory Response to Exercise in Patients With Chronic Heart Failure and Preserved Exercise Tolerance
Authors: Ponikowski Piotr , Francis Darrel P. , Piepoli Massimo F. , Davies L. Ceri , Chua Tuan Peng , Davos Constantinos H. , Florea Viorel , Banasiak Waldemar , Poole-Wilson Philip A. , Coats Andrew J. S. , Anker Stefan D.
Published: June 2012

Background
—In patients with chronic heart failure (CHF) and preserved exercise tolerance, the value of cardiopulmonary exercise testing for risk stratification is not known. Elevated slope of ventilatory response to exercise (V̇
e
/V̇
co
2
) predicts poor prognosis in advanced CHF. Derangement of cardiopulmonary reflexes may trigger exercise hyperpnea. We assessed the relationship between cardiopulmonary reflexes and V̇
e
/V̇
co
2
and investigated the prognostic value of V̇
e
/V̇
co
2
in CHF patients with preserved exercise tolerance.

Methods and Results
—Among 344 consecutive CHF patients, we identified 123 with preserved exercise capacity, defined as a peak oxygen consumption (peak V̇
o
2
) ≥18 mL · kg
−1
· min
−1
(age 56 years; left ventricular ejection fraction 28%; peak V̇
o
2
23.5 mL · kg
−1
· min
−1
). Hypoxic and hypercapnic chemosensitivity (n=38), heart rate variability (n=34), baroreflex sensitivity (n=20), and ergoreflex activity (n=20) were also assessed. We identified 40 patients (33%) with high V̇
e
/V̇
co
2
(ie, >34.0). During follow-up (49±22 months, >3 years in all survivors), 34 patients died (3-year survival 81%). High V̇
e
/V̇
co
2
(hazard ratio 4.3,
P
<0.0001) but not peak V̇
o
2
(
P
=0.7) predicted mortality. In patients with high V̇
e
/V̇
co
2
, 3-year survival was 57%, compared with 93% in patients with normal V̇
e
/V̇
co
2
(
P
<0.0001). Patients with high V̇
e
/V̇
co
2
demonstrated impaired reflex control, as evidenced by augmented peripheral (
P
=0.01) and central (
P
=0.0006) chemosensitivity, depressed low-frequency component of heart rate variability (
P
<0.0001) and baroreflex sensitivity (
P
=0.03), and overactive ergoreceptors (
P
=0.003) compared with patients with normal V̇
e
/V̇
co
2
.

Conclusions
—In CHF patients with preserved exercise capacity, enhanced ventilatory response to exercise is a simple marker of a widespread derangement of cardiovascular reflex control; it predicts poor prognosis, which peak V̇
o
2
does not.
Hemodynamic Effects of Tezosentan, an Intravenous Dual Endothelin Receptor Antagonist, in Patients With Class III to IV Congestive Heart Failure
Authors: Torre-Amione Guillermo , Young James B. , Durand Jean-Bernard , Bozkurt Bykem , Mann Douglas L. , Kobrin Isaac , Pratt Craig M.
Published: June 2012

Background
—Endothelin-1, a powerful mediator of vasoconstriction, is increased in patients with congestive heart failure and appears to be a prognostic marker that strongly is correlated with the severity of disease. However, little is known about the potential immediate beneficial effects of acute blockade of the endothelin system in patients with symptomatic left ventricular dysfunction. We assessed the hemodynamic effects and safety of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with moderate to severe heart failure.

Methods and Results
—This randomized placebo-controlled study evaluated the hemodynamic effects of 6-hour infusions of tezosentan at 5, 20, 50, and 100 mg/h compared with placebo in 61 patients with New York Heart Association class III to IV heart failure. Plasma endothelin-1 and tezosentan concentrations were also determined. Treatment with tezosentan caused a dose-dependent increase in cardiac index ranging from 24.4% to 49.9% versus 3.0% with placebo. Tezosentan also dose-dependently reduced pulmonary capillary wedge pressure and pulmonary and systemic vascular resistances, with no change in heart rate. No episodes of ventricular tachycardia or hypotension requiring drug termination were observed during tezosentan infusion. Tezosentan administration resulted in dose-related increased plasma endothelin-1 concentrations.

Conclusions
—The present study demonstrated that tezosentan can be safely administered to patients with moderate to severe heart failure and that by virtue of its ability to antagonize the effects of endothelin-1, it induced vasodilatory responses leading to a significant improvement in cardiac index. Further studies are under way to determine the clinical effects of tezosentan in the setting of acute heart failure.
Impact of Aortic Stiffness Attenuation on Survival of Patients in End-Stage Renal Failure
Authors: Guerin Alain P. , Blacher Jacques , Pannier Bruno , Marchais Sylvain J. , Safar Michel E. , London Gérard M.
Published: June 2012

Background
—Aortic pulse wave velocity (PWV) is a predictor of mortality in patients with end-stage renal failure (ESRF). The PWV is partly dependent on blood pressure (BP), and a decrease in BP can attenuate the stiffness. Whether the changes in PWV in response to decreases in BP can predict mortality in ESRF patients has never been investigated.

