bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a Cardiac Sodium Channel Insensitive to Synthetic Modulators
Authors: Mevissen Meike , Denac Helena , Schaad Andreas , Portier Christopher J. , Scholtysik Guenter
Published: June 2007

Background: DPI 201-106 (DPI) was the first synthetic compound showing cardioselective modulation of voltage-gated sodium channels (VGSCs) resulting in a positive inotropic effect. Currently, the exact mode of action for this class of compounds is not known.

Methods: Effects of different natural and synthetic sodium channel modulators were investigated in cardiac tissue of several species with conventional electrophysiologic methods.

Results: In electrically driven cardiac tissues, all compounds investigated increased force of contraction (FC) and action potential duration (APD) with increasing concentrations except for DPI in cattle trabecular muscle, which demonstrated no effect. Interestingly, calculation of EC50 levels at 30% repolarization demonstrates that natural VGSC-ligands were highly potent in prolonging the APD in cattle whereas no positive trends could be obtained for DPI and SDZ 211-939 (SDZ) in cattle.

Conclusions: These results demonstrate that the binding site for DPI and SDZ is distinct from sites 2 or 3 of the VGSC ox-subunit. Moreover, this is the first time that these compounds show no effect or even shortening of APD. This finding will enable the characterization of the mode of action and probably the binding site for synthetic VGSC-modulators.
Prevention of Ventricular Fibrillation During Acute Myocardial Ischemia: Control of Free Fatty Acids
Authors: Oliver M. F.
Published: June 2007

Fatal ventricular fibrillation is a common complication of acute coronary syndromes. Effective preventive measures are not available. Immediate restriction of free fatty acid availability should optimize ischemic myocardial metabolism, reduce ventricular vulnerability, and increase glucose utilization. Rapid inhibition of lipoprotein lipase activity will achieve this. The clinical effects of antilipolytic treatment require further study.
Pimozide (Orap®) Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current in Native Cardiac Myocytes
Authors: Drolet Benoit , Rousseau Guy , Daleau Pascal , Cardinal René , Simard Chantale , Turgeon Jacques
Published: June 2007

Background: Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with pimozide, a potent neuroleptic useful in the management of motor and phonic tics associated with Tourette syndrome. To further elucidate the mechanism underlying these clinical observations, the effects of pimozide on monophasic action potential duration (MAPD9O) and on potassium currents involved in the repolarization of native isolated ventricular myocytes were examined.

Methods and Results: Studies were undertaken in eight isolated guinea pig hearts that demonstrated reverse rate-dependent prolongation of cardiac repolarization by pimozide 100 nmol/L. Action potential duration increased 24% from baseline 115 ± 2 to 142 ± 4 msec with pimozide 100 nmol/L during pacing at 250 msec cycle length, while a 10% increase from 97 ± 2 to 107 ± 3 msec was seen with pacing at a cycle length of 150 msec. Experiments in native isolated ventricular myocytes (n = 20) demonstrated concentration-dependent block of the rapid component (I,) of the delayed rectifier potassium current: tail current was decreased by 50% at 15 nmol/L.

Conclusions: Pimozide possesses cardiac electrophysiological effects similar to those of class III antiarrhythmic drugs. These effects are concentration-dependent and observed at recommended dosages of the drug. Since pimozide is strongly metabolized by CYP3A4, special care should be taken to avoid potential pharmacokinetic interactions leading to high plasma levels of pimozide and proarrhythmia.
Effects of Tedisamil on Cardiovascular Tissues Isolated from Normoand Hypertensive Rats
Authors: Doggrell Sheila A. , Nand Vinita
Published: June 2007

Background: This study was undertaken to characterize the effects of tedisamil on isolated rat cardiovascular tissues, and identify actions that could be beneficial or detrimental in the treatment of cardiac disease.

