bluuebunny/crossref_metadata_2025 huggingface dataset:
Progression of Aortic Valve Calcification
Authors: Pohle Karsten , Mäffert Ralph , Ropers Dieter , Moshage Werner , Stilianakis Nicolaos , Daniel Werner G. , Achenbach Stephan
Published: September 2007

Background

Recent studies demonstrated an influence of atherosclerotic risk factors on the progression of aortic valve stenosis. The extent of aortic valve calcification (AVC) was also found to be a strong predictor of stenosis progression. We investigated the influence of the LDL cholesterol level (LDL), other standard cardiovascular risk factors, and the extent of coronary calcification (CC) on the progression of AVC quantified by electron beam tomography (EBT).

Methods and Results

In 104 patients (64.7±8 years, 89 male) with an EBT scan positive for AVC, CC and AVC were quantified using a volumetric score. EBT was repeated at a mean interval of 15 months (10 to 36 months), and the progression of AVC and CC was determined. Patients were divided into 2 groups according to LDL: group 1, LDL≤3.36 mmol/L (130 mg/dL), 57 patients; group 2, LDL>3.36 mmol/L (130 mg/dL), 47 patients. Mean values for CC were 546±932 mm
3
in scan 1 and 665±1085 mm
3
in scan 2 for AVC 324±796 mm
3
and 404±1076 mm
3
, respectively. The mean progression of CC was 27±37% (group 1, 16±22%; group 2, 39±46%,
P
≤0.001) and of AVC was 25±38% (group 1, 9±22%; group 2, 43±44%,
P
≤0.001).

Conclusions

Quantification of AVC by EBT permits new insights into the progression of aortic valve sclerosis. We observed a strong influence of LDL cholesterol level on the progression of AVC and CC, suggesting that lipid-lowering therapy may decrease the progression of aortic valve calcification.
Spatial Heterogeneity of Calcium Transient Alternans During the Early Phase of Myocardial Ischemia in the Blood-Perfused Rabbit Heart
Authors: Qian You-Wen , Clusin William T , Lin Shien-Fong , Han Jennifer , Sung Ruey J
Published: September 2007

Background

Optical mapping of cytosolic calcium transients in intact mammalian hearts is now possible using long-wavelength [Ca
2+
]
i
indicators. We propose that beat-to-beat [Ca
2+
]
i
transient alternans during ischemia may lead to spatial and temporal heterogeneity of calcium-activated membrane currents.

Methods and Results

To test this hypothesis, isolated rabbit hearts were loaded with the fluorescent [Ca
2+
]
i
indicator, rhod-2 AM, and imaged at 300 frames/sec during blood-perfused ischemic trials. High-quality [Ca
2+
]
i
transients were recorded in each of 8 hearts.[Ca
2+
]
i
transient alternans was never present in control records but occurred in each of the hearts during ischemia, with onset after 2 to 4 minutes. Alternans was confined to circumscribed regions of the heart surface 5 to 15 mm across. Multiple regions of alternans were found in most hearts, and regions that were out of phase with one another were found in 6 hearts. Quantitative maps of alternans were constructed by calculating an alternans ratio. This ratio behaved as a continuous variable that reached a maximum value in the center of the regions with alternans.

Conclusions

These results demonstrate marked spatial heterogeneity of the [Ca
2+
]
i
transient during the early phase of ischemia, which could produce electrical instability and arrhythmias in large mammalian hearts.
Scaffold-Based Three-Dimensional Human Fibroblast Culture Provides a Structural Matrix That Supports Angiogenesis in Infarcted Heart Tissue
Authors: Kellar Robert S. , Landeen Lee K. , Shepherd Benjamin R. , Naughton Gail K. , Ratcliffe Anthony , Williams Stuart K.
Published: September 2007

Background

We have developed techniques to implant angiogenic patches onto the epicardium over regions of infarcted cardiac tissue to stimulate revascularization of the damaged tissue. These experiments used a scaffold-based 3D human dermal fibroblast culture (3DFC) as an epicardial patch. The 3DFC contains viable cells that secrete angiogenic growth factors and has previously been shown to stimulate angiogenic activity. The hypothesis tested was that a viable 3DFC cardiac patch would stimulate an angiogenic response within an area of infarcted cardiac tissue.

Methods and Results

A coronary occlusion of a branch of the left anterior descending coronary artery was performed by thermal ligation in severe combined immunodeficient mice. 3DFCs with or without viable cells were sized to the damaged area, implanted in replicate mice onto the epicardium at the site of tissue injury, and compared with animals that received infarct surgery but no implant. Fourteen and 30 days after surgery, hearts were exposed and photographed, and tissue samples were prepared for histology and cytochemistry. Fourteen and 30 days after surgery, the damaged myocardium receiving viable 3DFC exhibited a significantly greater angiogenic response (including arterioles, venules, and capillaries) than nonviable and untreated control groups.

Conclusions

In this animal model, viable 3DFC stimulates angiogenesis within a region of cardiac infarction and can augment a repair response in damaged tissue. Therefore, a potential use for 3DFC is the repair of myocardial tissue damaged by infarction.
Tibioperoneal (Outflow Lesion) Angioplasty Can Be Used as Primary Treatment in 235 Patients With Critical Limb Ischemia
Authors: Dorros Gerald , Jaff Michael R. , Dorros Ari M. , Mathiak Lynne M. , He Thomas
Published: September 2007

Background

In a prospective, nonrandomized, consecutive series of tibioperoneal vessel angioplasty (TPVA), critical limb ischemia (CLI) patients’ data were analyzed with regard to immediate and follow-up success.