Methods and Results
—One hundred fifty ESRF patients (aged 52±16 years) were monitored for 51±38 months. From entry until the end of follow-up, the changes of PWV in response to decreased BP were measured ultrasonographically. BP was controlled by adjustment of “dry weight” and, when necessary, with ACE inhibitors, calcium antagonists, and/or β-blockers, in combination if necessary. Fifty-nine deaths occurred, including 40 cardiovascular and 19 noncardiovascular events. Cox analyses demonstrated that independent of BP changes, the predictors of all-cause and cardiovascular mortality were as follows: absence of PWV decrease in response to BP decrease, increased left ventricular mass, age, and preexisting cardiovascular disease. Survival was positively associated with ACE inhibitor use. After adjustment for all confounding factors, the risk ratio for the absence of PWV decrease was 2.59 (95% CI 1.51 to 4.43) for all-cause mortality and 2.35 (95% CI 1.23 to 4.41) for cardiovascular mortality. The risk ratio for ACE inhibitor use was 0.19 (95% CI 0.14 to 0.43) for all-cause mortality and 0.18 (95% CI 0.06 to 0.55) for cardiovascular mortality.

Conclusions
—These results indicate that in ESRF patients, the insensitivity of PWV to decreased BP is an independent predictor of mortality and that use of ACE inhibitors has a favorable effect on survival that is independent of BP changes.
Chronic Infections and the Risk of Carotid Atherosclerosis
Authors: Kiechl Stefan , Egger Georg , Mayr Manuel , Wiedermann Christian J. , Bonora Enzo , Oberhollenzer Friedrich , Muggeo Michele , Xu Qingbo , Wick Georg , Poewe Werner , Willeit Johann
Published: June 2012

Background
—Chronic infections have been implicated in the pathogenesis of atherosclerosis, yet from an epidemiological perspective, this concept remains controversial.

Methods and Results
—The Bruneck Study is a prospective population-based survey on the pathogenesis of atherosclerosis. In 826 men and women 40 to 79 years old (1990 baseline), 5-year changes in carotid atherosclerosis were thoroughly assessed by high-resolution duplex scanning. The presence of chronic respiratory, urinary tract, dental, and other infections was ascertained by standard diagnostic criteria. Chronic infections amplified the risk of atherosclerosis development in the carotid arteries. The association was most pronounced in subjects free of carotid atherosclerosis at baseline (age-/sex-adjusted odds ratio [95% CI] for any chronic infection versus none, 4.08 [2.42 to 6.85];
P
<0.0001) and applied to all types of chronic (bacterial) infections. It remained independently significant after adjustment for classic vascular risk attributes and extended to low-risk individuals free of conventional risk factors. Among subjects with chronic infections, atherosclerosis risk was highest in those with a prominent inflammatory response. Markers of systemic inflammation, such as soluble adhesion molecules and circulating bacterial endotoxin, and levels of soluble human heat-shock protein 60 and antibodies to mycobacterial heat-shock protein 65 were elevated in subjects with chronic infections and predictive of an increased risk of atherosclerosis.

Conclusions
—The present study provides solid evidence for a role of common chronic infections in human atherogenesis. Induction of systemic inflammation and autoimmunity may be potential pathophysiological links.
Transforming Growth Factor-β
1
Stimulates
l
-Arginine Transport and Metabolism in Vascular Smooth Muscle Cells
Authors: Durante William , Liao Lan , Reyna Sylvia V. , Peyton Kelly J. , Schafer Andrew I.
Published: June 2012

Background
—Transforming growth factor-β
1
(TGF-β
1
) contributes to arterial remodeling by stimulating vascular smooth muscle cell (VSMC) growth and collagen synthesis at sites of vascular injury. Because
l
-arginine is metabolized to growth-stimulatory polyamines and to the essential collagen precursor
l
-proline, we examined whether TGF-β
1
regulates the transcellular transport and metabolism of
l
-arginine by VSMCs.

Methods and Results
—TGF-β
1
increased
l
-arginine uptake, and this was associated with a selective increase in cationic amino acid transporter-1 (CAT-1) mRNA. In addition, TGF-β
1
stimulated
l
-arginine metabolism by inducing arginase I mRNA and arginase activity. TGF-β
1
also stimulated
l
-ornithine catabolism by elevating ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT) activity. TGF-β
1
markedly increased the capacity of VSMCs to generate the polyamine putrescine and
l
-proline from extracellular
l
-arginine. The TGF-β
1
–mediated increase in putrescine and
l
-proline production was reversed by methyl-
l
-arginine, a competitive inhibitor of cationic amino acid transport, or by hydroxy-
l
-arginine, an arginase inhibitor. Furthermore, the formation of putrescine was inhibited by the ODC inhibitor α-difluoromethylornithine, and
l
-proline generation was blocked by the OAT inhibitor
l
-canaline.
l
-Canaline also inhibited TGF-β
1
–stimulated type I collagen synthesis.