Results: Tedisamil prolonged the Wistar Kyoto normotensive rat (WKY) left ventricular action potential and augmented the force of contraction of left ventricle strips. On the 12-month-old SHR model of cardiac hypertrophy, the augmenting effects of tedisamil at 10-6 and 3 x 10-6 M were reduced. On the 21-month-old SHR model of heart failure, the augmenting effects of tedisamil at 10-6 and 3 x 10-6 M were further reduced. The augmenting effect of tedisamil at 10-5 M was reduced to 47%. The rate of the right atrium of 16- to 17-month-old WKY was reduced by tedisamil at 10-5 and 104 M, and tedisamil had a similar effect on the SHR right atrium. Tedisamil at 10-6-3 x 10-5 M contracted the portal veins of WKY and aortae of 12-month-old WKY and SHR.

Conclusions: The positive inotropic and negative chronotropic effects of tedisamil in the rat, which are partially or fully maintained in hypertrophied or failing myocardium would be beneficial in the treatment of heart failure. In contrast, the vasoconstrictor action of tedisamil will be detrimental in heart failure.
Myocardial Bradykinin Following Acute Angiotensin-Converting Enzyme Inhibition, AT1 Receptor Blockade, or Combined Inhibition in Congestive Heart Failure
Authors: Multani M. Marlina , Krombach R. Stephen , Goldberg Aron T. , King Mary K. , Hendrick Jennifer W. , Sample Jeff A. , Baicu Simona C. , Joffs Cassandra , deGasparo Marc , Spinale Francis G.
Published: June 2007

Background: The present study examined the effects of acute angiotensin-converting enzyme inhibition (ACEI), AT, receptor blockade (AT, block), or combined treatment on in vitro and in vivo bradykinin (BK) levels.

Methods: BK levels were measured in isolated porcine myocyte preparations (n = 13) in the presence of exogenous BK (10-8 M); with an ACEI (benezaprilat; 0.1 mM) and BK; an AT, block (valsartan; 10-5 M) and BK; and combined treatment and BK. In a second study, myocardial microdialysis was used to measure porcine interstitial BK levels in both normal (n = 14) and pacing-induced congestive heart failure (CHF) (240 beats/min, 3 weeks, n = 16) under the following conditions: baseline, following ACEI (benezaprilat, 0.0625 mg/kg) or AT, block (valsartan, 0. I mg/kg), and a combined treatment (benezaprilat, 0.0625 mg/kg; valsartan, 0.1 mg/kg).

Results: In the left ventricular myocyte study, BK levels increased over 93% with all treatments compared to untreated values (P < 0.05). In the in vivo study, basal interstitial BK values were lower in the CHF group than in controls (2.64 ± 0.57 vs 5.91 + 1.4 nM, respectively, P < 0.05). Following acute infusion of the ACEI, BK levels in the CHF state increased from baseline (57% ± 22; P < 0.05). Following combined ACEIIAT, block, BK levels increased from baseline in both control (42% ± 11) and CHF groups (60% ± 22; P < 0.05 for both).

Conclusion: These findings suggest that ACEI, or combined ACEI/AT, block increased BK at the level of the myocyte and potentiated BK levels in the CHF myocardial interstitium.
Treatment of Edema and Increased Capillary Filtration in Venous Hypertension with HR (Paroven, Venoruton; 0-(β-hydroxyethyl)-rutosides): A Clinical, Prospective, Placebo-Controlled, Randomized, Dose-Ranging Trial
Authors: Cesarone M. R. , Incandela L. , DeSanctis M. T. , Belcaro G. , Griffin M. , Ippolito E. , Acerbi G.
Published: June 2007

The variation of capillary filtration rate (CFR) and ankle edema (AE) were evaluated in three groups of patients with venous hypertension with ambulatory venous pressure > 42 mmHg and in healthy subjects before and after treatment for four weeks with HR (Paroven, Venoruton; 0-(P-hydroxyethyl)-rutosides), a venoactive drug acting on the microcirculation and on capillary permeability. Group A (30 patients) was treated with HR 500 mg tid; group B (30 patients) was treated with 1 g tid; group C (30 patients) was treated with placebo; group D (10 healthy subjects) was treated with HR 1 g/day in a randomised study. CFR was assessed by venous occlusion plethysmography. Subjective symptoms of venous hypertension were assessed by an analogue scale line considering four symptoms: swelling sensation, restless lower extremity, pain and cramps, and tiredness.