Methods and Results

TPVA was successful in 270 of 284 critically ischemic limbs (95%), with 167 limbs (59%) requiring dilatation of 333 ipsilateral inflow obstructions to access and successfully dilate 486 of 529 (92%) tibioperoneal lesions. A clinical success (relief of rest pain or improvement of lower-extremity blood flow) was attained in 270 limbs at risk (95%). Clinical 5-year follow-up of 215 of 221 successful CLI patients (97%) with 266 successfully revascularized limbs revealed that bypass surgery occurred in 8% and significant amputations in 9% of limbs; 91% of the limbs were salvaged. The cohort’s probability of survival was 56%: 58% for Fontaine class III and 33% for class IV patients. Class III compared with class IV patients had significantly (
P
<0.05) fewer surgical bypasses (3% versus 16%) and amputations: above-knee, 1% versus 4%; below-knee, 3% versus 12%; and transmetatarsal, <1% versus 21%.

Conclusions

TPVA, often in combination with inflow lesions, is an effective primary treatment for critical limb ischemia. The poor cumulative survival reflects the existence of severe comorbidities, which could potentially be affected by aggressive and effective cardiovascular diagnostic and therapeutic strategies.
Left Ventricular Hypertrophy as an Independent Predictor of Acute Cerebrovascular Events in Essential Hypertension
Authors: Verdecchia Paolo , Porcellati Carlo , Reboldi Gianpaolo , Gattobigio Roberto , Borgioni Claudia , Pearson Thomas A. , Ambrosio Giuseppe
Published: September 2007

Background

It is uncertain whether left ventricular hypertrophy (LVH) confers an increased risk for cerebrovascular disease in apparently healthy patients with essential hypertension.

Methods and Results

A total of 2363 initially untreated hypertensive patients (mean age 51±12 years, 47% women) free of previous cardiovascular disease were followed up for up to 14 years (mean 5 years). At entry, all patients underwent diagnostic tests, including ECG, echocardiography, and 24-hour ambulatory blood pressure (BP) monitoring. At entry, the prevalence of LVH was 17.6% by ECG (Perugia score) and 23.7% by echocardiography (LVM >125 g/m
2
). Over the subsequent years, 105 patients experienced a first stroke or transient ischemic attack. The cerebrovascular event rate was higher among patients with LVH at entry, diagnosed by either ECG or echocardiography, than among those without hypertrophy (both
P
<0.01). After control for the significant influence of age, sex, diabetes, and 24-hour mean ambulatory BP, LVH by ECG conferred an increased risk for cerebrovascular events (relative risk [RR] 1.79; 95% CI 1.17 to 2.76). LVH by echocardiography also conferred a higher risk for cerebrovascular events (RR 1.64; 95% CI 1.07 to 2.68). For each increase in LV mass of 1 SD (29 g/m
2
), there was a significant independent increase in the risk for cerebrovascular events (RR 1.31; 95% CI 1.09 to 1.58).

Conclusions

In apparently healthy patients with essential hypertension, LVH diagnosed by ECG or echocardiography confers an excess risk for stroke and transient ischemic attack independently of BP and other individual risk factors.
Bradykinin Contributes to the Vasodilator Effects of Chronic Angiotensin-Converting Enzyme Inhibition in Patients With Heart Failure
Authors: Witherow Fraser N. , Helmy Ahmed , Webb David J. , Fox Keith A.A. , Newby David E.
Published: September 2007

Background

Bradykinin, an endogenous vasodilator peptide, is metabolized by ACE. The aims of the present study were to determine the doses of B9340, a bradykinin receptor antagonist, that inhibit vasodilatation to exogenous bradykinin and to assess the contribution of bradykinin to the maintenance of basal vascular tone in patients with heart failure receiving chronic ACE inhibitor therapy.

Methods and Results

Forearm blood flow was measured using bilateral venous occlusion plethysmography. On three occasions in a double-blind randomized manner, 8 healthy volunteers received intrabrachial infusions of placebo or B9340 (at 4.5 and 13.5 nmol/min). On each occasion, placebo or B9340 was coinfused with bradykinin (30 to 3000 pmol/min) and substance P (4 to 16 pmol/min). B9340 caused no change in basal FBF but produced dose-dependent inhibition of the vasodilatation to bradykinin (
P
<0.001) but not substance P. The effects of bradykinin antagonism were studied in 17 patients with NYHA grade II through IV heart failure maintained on chronic ACE inhibitor therapy. Incremental doses of B9340, but not HOE-140, produced a dose-dependent vasoconstriction (
P
=0.01). After withdrawal of ACE inhibitor therapy, B9340 produced no significant change in forearm blood flow. After reinstitution of therapy, B9340 again resulted in vasoconstriction (
P
<0.03).

Conclusions

B9340 is a potent and selective inhibitor of bradykinin-induced vasodilatation. Bradykinin does not contribute to the maintenance of basal peripheral arteriolar tone in healthy humans or patients with heart failure but contributes to the vasodilatation associated with chronic ACE inhibitor therapy in patients with heart failure via the B
1
receptor.
Novel Cardiac Troponin T Mutation as a Cause of Familial Dilated Cardiomyopathy
Authors: Li Duanxiang , Czernuszewicz Grazyna Z. , Gonzalez Oscar , Tapscott Terry , Karibe Akihiko , Durand Jean-Bernard , Brugada Ramon , Hill Rita , Gregoritch Jane M. , Anderson Jeffrey L. , Quiñones Miguel , Bachinski Linda L. , Roberts Robert
Published: September 2007

Background

Familial dilated cardiomyopathy (FDCM) and hypertrophic cardiomyopathy (FHCM) are the 2 most common forms of primary cardiac muscle diseases. Studies indicate that mutations in sarcomeric proteins are responsible for FHCM and suggest that mutations in cytoskeletal proteins cause FDCM. Evidence is evolving, however, that such conclusions are premature.