Conclusions
—These results demonstrate that TGF-β
1
stimulates polyamine and
l
-proline synthesis by inducing the genes that regulate the transport and metabolism of
l
-arginine. In addition, they show that TGF-β
1
–stimulated collagen production is dependent on
l
-proline formation. The ability of TGF-β
1
to upregulate
l
-arginine transport and direct its metabolism to polyamines and
l
-proline may contribute to arterial remodeling at sites of vascular damage.
Evidence of Macrophage Foam Cell Formation by Very Low-Density Lipoprotein Receptor
Authors: Kosaka Shotaro , Takahashi Sadao , Masamura Katsuhiko , Kanehara Hideo , Sakai Juro , Tohda Gen , Okada Eiko , Oida Koji , Iwasaki Tadao , Hattori Hiroaki , Kodama Tatsuhiko , Yamamoto Tokuo , Miyamori Isamu
Published: June 2012

Background
—Expression of the VLDL receptor, primarily in macrophages, has been confirmed in human and rabbit atherosclerotic lesions. The high binding affinity of the VLDL receptor for remnant particles implicates the VLDL receptor pathway in the foam cell formation mechanism in macrophages. This study investigates the effect of interferon (IFN)-γ on VLDL receptor expression in phorbol-12-myristate-13-acetate (PMA)-treated THP-1, HL-60 macrophages, and human monocyte-derived macrophages.

Methods and Results
—THP-1 cells were induced to differentiate into macrophages by PMA treatment. IFN-γ was added to the medium, and expression of the VLDL receptor was determined.
125
I-β-VLDL degradation study and oil red O staining were examined. In THP-1 macrophages, VLDL receptor protein expression decreased at 2 days after PMA treatment but increased at 3 days and increased up to 5 days. Scavenger receptor proteins, which were not originally present, appeared at 3 days after PMA treatment. IFN-γ inhibited VLDL receptor expression in a dose-and time-dependent manner in macrophages. However, no inhibitory effect was observed in monocytes. Moreover, IFN-γ receptor mRNA increased during differentiation to macrophages.
125
I-β-VLDL degradation study and oil red O staining showed that IFN-γ significantly inhibited foam cell formation after the uptake of β-VLDL. LDL receptor–related protein (LRP) and LDL receptor mRNAs were not expressed in macrophages. In PMA-treated HL-60 macrophages and human monocyte-derived macrophages, IFN-γ also inhibited VLDL receptor expression and foam cell formation by β-VLDL.

Conclusions
—VLDL receptor expression is upregulated during monocyte-macrophage differentiation. IFN-γ inhibits VLDL receptor expression and foam cell formation only in macrophages. Remnant particles induce macrophage foam cell formation through the VLDL receptor pathway.
Stanol/Sterol Ester–Containing Foods and Blood Cholesterol Levels
Authors: Lichtenstein Alice H. , Deckelbaum Richard J.
Published: June 2012

Abstract
—Considerable attention in the recent past has focused on the potential benefits or adverse effects of butter versus different types of margarines, usually with respect to their relative content of polyunsaturated, saturated, and
trans
fatty acids, and the impact of these on low-density lipoprotein (LDL) cholesterol levels. Recently, a new class of margarines and other fat-derived products (eg, salad dressings, mayonnaise) containing plant-derived sterols that are intended for use to lower blood cholesterol levels have been introduced into the food supply. These products are being marketed as adjuncts to low-saturated-fat and low-cholesterol diets to maximize reductions in LDL cholesterol levels achievable by dietary means.
Rapid Reduction in C-Reactive Protein With Cerivastatin Among 785 Patients With Primary Hypercholesterolemia
Authors: Ridker Paul M. , Rifai Nader , Lowenthal Susan Pitman
Published: June 2012

Background
—Long-term therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) has been shown to reduce levels of C-reactive protein (CRP). However, the generalizability, speed of onset, and dose-response characteristics of this effect are uncertain.

Methods and Results
—We measured CRP, LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) levels among 785 patients with primary hypercholesterolemia at baseline and after 8 weeks of therapy with either 0.4 or 0.8 mg of cerivastatin. Overall, cerivastatin resulted in a 13.3% reduction in median CRP levels (
P
<0.001) and a 24.5% reduction in mean CRP levels (
P
<0.001). Although LDL-C promptly decreased in a dose-dependent manner (mean LDL-C reduction, 37.3% for 0.4 mg and 42.2% for 0.8 mg of cerivastatin), no clear dose-response effect of cerivastatin on CRP was observed, nor was there any substantive correlation between the magnitude of change in CRP and the magnitude of change in LDL-C (
r
=−0.08) or the magnitude of change in HDL-C (
r
=−0.04). Thus, <2% of the variance in the percent change in CRP over 8 weeks could be attributed to the percent change in either of these lipid parameters. Further, there was no evidence of correlation between baseline CRP levels and baseline lipid levels or between end-of-study CRP levels and end-of-study lipid levels.