Results: There were no significant differences for sex and age distribution among the groups; no significant differences were found for ambulatory venous pressure and refilling time and parameters of venous hypertension among groups. There was a significant difference between normal subjects and patients. There were no drop-outs and observed intolerance. In group A, there was a significant decrease of CFR (P < 0.01) after treatment. In group B (2 g/day), the decrease was greater than that in group A (P < 0.05). In group C (placebo) there was no significant difference before or after treatment. The variations in analogue score was higher with the higher dosage. The score of group A fell from 7.8 (SD 1.3) to 4 (1). Group B's score fell from 7.9 (2) to 3.1 (1.2). In group C (placebo) there was no change. The decrease in the score in the groups of patients was correlated with the variation in edema and CFR.

Conclusion: HR is effective in venous edema and hypertension. Its effects are dose-related.
Diabetes, Heart Rate, and Mortality
Authors: Singh Nalini
Published: June 2007

A large body of evidence indicates that a persistently high heart rate is associated with a significant risk for higher mortality and sudden death in individuals with a variety cardiovascu- lar disorders, as well as in the general population. Heart rates elevated beyond a certain threshold have been found to be a risk factor for mortality in patients with hypertension, in survivors of myocardial infarction, and in patients with impaired cardiac function. Conversely, a naturally slow heart rate, or one that is slow by virtue of sympathetic blockade induced by pharmacologic agents, may result in longer survival. This is particularly evident in the case of f-adrenergic blocking drugs, especially in patients after myocardial infarction and in those with acute as well as chronic cardiac failure, a syndrome in which there is a com- plex neurohormonal disturbance with elevated heart rate. Persistently elevated heart rate is also a feature of diabetes mellitus associated with autonomic neuropathy. Whether this also constitutes an independent risk factor for sudden and augmented mortality is not well defined. In this review, the data on the role of increased heart rate as a risk factor for mortality are examined in the context of other factors that may have therapeutic implications.
HR (Venoruton1000, Paroven, 0-[beta-hydroxyethyl]-rutosides) vs. Daflon 500 in Chronic Venous Disease and Microangiopathy: An Independent Prospective, Controlled, Randomized Trial
Authors: Belcaro G. , Cesarone M. R. , Bavera P. , Ricci A. , Renton S. , Leon M. , Ippolito E. , Dugall M. , Acerbi G.
Published: June 2007

Objectives: The aim of this study was to demonstrate whether and how HR (Venoruton1000, Paroven, 0-[beta-hydroxyethyl]-rutosides) and Daflon (diosmin, 500 mg) were comparatively effective in improving the microcirculation in venous hypertension and microangiopathy.

Methods: A group of 90 patients with severe venous hypertension due to chronic venous insufficiency, ankle swelling, and lipodermatosclerosis were included. After informed consent, patients were randomized into a Venoruton and a Daflon (DF) group: patients in the Venoruton group received oral HR (2 g/day for 8 weeks); those in the Daflon group received three 500-mg tablets daily every 8 hours. The two groups were comparable for age and sex distribution. The mean age was 41 years (SD ± 11) in the Venoruton group (46 patients) and 41.3 (SD ± 12) in the DF group (44 patients).

Results: There were no differences in microcirculatory parameters between the Venoruton and DF treatment groups at inclusion. There was no significant change between inclusion and measurements at 8 weeks in the DF group. In comparison, a significant decrease ( P < .05) in RF (resting skin flux) and RAS (rate of ankle swelling) was observed in the Venoruton group ( P < .00 1). The decrease in capillary filtration was associated with improvement in signs and symptoms (measured by an analogue scale line) ( P < .05). Symptomatic improvement was clinically and statistically significant and important only in the Venoruton group. No side effects and no drop-outs were observed.