Methods and Results

A novel missense mutation in the cardiac troponin T gene was identified by direct sequencing and confirmed by endonuclease restriction analysis in a large family with FDCM that we had previously mapped to chromosome 1q32. The mutation substitutes tryptophan for a highly conserved amino acid, arginine, at amino acid residue 141 (Arg141Trp). The mutation occurs within the tropomyosin-binding domain of cardiac troponin T and alters the charge of the residue. This mutation cosegregates with the disease, being present in all 14 living affected individuals. The mutation was not found in 100 normal control subjects. Clinical features were congestive heart failure with premature deaths. The age of onset and severity of the disease are highly variable, with incomplete penetrance. Because 15 mutations in troponin T are known to cause FHCM, 219 probands with FHCM were screened, and none had the mutation.

Conclusions

Thus, the novel cardiac troponin T mutation Arg141Trp is responsible for FDCM in our family. Because several mutations in troponin T have already been recognized to be responsible for FHCM, it appears that the phenotype, whether it be hypertrophy or dilatation, is determined by the specific mutation rather than the gene.
Clinical and Angiographic Factors Associated With Asymptomatic Restenosis After Percutaneous Coronary Intervention
Authors: Ruygrok Peter N. , Webster Mark W.I. , de Valk Vincent , van Es Gerrit-Anne , Ormiston John A. , Morel Marie-Angèle M. , Serruys Patrick W.
Published: September 2007

Background

Angiographic restenosis after percutaneous coronary interventional procedures is more common than recurrent angina. Clinical and angiographic factors associated with asymptomatic versus symptomatic restenosis after percutaneous coronary intervention were compared.

Methods and Results

All patients with angiographic restenosis from the BENESTENT I, BENESTENT II pilot, BENESTENT II, MUSIC, WEST 1, DUET, FINESS 2, FLARE, SOPHOS, and ROSE studies were analyzed. Multivariate analysis evaluated 46 clinical and angiographic variables, comparing those with and without angina. The 10 studies recruited 2690 patients who underwent percutaneous revascularization and 6-month follow-up angiography (86% of those eligible). Restenosis (≥50% diameter stenosis) occurred in 607 patients and was clinically silent in 335 (55%). Male sex (
P
=0.008), absence of antianginal therapy with nitrates (
P
=0.0002) and calcium channel blockers (
P
=0.02) at 6 months, greater reference diameter after the procedure (
P
=0.04), greater reference diameter at follow-up (
P
=0.004), and lesser lesion severity (percent stenosis) at 6 months (
P
=0.0004) were univariate predictors of asymptomatic restenosis. By multivariate analysis, only male sex (
P
=0.04), greater reference diameter at follow-up (
P
=0.002), and lesser lesion severity at 6 months (
P
=0.0001) were associated with restenosis without angina.

Conclusions

Approximately half of patients with angiographic restenosis have no symptoms. The only multivariate predictors of silent restenosis at 6 months were male sex, greater reference diameter at follow-up, and lesser lesion severity on follow-up angiography.
Failure of a Novel Balloon-Expandable γ-Emitting (
103
Pd) Stent to Prevent Edge Effects
Authors: Hehrlein Christoph , DeVries Jennifer J. , Arab Amina , Haller Scott D. , Schloesser Klaus , Tio Ferman O. , Fischell Tim A.
Published: September 2007

Background

Balloon-expandable β-particle–emitting (
32
P) stents inhibit within-stent neointimal hyperplasia but induce lumen narrowing beyond the stent margins, ie, the so-called “edge effects.”

Methods and Results

We prospectively investigated the performance of novel stents impregnated with the γ-emitting isotope
103
Pd, designed to reduce edge effects, in 24 rabbits. The stents had a length of 18 mm and were mounted on 20-mm-long delivery balloons for deployment. Angiograms were obtained immediately and 1 month after direct implantation of control and 1-, 2-, and 4-mCi
103
Pd stents into the iliac arteries without predilatation or postdilatation. Late lumen loss was measured with quantitative angiography. Neointimal hyperplasia and vascular remodeling were evaluated by histomorphometry. Late lumen loss was inhibited within
103
Pd stents (control 0.18 mm, 1 mCi 0.08 mm, 2 mCi 0.05 mm, and 4 mCi −0.03 mm,
P
<0.05 all activities versus control). Conversely, late lumen loss occurred at the edges of
103
Pd stents, correlating with areas of high balloon/artery ratios and vessel overstretch injury. Edge effects were primarily due to neointimal hyperplasia but were also caused by negative vessel remodeling at high stent activities.

Conclusions

Edge effects after implantation of radioisotope stents can occur independently of the isotope chosen for stent impregnation.
Comparison of Various Electrophoretic Characteristics of LDL Particles and Their Relationship to the Risk of Ischemic Heart Disease
Authors: St-Pierre A.C. , Ruel I.L. , Cantin B. , Dagenais G.R. , Bernard P.-M. , Després J.-P. , Lamarche B.
Published: September 2007

Background

Several cross-sectional studies and 3 prospective, nested, case-control studies have indicated that individuals with small, dense low density lipoprotein (LDL) particles are at increased risk for ischemic heart disease (IHD). However, whether LDL particle size is an independent risk factor for future IHD events remains controversial. The objective of the present study was to further analyze the cardiovascular risk associated with various electrophoretic characteristics of LDL particles in men.

Methods and Results

LDL particles were characterized by polyacrylamide gradient gel electrophoresis (PAGGE) in a cohort of 2034 men of the Quebec Cardiovascular Study. All men were initially free of IHD and were followed up for a period of 5 years, during which 108 first IHD events were recorded. Among all LDL characteristics investigated by PAGGE, including LDL peak particle size, the cholesterol concentration in LDL particles with a diameter smaller than 255 Å showed the strongest association with the risk of IHD (relative risk=4.6 in men in the third vs first tertile of the distribution,
P
<0.001). Multivariate logistic and survival models indicated that the relationship between LDL cholesterol levels in particles with a diameter <255 Å and IHD risk was independent of all nonlipid risk factors and of LDL cholesterol, high density lipoprotein cholesterol, triglyceride, and lipoprotein(a) levels.