Conclusions
—Among 785 patients with primary hypercholesterolemia, CRP levels were significantly reduced within 8 weeks of initiating cerivastatin therapy in a lipid-independent manner.
Common Genetic Variation in
ABCA1
Is Associated With Altered Lipoprotein Levels and a Modified Risk for Coronary Artery Disease
Authors: Clee Susanne M. , Zwinderman Aeilko H. , Engert James C. , Zwarts Karin Y. , Molhuizen Henri O. F. , Roomp Kirsten , Jukema J. Wouter , van Wijland Michel , van Dam Marjel , Hudson Thomas J. , Brooks-Wilson Angela , Genest Jacques , Kastelein John J. P. , Hayden Michael R.
Published: June 2012

Background
—Low plasma HDL cholesterol (HDL-C) is associated with an increased risk of coronary artery disease (CAD). We recently identified the ATP-binding cassette transporter 1 (
ABCA1
) as the major gene underlying the HDL deficiency associated with reduced cholesterol efflux. Mutations within the
ABCA1
gene are associated with decreased HDL-C, increased triglycerides, and an increased risk of CAD. However, the extent to which common variation within this gene influences plasma lipid levels and CAD in the general population is unknown.

Methods and Results
—We examined the phenotypic effects of single nucleotide polymorphisms in the coding region of
ABCA1
. The R219K variant has a carrier frequency of 46% in Europeans. Carriers have a reduced severity of CAD, decreased focal (minimum obstruction diameter 1.81±0.35 versus 1.73±0.35 mm in noncarriers,
P
=0.001) and diffuse atherosclerosis (mean segment diameter 2.77±0.37 versus 2.70±0.37 mm,
P
=0.005), and fewer coronary events (50% versus 59%,
P
=0.02). Atherosclerosis progresses more slowly in carriers of R219K than in noncarriers. Carriers have decreased triglyceride levels (1.42±0.49 versus 1.84±0.77 mmol/L,
P
=0.001) and a trend toward increased HDL-C (0.91±0.22 versus 0.88±0.20 mmol/L,
P
=0.12). Other single nucleotide polymorphisms in the coding region had milder effects on plasma lipids and atherosclerosis.

Conclusions
—These data suggest that common variation in
ABCA1
significantly influences plasma lipid levels and the severity of CAD.
Intracoronary Doppler– and Quantitative Coronary Angiography–Derived Predictors of Major Adverse Cardiac Events After Stent Implantation
Authors: Haude Michael , Baumgart Dietrich , Verna Edoardo , Piek Jan J. , Vrints Chris , Probst Peter , Erbel Raimund
Published: June 2012

Background
—Distal coronary flow velocity reserve (CVR) is significantly improved after a successful balloon angioplasty (PTCA). Furthermore, a postinterventional CVR >2.5 and a percent diameter stenosis (%DS) ≤35% are predictive for a low incidence of major adverse cardiac events (MACE) at 6 months of 16%. Similar results are lacking for coronary stenting.

Methods and Results
—In 150 patients, baseline and hyperemic coronary flow velocities were recorded with a Doppler guidewire distal to the target lesion and in an unobstructed reference artery before and after PTCA, after stenting, and at 6 months. Distal CVR and relative CVR (CVR
rel
) were calculated. Logistic regression and receiver operating characteristic analyses were applied to determine prognostic cutoff values of CVR, CVR
rel
, %DS, and minimal lumen diameter separately and in combination to predict MACE at 6 months. After stenting, CVR (2.96±0.87 versus 2.40±0.7;
P
=0.001), CVR
rel
(1.02±0.24 versus 0.81±0.24;
P
=0.001), and minimal lumen diameter (2.98±0.56 versus 2.11±0.74 mm;
P
=0.001) were significantly higher than after PTCA. Thirty-three patients developed MACE. A postinterventional CVR
rel
>0.88 was the best single predictor of MACE, with an incidence of 6.8%, whereas the combination of a CVR
rel
>0.88 and a %DS ≤11.2% predicted an incidence of MACE of 1.5%.

Conclusions
—Measurement of CVR
rel
and %DS after stent implantation are best suitable to predict MACE at 6 months.
Structural Alterations in Subcutaneous Small Arteries of Normotensive and Hypertensive Patients With Non–Insulin-Dependent Diabetes Mellitus
Authors: Rizzoni Damiano , Porteri Enzo , Guelfi Daniele , Muiesan Maria Lorenza , Valentini Umberto , Cimino Antonio , Girelli Angela , Rodella Luigi , Bianchi Rossella , Sleiman Intissar , Rosei Enrico Agabiti
Published: June 2012

Background
—It is not presently known whether non–insulin-dependent diabetes mellitus (NIDDM) is associated with the presence of structural alterations in small arteries or whether the combination of hypertension and NIDDM may have an additive effect on endothelial dysfunction. Therefore, we investigated subcutaneous small arteries in 12 normotensive subjects (NT group), 18 patients with essential hypertension (EH group), 13 patients with NIDDM, and 11 patients with NIDDM and EH (NIDDM+EH group).

Methods and Results
—Subcutaneous small arteries were evaluated by a micromyographic technique. The internal diameter, the media-to-lumen ratio, remodeling and growth indices, and the collagen-to-elastin ratio were calculated. Concentration-response curves to acetylcholine, bradykinin, the endothelium-independent vasodilator sodium nitroprusside, and endothelin-1 were performed. The media-to-lumen ratio was higher in the EH, NIDDM, and NIDDM+EH groups compared with the NT group. EH patients showed the presence of eutrophic remodeling, whereas NIDDM and NIDDM+EH patients showed 40% to 46% cell growth. The collagen-to-elastin ratio was significantly increased in the EH and NIDDM+EH groups compared with the NT group. The vasodilatation to acetylcholine and bradykinin was similarly reduced in EH, NIDDM, and NIDDM+EH groups compared with the NT group. The contractile responses to endothelin-1 were similarly reduced in EH, NIDDM, and NIDDM+EH patients.