Conclusion: Venous microangiopathy was improved by the treatment with Venoruton. The comparison with Daflon indicates that HR is comparatively more effective both on microcirculatory parameters and on signs and symptoms.
Contrast Ultrasound Targeted Drug and Gene Delivery: An Update on a New Therapeutic Modality
Authors: Price Richard J. , Kaul Sanjiv
Published: June 2007

The effective delivery of intravascular drugs and genes to regions of pathology is dependent on a number of factors that are often difficult to control. Foremost is the site-specific delivery of the payload to the region of pathology and the subsequent transport of the payload across the endothelial barrier. Ultrasound contrast agent microbubbles, which are typically used for image enhancement, are capable of amplifying both the targeting and transport of drugs and genes to tissue. Microbubble targeting can be achieved by the intrinsic binding properties of the microbubble shells or through the attachment of site-specific ligands. Once microbubbles have been targeted to the region of interest, microvessel walls can be permeabilized by destroying the microbubbles with low-frequency, high-power ultrasound. A second level of targeting specificity can be achieved by carefully controlling the ultrasound field and limiting microbubble destruction to the region of interest. When microbubbles are destroyed, drugs or genes that are housed within them or bound to their shells can be released to the blood stream and then delivered to tissue by convective forces through the permeabilized microvessels. An alternative strategy is to increase payload volume by coinjecting drug or gene-bearing vehicles, such as liposomes, with the microbubbles. In this manifestation, microbubbles are used for creating sites of microvessel permeabilization that facilitate drug or gene vehicle transport. Recent work in the emerging field of contrast ultrasound-based therapeutics, with particular emphasis on the delivery of drugs and genes to tissue through microvascular networks is reviewed.
The Effect of Isoproterenol on the Class III Effect of Azimilide in Humans
Authors: Dorian Paul , Dunnmon Preston , Elstun Laura , Newman David
Published: June 2007

Background: Many class III antiarrhythmic agents lose efficacy under f-adrenergic stimulation and at high heart rates (reverse rate dependence). This effect is thought to be due to selective blockade of the rapidly (Ij), but not the slowly (IKS, activating component of the delayed inward rectifier potassium current. Azimilide is an investigational class III antiarrhythmic agent that blocks both Ir and 1KS.

Methods: We investigated the electrophysiologic effect of azimilide with and without P-adrenergic stimulation in humans. Right ventricular effective refractory period at cycle lengths of 600 and 400 milliseconds and monophasic right ventricular action potential duration at 90% repolarization at cycle lengths of 250, 300, 400, 500 and 600 milliseconds were measured in 13 patients at baseline. Isoproterenol was then infused to increase the heart rate to 125% of baseline, and the pacing protocol was repeated. Patients then received, in a single-blind randomized manner, azimilide dihydrochloride (4.5 mg/kg intravenous loading dose followed by 0.625 mg/kg/h) plus either isoproterenol at the previous dose, or saline. After measurements were taken, treatment groups were crossed over, the azimilide infusion was continued and the procedure repeated.

Results: Azimilide significantly (P < 0.05) prolonged monophasic action potential duration compared to baseline at all cycle lengths except for the 250 millisecond cycle length. In the presence of isoproterenol, azimilide maintained its class III effect, prolonging the action potential duration at 90% repolarization by a mean of 8.7 ± 3.9 milliseconds, (3.7 ± 1.7%), whereas isoproterenol alone shortened the action potential duration at 90% repolarization by -2.6 ± 3.2 milliseconds (-1.2 ± 1.4%) (P = 0.0051). Isoproterenol alone shortened the right ventricular effective refractory period by -13.6 ± 3.4 milliseconds, whereas with isoproterenol in the presence of azimilide, the right ventricular effective refractory period was essentially unaffected (-1.4 ± 3.4 milliseconds, P = 0.0085).