Conclusions

Results from this large, population-based, prospective study suggest that further characterization of LDL particles by PAGGE, in addition to the traditional lipid profile, may improve our ability to predict IHD events in men.
Intraplatelet Tetrahydrobiopterin Plays an Important Role in Regulating Canine Coronary Arterial Thrombosis by Modulating Intraplatelet Nitric Oxide and Superoxide Generation
Authors: Kanaya Seiji , Ikeda Hisao , Haramaki Nobuya , Murohara Toyoaki , Imaizumi Tsutomu
Published: September 2007

Background

Platelet-derived nitric oxide inhibits platelet aggregation via constitutive NO synthase (NOS). Tetrahydrobiopterin (BH
4
), a cofactor of NOS, augments NO formation, whereas its deficiency decreases NO bioactivity and increases superoxide generation by NOS. The roles of intraplatelet BH
4
in platelet aggregation and thrombus formation, however, are unknown. Accordingly, we investigated whether intraplatelet BH
4
is involved in regulating cyclic flow variations (CFVs) and platelet aggregation in a canine model with stenosed and endothelium-injured coronary arteries that mimics acute coronary syndromes in humans.

Methods and Results

After developing CFVs, dogs received saline or BH
4
(10 or 30 mg/kg) intravenously. Intraplatelet BH
4
and cGMP levels were decreased and intraplatelet nitrotyrosine production was increased during CFVs. ADP- and U46619-induced ex vivo platelet aggregation and platelet P-selectin expression were augmented during CFVs. BH
4
administration restored intraplatelet BH
4
and cGMP levels and decreased intraplatelet nitrotyrosine production, resulting in reduced CFVs and inhibited ex vivo platelet aggregation and platelet P-selectin expression. CFVs again developed after
N
G
-monomethyl-
l
-arginine, an inhibitor of NOS, in BH
4
-treated dogs. Ex vivo platelet NOS activity at baseline, during CFVs, and after BH
4
administration did not differ.

Conclusions

Intraplatelet BH
4
may play an important role in regulating thrombus formation by modulating platelet-derived nitric oxide and superoxide generation by platelet NOS.
Mitochondrial Abnormalities in Tumor Necrosis Factor-α–Induced Heart Failure Are Associated With Impaired DNA Repair Activity
Authors: Li Yun You , Chen Dexi , Watkins Simon C. , Feldman Arthur M.
Published: September 2007

Background

Recent studies suggest that mutations in cardiac mitochondrial DNA (mtDNA) may contribute to the development of dilated cardiomyopathy. The mechanisms that regulate those mutations, however, remain undefined. Thus, we studied cardiac mtDNA repair mechanisms, mtDNA damage, and mitochondrial structure and function in mice with heart failure secondary to overexpression of TNF-α (TNF1.6 mice).

Methods and Results

We studied mtDNA repair by measuring the uracil DNA glycosylase (mtUDG) and base excision repair activities. mtDNA damage was assessed by Southern blot of Fpg protein–digested mtDNA. Mitochondrial ultrastructural changes were examined by electron microscopy, and function by cytochrome
c
oxidase and succinate dehydrogenase activity assays. The results showed that both mtUDG and base excision repair activities were significantly reduced in TNF1.6 mouse heart. Fpg-sensitive sites were markedly increased in TNF1.6 mouse cardiac mtDNA, suggesting increased mtDNA damage. Mitochondrial function as demonstrated by cardiac cytochrome
c
oxidase activity was also markedly reduced. Cardiac ATP content was not changed, however, suggesting a shift from oxidative phosphorylation to glycolysis, as shown by increased LDH and ALT activities and lactate/pyruvate ratio. Ultrastructurally, the TNF1.6 mouse cardiac mitochondria became irregular in shape and smaller, and the cristae were decreased and appeared disorganized, with breaks.

Conclusions

These results suggest that mtDNA mutations and mitochondrial structural and functional alterations in TNF-α–induced heart failure may be associated with reduced mtDNA repair activity, and the pathophysiological effects of TNF-α on the heart may be mediated, at least in part, through these changes in mitochondria.
Upregulation of CD40 and CD40 Ligand (CD154) in Patients With Moderate Hypercholesterolemia
Authors: Garlichs C.D. , John S. , Schmeißer A. , Eskafi S. , Stumpf C. , Karl M. , Goppelt-Struebe M. , Schmieder R. , Daniel W.G.
Published: September 2007

Background

Hypercholesterolemia, a risk factor for cardiovascular disease, is associated with inflammation and hypercoagulability. Both can be mediated by the CD40 system. This study investigated whether the CD40 system is upregulated in patients with moderate hypercholesterolemia and whether it is influenced by therapy with a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.

Methods and Results

Fifteen patients with moderate hypercholesterolemia and 15 healthy control subjects were investigated. CD154 and P-selectin were analyzed on platelets and CD40 was analyzed on monocytes before and under therapy with the statin cerivastatin by double-label flow cytometry. Blood concentrations of soluble CD154 and monocyte chemoattractant protein-1 (MCP-1) were evaluated. Our main findings were as follows. Patients with moderate hypercholesterolemia showed a significant increase of CD154 and P-selectin on platelets and CD40 on monocytes compared with healthy subjects. Soluble CD154 showed a nonsignificant trend for higher plasma levels in patients. A positive correlation was found for total or LDL cholesterol and CD154, but not for CD40 on monocytes. The latter was upregulated in vitro by C-reactive protein, which was found to be significantly elevated in patients with moderate hypercholesterolemia. CD154 on platelets proved to be biologically active because it enhanced the release of MCP-1, which was markedly elevated in an in vitro platelet-endothelial cell coculture model and in the serum of patients. Short-term therapy with a HMG-CoA reductase inhibitor significantly downregulated CD40 on monocytes and serum levels of MCP-1.