Conclusions
—Our data suggest that the effects of NIDDM and EH on small artery morphology are quantitatively similar but qualitatively different and that the presence of hypertension in diabetic patients has little additive effect on small artery morphology and none on endothelial dysfunction.
Novel Gene Mutations in Patients With Left Ventricular Noncompaction or Barth Syndrome
Authors: Ichida Fukiko , Tsubata Shinichi , Bowles Karla R. , Haneda Noriyuki , Uese Keiichiro , Miyawaki Toshio , Dreyer W. Jeffrey , Messina John , Li Hua , Bowles Neil E. , Towbin Jeffrey A.
Published: June 2012

Background
—Mutations in the gene
G4.5
result in a wide spectrum of severe infantile cardiomyopathic phenotypes, including isolated left ventricular noncompaction (LVNC), as well as Barth syndrome (BTHS) with dilated cardiomyopathy (DCM). The purpose of this study was to investigate patients with LVNC or BTHS for mutations in
G4.5
or other novel genes.

Methods and Results
—DNA was isolated from 2 families and 3 individuals with isolated LVNC or LVNC with congenital heart disease (CHD), as well as 4 families with BTHS associated with LVNC or DCM, and screened for mutations by single-strand DNA conformation polymorphism analysis and DNA sequencing. In 1 family with LVNC and CHD, a C→T mutation was identified at nucleotide 362 of α
-dystrobrevin
, changing a proline to leucine (P121L). Mutations in
G4.5
were identified in 2 families with isolated LVNC: a missense mutation in exon 4 (C118R) in 1 and a splice donor mutation (IVS10+2T→A) in intron 10 in the other. In a family with cardiomyopathies ranging from BTHS or fatal infantile cardiomyopathy to asymptomatic DCM, a splice acceptor mutation in exon 2 of
G4.5
(398-2 A→G) was identified, and a 1-bp deletion in exon 2 of G4.5, resulting in a stop codon after amino acid 41, was identified in a sporadic case of BTHS.

Conclusions
—These data demonstrate genetic heterogeneity in LVNC, with mutation of a novel gene, α
-dystrobrevin
, identified in LVNC associated with CHD. In addition, these results confirm that mutations in
G4.5
result in a wide phenotypic spectrum of cardiomyopathies.
Impact of Low Birth Weight and Cardiovascular Risk Factors on Endothelial Function in Early Adult Life
Authors: Leeson C. P. M. , Kattenhorn M. , Morley R. , Lucas A. , Deanfield J. E.
Published: June 2012

Background
—Low birth weight is related to increased risk of coronary heart disease in adults and recently has been associated with vascular endothelial dysfunction in children. We investigated whether the relation between birth weight and endothelial function was still present in early adult life and whether there was an interaction with emerging risk factors.

Methods and Results
—In 315 adults (165 women, 150 men, aged 20 to 28 years), high-resolution ultrasound was used to determine endothelium-dependent and -independent vascular responses of the brachial artery. Vascular measures were related to classic risk factors (smoking history, lipid profile, blood pressure, fasting insulin, exercise capacity, body mass index, and combined risk score) and birth weight. Low birth weight was associated with reduced flow-mediated dilation (coefficient=0.18 kg
−1
, 95% CI 0.004 to 0.35,
P
=0.04) but not with endothelium-independent dilation. The difference in flow-mediated dilation between the top and bottom fifths of birth weight was the same as between smokers and nonsmokers. Increasing levels of acquired risk factors overwhelmed the association, and there was a significant interaction of risk score with the birth weight–endothelial function relation (coefficient of interaction term [birth weight×risk score] = −0.12, 95% CI −0.22 to −0.03,
P
=0.01).

Conclusions
—Low birth weight is associated with endothelial dysfunction in young adults. This is most marked in individuals with lower risk factor profiles and may be relevant to the pathogenesis of atherosclerosis in later life.
Characterization of Sodium Channel α- and β-Subunits in Rat and Mouse Cardiac Myocytes
Authors: Malhotra Jyoti Dhar , Chen Chunling , Rivolta Ilaria , Abriel Hugues , Malhotra Ricky , Mattei Laura N. , Brosius Frank C. , Kass Robert S. , Isom Lori L.
Published: June 2012

Background
—Sodium channels isolated from mammalian brain are composed of α-, β
1
-, and β
2
-subunits. The composition of sodium channels in cardiac muscle, however, has not been defined, and disagreement exists over which β-subunits are expressed in the myocytes. Some investigators have demonstrated β
1
expression in heart. Others have not detected any auxiliary subunits. On the basis of Northern blot analysis of total RNA, β
2
expression has been thought to be exclusive to neurons and absent from cardiac muscle.