Conclusion

Patients with moderate hypercholesterolemia show upregulation of the CD40 system, which may contribute to the known proinflammatory, proatherogenic, and prothrombotic milieu found in these patients.
Prevention of Distal Embolization During Coronary Angioplasty in Saphenous Vein Grafts and Native Vessels Using Porous Filter Protection
Authors: Grube Eberhard , Gerckens Ulrich , Yeung Alan C. , Rowold Sascha , Kirchhof Nicole , Sedgewick Jerry , Yadav Jay S. , Stertzer Simon
Published: September 2007

Background

Although distal embolization and the “no-reflow” phenomenon are well described in saphenous vein graft (SVG) interventions, the frequency, magnitude, and characterization of embolized debris have not been evaluated in routine coronary interventions. A unique embolus protection device described herein provides a means of containing and retrieving plaque material dislodged during percutaneous coronary interventions. This report details the first clinical experience of the effectiveness and safety of an emboli protection system in 11 SVG lesions and 15 native coronary artery lesions.

Methods and Results

The AngioGuard Emboli Capture Guidewire (Cordis) consists of a PTCA wire with an expandable filter at the distal tip. The porous membrane permits normal distal blood flow, while trapping potential emboli by filtration. After crossing the lesion, the filter is expanded, and routine angioplasty is performed over the same wire. Emboli retrieval is achieved by collapsing the filter and retracting the emboli capture wire (ECW). In 26 patients, standard angioplasty was performed over the ECW; 20 of these 26 patients received a stent. Collected debris was sent for histopathological analysis. Plaque debris was retrieved after native coronary and SVG interventions in all cases. The ECW was positioned and retrieved without complications. No major adverse events occurred. Myocardial infarctions and no-reflow were not observed.

Conclusions

The embolization of plaque fragments frequently occurs during coronary and SVG intervention. Distal embolization leading to microvascular obstruction and no-reflow could be successfully minimized by using the ECW.
Biatrial Activation in Isthmus-Dependent Atrial Flutter
Authors: Rodriguez Luz-Maria , Timmermans Carl , Nabar Ashish , Hofstra Leonard , Wellens Hein J.J.
Published: September 2007

Background

The aim of this study was to determine the biatrial activation pattern in isthmus-dependent atrial flutter (AFL) to understand the functional interatrial connections and the activation pattern of the left atrium (LA).

Methods and Results

Biatrial activation was performed, using an electroanatomic mapping system, in 10 patients undergoing right atrial isthmus ablation for counterclockwise (n=7) or clockwise (n=3) AFL. The AFL circuit was peritricuspid and propagated slowly (0.5±0.2 m/s) through the isthmus. LA was activated by two wave fronts, with discrete breakthroughs in the superior, mid, or inferior atrial septum. The activation of LA overlapped 50±16% of the AFL cycle length. In counterclockwise AFL, at least one breakthrough was located in the inferior atrial septum. LA activation began immediately after the exit of the flutter wave from the isthmus and was directed inferosuperiorly in all patients, being synchronous with the atrial septal activation. The septal breakthroughs in patients with clockwise AFL were variably located. The direction of LA activation was superoinferior in 2 and inferosuperior in 1 patient.

Conclusions

The circuit of isthmus-dependent AFL was entirely in the right atrium. LA activation was a bystander and followed trans-septal conduction across the inferior coronary sinus-LA connection, Bachmann’s bundle, and/or fossa ovalis.
Quantification of Cerebral Perfusion With “Real-Time” Contrast-Enhanced Ultrasound
Authors: Rim Se-Joong , Leong-Poi Howard , Lindner Jonathan R. , Couture Daniel , Ellegala Dilantha , Mason Holland , Durieux Marcel , Kassel Neal F. , Kaul Sanjiv
Published: September 2007

Background

No noninvasive technique is currently capable of “real-time” assessment and monitoring of cerebral blood flow (CBF). We hypothesized that cerebral perfusion could be accurately measured and monitored in “real time” with contrast-enhanced ultrasound (CEU).

Methods and Results

Cerebral perfusion was assessed in 9 dogs through a craniotomy with CEU at baseline and during hypercapnia and hypocapnia while normoxia was maintained. Cerebral microvascular blood volume (A), microbubble velocity (β), and blood flow (A×β) were calculated from time-versus–acoustic intensity relations. Compared with baseline, hypercapnia and hypocapnia significantly increased and decreased CBF, respectively, as measured by CEU. These changes in blood flow were mediated by changes in both A and β. A good correlation was found between A×β derived from CEU and CBF measured by radiolabeled microspheres (
y
=0.67
x
−0.04,
r
=0.91,
P
<0.001).

Conclusions

Changes in both cerebral microvascular blood volume and red blood cell velocity can be accurately assessed with CEU. Thus, CEU has the potential for bedside measurement and monitoring of cerebral perfusion in real time in patients with craniotomies or burr holes.
Effects of Angiotensin-Converting Enzyme Inhibition on the Development of the Atrial Fibrillation Substrate in Dogs With Ventricular Tachypacing–Induced Congestive Heart Failure
Authors: Li Danshi , Shinagawa Kaori , Pang Li , Leung Tack Ki , Cardin Sophie , Wang Zhiguo , Nattel Stanley
Published: September 2007

Background

Atrial structural remodeling creates a substrate for atrial fibrillation (AF), but the underlying signal transduction mechanisms are unknown. This study assessed the effects of ACE inhibition on arrhythmogenic atrial remodeling and associated mitogen-activated protein kinase (MAPK) changes in a dog model of congestive heart failure (CHF).

Methods and Results

Dogs were subjected to various durations of ventricular tachypacing (VTP, 220 to 240 bpm) in the presence or absence of oral enalapril 2 mg · kg
−1
· d
−1
. VTP for 5 weeks induced CHF, local atrial conduction slowing, and interstitial fibrosis and prolonged atrial burst pacing–induced AF. Atrial angiotensin II concentrations and MAPK expression were increased by tachypacing, with substantial changes in phosphorylated forms of c-Jun N-terminal kinase (JNK), extracellular signal–regulated kinase (ERK), and p38-kinase. Enalapril significantly reduced tachypacing-induced changes in atrial angiotensin II concentrations and ERK expression. Enalapril also attenuated the effects of CHF on atrial conduction (conduction heterogeneity index reduced from 3.1±0.4 to 1.9±0.2 ms/mm,
P
<0.05), atrial fibrosis (from 11.9±1.1% to 7.5±0.4%,
P
<0.01), and mean AF duration (from 651±164 to 218±75 seconds,
P
<0.05). Vasodilator therapy of a separate group of VTP dogs with hydralazine and isosorbide mononitrate did not alter CHF-induced fibrosis or AF promotion.

Conclusions

CHF-induced increases in angiotensin II content and MAPK activation contribute to arrhythmogenic atrial structural remodeling. ACE inhibition interferes with signal transduction leading to the AF substrate in CHF and may represent a useful new component to AF therapy.
Molecular Basis of Downregulation of G-Protein–Coupled Inward Rectifying K+Current (IK,ACh) in Chronic Human Atrial Fibrillation
Authors: Dobrev D. , Graf E. , Wettwer E. , Himmel H.M. , Hála O. , Doerfel C. , Christ T. , Schüler S. , Ravens U.
Published: September 2007

BackgroundClinical and experimental evidence suggest that the parasympathetic nervous system is involved in the pathogenesis of atrial fibrillation (AF). However, it is unclear whether changes in G-protein-coupled inward rectifying K+current (IK,ACh) contribute to chronic AF.

Methods and ResultsIn the present study, we used electrophysiological recordings and competitive reverse-transcription polymerase chain reaction to study changes inIK,AChand the level of theIK,AChGIRK4 subunit in isolated human atrial myocytes and the atrial tissue of 39 patients with sinus rhythm and 24 patients with chronic AF. The density ofIK,AChwas ≈50% smaller in myocytes from patients with AF compared with those in sinus rhythm, and this was accompanied by decreased levels of GIRK4 mRNA. The current density of the inward rectifying K+current (IK1) was 2-fold larger during AF than in sinus rhythm, in correspondence with an increase in Kir2.1 mRNA. The largerIK1in AF is consistent with more negative membrane potentials in right atrial trabeculae from AF patients. Moreover, action potential duration was reduced in AF, and the action potential shortening produced by muscarinic receptor stimulation was attenuated, indicating that the changes ofIK1andIK,AChwere functionally relevant.

ConclusionsChronic human AF induces transcriptionally mediated upregulation ofIK1but downregulation ofIK,AChand attenuates the muscarinic receptor–mediated shortening of atrial action potentials. This suggests that atrial myocytes adapt to a chronically high rate by downregulatingIK,AChto counteract the shortening of the atrial effective refractory period due to electrical remodeling.
Endothelial Dysfunction, Oxidative Stress, and Risk of Cardiovascular Events in Patients With Coronary Artery Disease
Authors: Heitzer Thomas , Schlinzig Titus , Krohn Karoline , Meinertz Thomas , Münzel Thomas
Published: September 2007

Background

Endothelial function is impaired in coronary artery disease and may contribute to its clinical manifestations. Increased oxidative stress has been linked to impaired endothelial function in atherosclerosis and may play a role in the pathogenesis of cardiovascular events. This study was designed to determine whether endothelial dysfunction and vascular oxidative stress have prognostic impact on cardiovascular event rates in patients with coronary artery disease.

Methods and Results

Endothelium-dependent and -independent vasodilation was determined in 281 patients with documented coronary artery disease by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography. The effect of the coadministration of vitamin C (24 mg/min) was assessed in a subgroup of 179 patients. Cardiovascular events, including death from cardiovascular causes, myocardial infarction, ischemic stroke, coronary angioplasty, and coronary or peripheral bypass operation, were studied during a mean follow-up period of 4.5 years. Patients experiencing cardiovascular events (n=91) had lower vasodilator responses to acetylcholine (
P
<0.001) and sodium nitroprusside (
P
<0.05), but greater benefit from vitamin C (
P
<0.01). The Cox proportional regression analysis for conventional risk factors demonstrated that blunted acetylcholine-induced vasodilation (
P
=0.001), the effect of vitamin C (
P
=0.001), and age (
P
=0.016) remained independent predictors of cardiovascular events.

Conclusions

Endothelial dysfunction and increased vascular oxidative stress predict the risk of cardiovascular events in patients with coronary artery disease. These data support the concept that oxidative stress may contribute not only to endothelial dysfunction but also to coronary artery disease activity.
β-Adrenergic Receptor Blockers Restore Cardiac Calcium Release Channel (Ryanodine Receptor) Structure and Function in Heart Failure
Authors: Reiken Steven , Gaburjakova Marta , Gaburjakova Jana , He Kun-lun , Prieto Alfonso , Becker Eva , Yi Geng-hua , Wang Jie , Burkhoff Daniel , Marks Andrew R.
Published: September 2007

Background

β-Adrenergic receptor blockade is one of the most effective treatments for heart failure, a leading cause of mortality worldwide. The use of β-adrenergic receptor blockers in patients with heart failure is counterintuitive, however, because they are known to decrease contractility in normal hearts. The ryanodine receptor (RyR2) on cardiac sarcoplasmic reticulum is the key calcium release channel required for excitation-contraction coupling. In failing hearts, the stoichiometry and function of the RyR2 macromolecular complex is altered. Decreased levels of phosphatases (PP1 and PP2A) and hyperphosphorylation by protein kinase A result in dissociation of the regulatory protein FKBP12.6 and channels with increased open probability.