Methods and Results
—The goal of this study was to define the subunit composition of cardiac sodium channels in myocytes. We show that cardiac sodium channels are composed of α-, β
1
-, and β
2
-subunits. Nav1.5 and Nav1.1 are expressed in myocytes and are associated with β
1
- and β
2
-subunits. Immunocytochemical localization of Nav1.1, β
1
, and β
2
in adult heart sections showed that these subunits are expressed at the Z lines, as shown previously for Nav1.5. Coexpression of Nav1.5 with β
2
in transfected cells resulted in no detectable changes in sodium current.

Conclusions
—Cardiac sodium channels are composed of α- (Nav1.1 or Nav1.5), β
1
-, and β
2
-subunits. Although β
1
-subunits modulate cardiac sodium channel current, β
2
-subunit function in heart may be limited to cell adhesion.
Randomized, Placebo-Controlled Study for Immunosuppressive Treatment of Inflammatory Dilated Cardiomyopathy
Authors: Wojnicz Romuald , Nowalany-Kozielska Ewa , Wojciechowska Celina , Glanowska Grażyna , Wilczewski Przemysław , Niklewski Tomasz , Zembala Marian , Poloński Lech , Rozek Marius M. , Wodniecki Jan
Published: June 2012

Background
—Previous studies have shown disappointing results for immunosuppressive treatment in patients with dilated cardiomyopathy. Therefore, we studied the effectiveness of such therapy in patients with HLA upregulation on biopsy.

Methods and Results
—Of 202 patients with dilated cardiomyopathy, 84 patients with increased HLA expression were randomized to receive either immunosuppression or placebo for 3 months; they were then followed for 2 years. After 2 years, there were no significant differences in the primary end point (a composite of death, heart transplantation, and hospital readmission) between the 2 study groups (22.8% for the immunosuppression group and 20.5% for the placebo). The secondary efficacy end point included changes in ejection fraction, end-diastolic diameter, end-diastolic volume, end-systolic volume and NYHA class; left ventricular ejection fraction increased significantly in the immunosuppression group compared with the placebo group (95% CI, 4.20 to 13.12;
P
<0.001) after 3 months of follow-up. The early favorable effects of immunosuppressive therapy on left ventricular volume, left ventricular diastolic dimension, and New York Heart Association class were also present. This improvement was maintained in the immunosuppression group at 2 years (ejection fraction: 95% CI, 6.94 to 19.04;
P
<0.001). In addition, on the basis of the protocol-specified definition of improvement, 71.8% patients in the immunosuppression group versus 20.9% patients in the placebo group met the criteria of improvement after 3 months (
P
<0.001). At the end of the follow-up period, 71.4% patients from the immunosuppression group versus 30.8% patients from the placebo group were improved (
P
=0.001).

Conclusions
—These data demonstrate a long-term benefit of immunosuppressive therapy in patients with dilated cardiomyopathy and HLA upregulation on biopsy specimens. Thus, restoration of immunosuppressive therapy for such patients should be considered.
Enhanced Generation of Reactive Oxygen Species in the Limb Skeletal Muscles From a Murine Infarct Model of Heart Failure
Authors: Tsutsui Hiroyuki , Ide Tomomi , Hayashidani Shunji , Suematsu Nobuhiro , Shiomi Tetsuya , Wen Jing , Nakamura Kei-ichiro , Ichikawa Kazuhiro , Utsumi Hideo , Takeshita Akira
Published: June 2012

Background

—

The generation of reactive oxygen species (ROS) is enhanced in the failing myocardium. We hypothesized that ROS were also increased in the limb skeletal muscles in heart failure.

Methods and Results

—

Myocardial infarction (MI) was created in mice by ligating the left coronary artery. After 4 weeks, the left ventricle was dilated and contractility was diminished by echocardiography. Left ventricular end-diastolic pressure was elevated after MI in association with an increase in lung weight/body weight and the presence of pleural effusion. The generation of ROS in the limb muscles, including the soleus and gastrocnemius muscles, which were excised after MI, was measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO). Overall, generation was increased, but it was attenuated in the presence of dimethylthiourea or 4,5-dihydroxy-1,2-benzenedisulfonic disodium salt in the reaction mixture, indicating increased generation of hydroxyl radicals originating from superoxide anion. Thiobarbituric acid-reactive substance formation was also increased in muscles after MI. Mitochondrial complex I and III activities were both decreased after MI, which may have caused the functional uncoupling of the respiratory chain and ROS production. Antioxidant enzyme activities, including superoxide dismutase, catalase, and glutathione peroxidase, were comparable between groups.

Conclusions

—

Skeletal muscle in post-MI heart failure expressed an increased amount of ROS in association with ROS-mediated lipid peroxidation. This supports the hypothesis that oxidative stress may cause (at least in part) skeletal muscle dysfunction in heart failure.
Simple Bedside Additive Tool for Prediction of In-Hospital Mortality After Percutaneous Coronary Interventions
Authors: Moscucci Mauro , Kline-Rogers Eva , Share David , O’Donnell Michael , Maxwell-Eward Ann , Meengs William L. , Kraft Phillip , DeFranco Anthony C. , Chambers James L. , Patel Kirit , McGinnity John G. , Eagle Kim A. ,   for the Blue Cross Blue Shield of Michigan Cardiovascular Consortium
Published: June 2012

Background

Risk-adjustment models for percutaneous coronary intervention (PCI) mortality have been recently reported, but application in bedside prediction of prognosis for individual patients remains untested.

Methods and Results

Between July 1, 1997 and September 30, 1999, 10 796 consecutive procedures were performed in a consortium of 8 hospitals. Predictors of in-hospital mortality were identified by use of multivariate logistic regression analysis. The final model was validated by use of the bootstrap technique. Additional validation was performed on an independent data set of 5863 consecutive procedures performed between October 1, 1999, and August 30, 2000. An additive risk-prediction score was developed by rounding coefficients of the logistic regression model to the closest half-integer, and a visual bedside tool for the prediction of individual patient prognosis was developed. In this patient population, the in-hospital mortality rate was 1.6%. Multivariate regression analysis identified acute myocardial infarction, cardiogenic shock, history of cardiac arrest, renal insufficiency, low ejection fraction, peripheral vascular disease, lesion characteristics, female sex, and advanced age as independent predictors of death. The model had excellent discrimination (area under the receiver operating characteristic curve, 0.90) and was accurate for prediction of mortality among different subgroups. Near-perfect correlation existed between calculated scores and observed mortality, with higher scores associated with higher mortality.

Conclusions

Accurate predictions of individual patient risk of mortality associated with PCI can be achieved with a simple bedside tool. These predictions could be used during discussions of prognosis before and after PCI.
Effects of Candesartan on Cough and Bronchial Hyperresponsiveness in Mildly to Moderately Hypertensive Patients With Symptomatic Asthma
Authors: Tanaka Hiroshi , Teramoto Shin , Oashi Kensuke , Saikai Toyohiro , Tanaka Shintaro , Suzuki Kazuhiko , Hashimoto Midori , Abe Shosaku
Published: June 2012

Background

Candesartan, an AT
1
receptor antagonist, has been reported to have no association with persistent cough in subjects with hypertension, but there has been no study on the safety of its administration to hypertensive patients with symptomatic asthma. The aim of this study was to compare the adverse effects of candesartan and calcium antagonists on cough, pulmonary function, and bronchial hyperresponsiveness in these patients.

Methods and Results

Sixty mildly to moderately hypertensive patients with bronchial asthma received either candesartan (n=30) or the calcium antagonists nifedipine or manidipine (n=30) for 6 months. The candesartan group included 5 subjects with a history of ACE inhibitor–induced cough. There were no differences between the 2 groups in patient characteristics, ACE gene polymorphism, pulmonary function, or bronchial hyperresponsiveness to methacholine. Control of hypertension was the primary end point; new cough detected by self-administrated questionnaire and an increase in cough frequency by visual analog scale were the second end point. No patient complained of persistent cough. Neither mean visual analog scale score nor pulmonary functions changed during this study. Bronchial hyperresponsiveness had a tendency to improve in the candesartan group, but there was no difference between the 2 groups.

Conclusions

Incidence, frequency, and severity of persistent cough, pulmonary functions, and bronchial hyperresponsiveness did not change in either the candesartan or calcium antagonist group. It is suggested that candesartan is as effective and safe as calcium antagonists in the treatment of hypertension associated with symptomatic asthma.
Ubiquitous Elevation of Matrix Metalloproteinase-2 Expression in the Vasculature of Patients With Abdominal Aneurysms
Authors: Goodall Stephen , Crowther Mat , Hemingway David M. , Bell Peter R. , Thompson Matt M.
Published: June 2012

Background

Patients with abdominal aortic aneurysms (AAAs) exhibit arterial dilation and altered matrix composition throughout the vasculature. Matrix metalloproteinase-2 (MMP-2) is the dominant elastase in small AAAs, and overexpression of MMP-2 in vascular smooth muscle cells (SMCs) may be a primary etiological event in aneurysm genesis. The aim of this study was to investigate MMP-2 production in vascular tissue remote from the abdominal aorta.

Methods and Results

Inferior mesenteric vein (IMV) was harvested from patients undergoing aneurysm repair (n=21) or colectomy for diverticular disease (n=13, control). Matrix composition of the vessels was determined by stereological techniques. MMPs were extracted from tissue homogenates and quantified by gelatin zymography and ELISA. MMP-2, membrane type-1 MMP (MT1-MMP), and tissue inhibitor of metalloproteinases type 2 (TIMP-2) expression were determined by Northern analysis. SMCs were isolated from IMV, and the production and expression of MMP-2 and TIMP-2 in the SMC lines were quantified. Tissue homogenates and isolated inferior mesenteric SMCs from patients with aneurysms demonstrated significantly elevated MMP-2 levels, with no difference in TIMP-2 or MT1-MMP. These differences were a result of increased MMP-2 expression. Histological examination revealed fragmentation of elastin fibers within venous tissue obtained from patients with AAA and a significant depletion of the elastin within the media. In situ zymography localized elastolysis to medial SMCs.