Methods and Results

Here, we show that systemic oral administration of a β-adrenergic receptor blocker reverses protein kinase A hyperphosphorylation of RyR2, restores the stoichiometry of the RyR2 macromolecular complex, and normalizes single-channel function in a canine model of heart failure.

Conclusions

These results may, in part, explain the improved cardiac function observed in heart failure patients treated with β-adrenergic receptor blockers.
Chronic Amiodarone Evokes No Torsade de Pointes Arrhythmias Despite QT Lengthening in an Animal Model of Acquired Long-QT Syndrome
Authors: van Opstal Jurren M. , Schoenmakers Marieke , Verduyn S. Cora , de Groot S.H. Marieke , Leunissen Jet D.M. , van der Hulst Ferenc F. , Molenschot Mirella M.C. , Wellens Hein J.J. , Vos Marc A.
Published: September 2007

Background

Amiodarone is an effective antiarrhythmic drug rarely associated with torsade de pointes arrhythmias (TdP). The noniodinated compound dronedarone could resemble amiodarone and be devoid of the adverse effects. In the dog with chronic complete atrioventricular (AV) block (CAVB) and acquired long-QT syndrome, the electrophysiological and proarrhythmic properties of the drugs were compared after 4 weeks of oral treatment.

Methods and Results

Amiodarone (n=7, 40 mg · kg
−1
· d
−1
) and dronedarone (n=8, 20 mg/kg BID) were started at 6 weeks of CAVB (baseline). Six dogs served as controls. Surface ECGs and endocardially placed monophasic action potential catheters in the left (LV) and right (RV) ventricles were recorded to assess QTc time, action potential duration (APD), interventricular dispersion (ΔAPD=LV APD minus RV APD), early afterdepolarizations (EADs), ectopic beats, and TdP. Both amiodarone (+21%) and dronedarone (+31%) increased QTc time. Amiodarone showed no increase in ΔAPD in 4 of 7 dogs, whereas dronedarone augmented ΔAPD in 7 of 8 animals. After dronedarone, TdP occurred in 4 of 8 dogs with the highest ΔAPD (105±20 ms). TdP was never seen with amiodarone, not even in the dogs that had ΔAPD values comparable to those with dronedarone. Furthermore, a difference existed in EADs and ectopic activity incidence (dronedarone 3 of 8; amiodarone 0 of 7), which was also seen during an epinephrine challenge.

Conclusions

In the CAVB dog model, both amiodarone and dronedarone prolong QT time (class III effect). The absence of TdP with amiodarone seems to be related to homogeneous APD lengthening in the majority of dogs and the lack of EADs and/or ventricular ectopic beats in all.
Time to Treatment Influences the Impact of ST-Segment Resolution on One-Year Prognosis
Authors: Fu Yuling , Goodman Shaun , Chang Wei-Ching , Van de Werf Frans , Granger Christopher B. , Armstrong Paul W.
Published: September 2007

Background

Early ST resolution after reperfusion is a prognostic indicator in acute myocardial infarction. Little information exists regarding the prognostic utility of ST resolution beyond 4 hours after fibrinolysis. Furthermore, the relation between time to treatment, ST resolution at 24 to 36 hours, and 1-year outcome has not been well studied. Accordingly, we undertook a prospective ECG substudy in the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) trial to examine this.

Methods and Results

Patients (n=13 100) were stratified into 3 ST-resolution categories, based on baseline and 24- to 36-hour ECGs: complete resolution (≥70%) in 6698 (51.1%) patients, partial resolution (30% to 70%) in 4610 (35.2%) patients, and no resolution (<30%) in 1792 (13.7%) patients; 1-year mortality rate was 5.1%, 8.0%, and 9.7%, respectively (
P
<0.001). Among patients treated <2 hours after symptom onset, 55.6% had complete ST resolution, whereas 52.1% and 43% of patients treated between 2 to 4 hours and 4 to 6 hours, respectively, had complete ST resolution (
P
<0.001). Within each category of ST resolution, patients treated <2 hours had lower 1-year mortality rates as compared with patients treated between 2 to 4 hours or >4 hours (3.8% versus 5.2% and 6.6%,
P
=0.002 in complete ST resolution; 5.7% versus 8.4% and 9.9%,
P
=0.001 in partial ST resolution; 7.1% versus 8.7% and 13%,
P
=0.006 in no resolution). The extent of ST resolution was closely and inversely correlated with 1-year mortality rates (
r
=−0.963,
P
<0.001).

Conclusions

ST resolution at 24 to 36 hours after fibrinolysis is influenced by time to treatment and inversely related to 1-year mortality rates. Time to treatment further differentiates between high- and low-risk patients and further highlights the importance of reducing time delay to initiation of fibrinolysis in acute myocardial infarction.
8-Oxo-dGTPase, Which Prevents Oxidative Stress-Induced DNA Damage, Increases in the Mitochondria From Failing Hearts
Authors: Tsutsui Hiroyuki , Ide Tomomi , Shiomi Tetsuya , Kang Dongchon , Hayashidani Shunji , Suematsu Nobuhiro , Wen Jing , Utsumi Hideo , Hamasaki Naotaka , Takeshita Akira
Published: September 2007

Background
—

Reactive oxygen species (ROS) can cause an oxidative modification of nucleotides, such as 8-oxo-7,8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP), which can lead to defects in DNA replication. The misincorporation of 8-oxo-dGTP into DNA is prevented by 8-oxo-dGTPase, which hydrolyzes 8-oxo-dGTP into 8-oxo-dGMP. The changes in this defensive system have not yet been examined in failing hearts, in which the generation of ROS increases.

Methods and Results
—

Myocardial infarction (MI) was created in mice by ligating the left coronary artery. Four weeks later, the left ventricle was dilated and contractility was diminished on echocardiography. The generation of ROS, as measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, increased in the noninfarcted left ventricle from MI mice. The formation of thiobarbituric acid-reactive substances also increased in the mitochondria from MI mice. 8-Oxo-dGTPase was detected in the mitochondrial fractions isolated from MI mice using a Western blot analysis with an antibody to its human homologue (hMTH1). Immunohistochemistry showed positive staining for hMTH1 was localized in the cardiac myocytes.

Conclusions
—

The level of 8-oxo-dGTPase increased in the mitochondria isolated from post-MI hearts as oxidative stress increased, thus suggesting that a preventive mechanism is activated against ROS-induced DNA damage. As a result, 8-oxo-dGTPase is considered a useful marker of mitochondrial oxidative stress in heart failure.
Comparative Efficacy of γ-Irradiation for Treatment of In-Stent Restenosis in Saphenous Vein Graft Versus Native Coronary Artery In-Stent Restenosis
Authors: Castagna Marco T. , Mintz Gary S. , Waksman Ron , Ahmed Javed M. , Maehara Akiko , Ajani Andrew E. , Bui Anh B. , Satler Lowell F. , Suddath William O. , Kent Kenneth M. , Pichard Augusto D. , Weissman Neil J.
Published: September 2007

Background
—

We used serial volumetric (post-irradiation and follow-up) intravascular ultrasound (IVUS) to compare the effectiveness of γ-irradiation (
192
Ir) in saphenous vein graft (SVG) versus native coronary artery in-stent restenosis (ISR).

Methods and Results
—

The study population consisted of 47 patients with native coronary artery ISR from WRIST (Washington Radiation for In-Stent Restenosis Trial) and 31 patients with SVG ISR (12 from the WRIST and 19 from SVGWRIST). After irradiation and at 6-month follow-up, stent, lumen, and intimal hyperplasia (IH, stent minus lumen) areas were measured every 1 mm. ISR length was similar in the 2 groups (29±12 versus 29±14 mm,
P
=0.9). Post-intervention measurements of stent (280±154 versus 324±270 mm
3
,
P
=0.4), lumen (184±91 versus 214±172 mm
3
,
P
=0.3), and IH (96±77 versus 109±119 mm
3
,
P
=0.5) volumes were similar in the 2 groups. The post-intervention minimum lumen cross sectional areas tended to be smaller in native artery ISR lesions (4.7±1.7 versus 5.4±1.6 mm
2
,
P
=0.11). During follow-up, there was a slight increase in IH volume (9±38 mm
3
) in native artery ISR lesions and a slight decrease in IH volume in SVG ISR lesions (−9±32 mm
3
,
P
=0.0463). There was also a slight decrease in minimum lumen area in the native artery ISR lesions versus a slight increase in minimum lumen area in the SVG ISR lesions (−0.8±1.7 versus 0.2±1.1,
P
=0.0087). As a result, the follow-up minimum lumen area in native artery lesions was smaller than in SVG ISR lesions (4.1±2.1 mm
2
versus 5.6±2.2 mm
2
,
P
=0.0067).

Conclusion
—

γ-Irradiation with
192
Ir brachytherapy appears to be as effective in SVGs as it is in native artery ISR lesions.
Effect of Resynchronization Therapy Stimulation Site on the Systolic Function of Heart Failure Patients
Authors: Butter Christian , Auricchio Angelo , Stellbrink Christoph , Fleck Eckart , Ding Jiang , Yu Yinghong , Huvelle Etienne , Spinelli Julio
Published: September 2007

Background
—

Cardiac resynchronization therapy (CRT) improves systolic function in heart failure patients with ventricular conduction delay by stimulating the left ventricle (LV) or both ventricles (biventricular, BV). Optimal LV site selection is of major clinical interest for CRT device implantation; however, the dependence of hemodynamics on LV stimulation site has not been established. Thus, the objective of this study was to compare the hemodynamic response to CRT for 2 LV coronary vein sites: the free wall and anterior wall.

Methods and Results
—

A total of 30 patients (mean NYHA class, 2.7; mean QRS interval, 152 ms; mean PR interval, 194 ms) enrolled in the PATH-CHF-II trial were studied. CRT was administered with LV and BV stimulation in VDD mode at 4 AV delays. LV stimulation was at the lateral free wall or anterior wall, whereas right ventricular stimulation was fixed near the apex. LV+dP/dt
max
and aortic pulse pressure changes from baseline during CRT were compared for LV sites. Free wall sites with LV and BV stimulation yielded significantly larger LV+dP/dt
max
(14% versus 6%,
P
<0.001 for LV; 12% versus 5%,
P
<0.001 for BV) and pulse pressure (8% versus 4%,
P
<0.001 for LV; 9% versus 5%,
P
<0.001 for BV) compared with anterior sites. In one third of patients, CRT at free wall sites increased LV+dP/dt
max
, whereas it decreased at anterior sites over most AV delays.

Conclusion
—

CRT with LV free wall stimulation produced significantly better LV systolic performance compared with anterior stimulation. Further studies are warranted to prove the clinical superiority of the LV free wall as a site for long-term CRT.