Conclusions

Patients with AAA have elevated MMP-2 levels in the vasculature remote from the aorta. This finding is due to increased MMP-2 expression from SMCs, a characteristic maintained in tissue culture. These data support both the systemic nature of aneurysmal disease and a primary role of MMP-2 in aneurysm formation.
Reliability of Multicenter Pediatric Echocardiographic Measurements of Left Ventricular Structure and Function
Authors: Lipshultz Steven E. , Easley Kirk A. , Orav E. John , Kaplan Samuel , Starc Thomas J. , Bricker J. Timothy , Lai Wyman W. , Moodie Douglas S. , Sopko George , Schluchter Mark D. , Colan Steven D. ,   for the Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study Group
Published: June 2012

Background

To assess the reliability of pediatric echocardiographic measurements, we compared local measurements with those made at a central facility.

Methods and Results

The comparison was based on the first echocardiographic recording obtained on 735 children of HIV-infected mothers at 10 clinical sites focusing on measurements of left ventricular (LV) dimension, wall thicknesses, and fractional shortening. The recordings were measured locally and then remeasured at a central facility. The highest agreement expressed as an intraclass correlation coefficient (ICC=0.97) was noted for LV dimension, with much lower agreement for posterior wall thickness (ICC=0.65), fractional shortening (ICC=0.64), and septal wall thickness (ICC=0.50). The mean dimension was 0.03 cm smaller in central measurements (95% prediction interval [PI], −0.32 to 0.25 cm) for which 95% PI reflects the magnitude of differences between local and central measurements. Mean posterior wall thickness was 0.02 cm larger in central measurements (95% PI, −0.18 to 0.22 cm). Mean fractional shortening was 1% smaller in central measurements. However, the 95% PI was −10% to 8%, indicating that a fractional shortening of 32% measured centrally could be anywhere between 22% and 40% when measured locally. Central measurements of mean septal thickness were ≈0.1 cm thicker than local ones (95% PI, −0.18 to 0.34 cm). Centrally measured wall thickness was more closely related to mortality and possibly was more valid than local measurements.

Conclusions

Although LV dimension was reliably measured, local measurements of LV wall thickness and fractional shortening differed from central measurements.
Nd:YAG laser with sapphire tip combined with balloon angioplasty in peripheral arterial occlusions. Long-term results.
Authors: Pilger E , Lammer J , Bertuch H , Stark G , Decrinis M , Pfeiffer K P , Krejs G J
Published: June 2012

In 167 patients with complete occlusion (greater than 3 cm) of the femoropopliteal artery, percutaneous transluminal laser angioplasty (PTLA) was performed after an unsuccessful attempt at crossing with a guide wire and was immediately followed by balloon dilatation. An Nd-YAG laser and an optical fiber delivery system with a sapphire tip serving as a contact probe were used for PTLA. In 132 of 167 (79%) patients, the occluded segment was successfully reopened. Clinical symptoms improved in 126 of 167 (75%) patients. PTLA was unsuccessful in 35 patients, and in 15 of these, injury of the vessel wall occurred. In one patient, surgical drainage of a large hematoma became necessary. All patients in whom recanalization had been achieved were randomized to receive long-term treatment with either phenprocumarol or acetylsalicylic acid (ASA) plus dipyridamole to prevent rethrombosis. At 36 months of follow-up, the cumulative patency rate (CPR) was 63%. A complete reobstruction in 32 patients (24%) and a partial reobstruction in 15 patients (11%) were found angiographically. The CPR after 36 months was significantly lower (p less than 0.05) in patients younger than 60 years of age (54%) than in patients older than 60 (68%); it was also significantly lower (p less than 0.05) in patients with reduced peripheral runoff (55%) due to obstructed arteries of the lower leg than in patients with unaffected runoff (73%). The CPR was 65% in recanalized segments shorter than 7 cm and was 62% in recanalized segments longer than 7 cm.(ABSTRACT TRUNCATED AT 250 WORDS)
Detection of patients at risk for paroxysmal atrial fibrillation during sinus rhythm by P wave-triggered signal-averaged electrocardiogram.
Authors: Fukunami M , Yamada T , Ohmori M , Kumagai K , Umemoto K , Sakai A , Kondoh N , Minamino T , Hoki N
Published: June 2012

To determine whether patients at risk for paroxysmal atrial fibrillation could be detected while in sinus rhythm, the signal-averaged electrocardiogram triggered by P waves was recorded in 42 patients with paroxysmal atrial fibrillation (Paf group) and in 50 control patients. The root mean square voltages (LP10, LP20, and LP30) for the last 10, 20, and 30 msec and the duration (Ad) of filtered (40-300 Hz) P wave of the spatial magnitude were measured. LP10 and LP20 were significantly lower in the Paf than in the control group (LP10, 1.92 +/- 0.58 versus 2.49 +/- 0.78 microV, p less than 0.001; LP20, 2.47 +/- 0.78 versus 3.46 +/- 1.20 microV, p less than 0.0001), although no significant difference in LP30 was found between groups. Ad was also significantly longer in the Paf than in the control group (137.0 +/- 14.3 versus 118.6 +/- 11.3 msec, p less than 0.001). These differences between the Paf and control groups remained significant even after dividing by the presence or absence of organic heart diseases. The criteria of "LP20 = 3.5 microV or less" and "Ad greater than 120 msec" as defining "atrial late potential" gave a sensitivity of 91% and a specificity of 76%. These findings suggest that patients at risk for paroxysmal atrial fibrillation could be detected while in sinus rhythm by using the P wave-triggered signal-averaged electrocardiogram.