Conclusions: Azimilide maintained its class III effect in the presence of isoproterenol and at increased heart rates, suggesting that IKS block may be of particular benefit in these circumstances.
Effects of Adrenomedullin on Human Myocyte Contractile Function and β-Adrenergic Response
Authors: Mukherjee Rupak , Multani Marlina M. , Sample Jeffrey A. , Dowdy Kathryn B. , Zellner James L. , Hoover Donald B. , Spinale Francis G.
Published: June 2007

Background: Adrenomedullin has been demonstrated to cause systemic vasodilation, and increased plasma adrenomedullin levels have been observed in cardiovascular disease states such as heart failure. While adrenomedullin receptors have been localized to the myocardium, the effects of adrenomedullin on human myocyte contractility remained unknown.

Methods and Results: Left ventricular myocytes were isolated from myocardial biopsies of patients (n = 16) undergoing elective coronary artery bypass surgery with normal left ventricular ejection fractions (51 ± 1%). A total of 233 left ventricular myocytes were studied by videomicroscopy. Myocyte shortening velocity (,um/s) was measured at baseline and following the addition of either 3 nM, 30 nM, or 60 nM of adrenomedullin. The change in myocyte shortening velocity with increasing concentrations of adrenomedullin was computed. At all concentrations, adrenomedullin reduced myocyte shortening velocity from baseline values (P < 0.05). Next, the potential interaction of adrenomedullin with the P-adrenergic receptor system was examined using 25 nM isoproterenol. The 3-adrenergic receptor-mediated increase in the myocyte shortening velocity was blunted with adrenomedullin (29 ± 7 vs 63 ± 13 tm/s, P < 0.05).

Conclusions: These unique findings demonstrate that adrenomedullin reduced contractility in isolated human left ventricular myocytes and exhibited a negative interaction with the fadrenergic receptor system. Past studies have shown that adrenomedullin induces nitric oxide synthesis and that nitric oxide can uncouple myocyte metabolism. Thus, while adrenomedullin causes systemic vasodilation, this peptide can also exert a negative contractile effect in human left ventricular myocytes.
Delayed Profound Thrombocytopenia Presenting 7 Days After Use of Abciximab (ReoPro)
Authors: Sharma Sanjiv , Bhambi Brijesh , Nyitray William , Sharma Geetanjali , Shambaugh Shawn , Antonescu Adrian , Shukla Pankaj , Denny Eileen
Published: June 2007

A case of a 65-year-old woman presenting with delayed profound thrombocytopenia 7 days after the use of abciximab (ReoPro) in the setting of percutaneous coronary intervention is described. The patient had normal platelet counts for the first 24 hours after the use of abciximab (ReoPro). She presented with petechiae and profound thrombocytopenia 1 week later. The patient was treated successfully with a platelet transfusion and recovered uneventfully. Profound thrombocytopenia occurs acutely within the first few hours after abciximab (ReoPro) use, so this case was unique in that the profound thrombocytopenia presented 1 week after use of abciximab (ReoPro).
Tedisamil in Coronary Disease: Additional Benefits in the Therapy of Atrial Fibrillation?
Authors: Opie Lionel H.
Published: June 2007

Atrial fibrillation has recently come into clinical and research focus. In particular, ventricular rate control has been carefully compared with atrial rhythm control. Additionally, the recent discovery of atrial stunning has initiated clinical and research interest in atrial remodeling. Atrial fibrillation is more likely to occur when the atria are damaged by increased fibrosis. The ideal way to prevent atrial fibrillation and the risk of repetition is by tackling the root causes, such as ischemic heart disease, heart failure, and left ventricular hypertrophy. Tedisamil is an unusual antifibrillatory compound that has a novel mechanism of action by inhibiting the transient outward current (Ito) and the repolarizing potassium currents in the sinoatrial node. Tedisamil works acutely against atrial fibrillation. Importantly, atrial fibrillation is often caused by or related to cardiac ischemia, and conversely, ischemia is caused by the increased oxygen demand of atrial fibrillation. Hence, the double properties of tedisamil as a drug that both inhibits atrial fibrillation and acts in an anti-ischemic mode are an attractive basis for future clinical research.
Omapatrilat Induces Profound Renal Vasodilation but Does Not Affect Coronary Hemodynamics
Authors: Varagic Jasmina , Susic Dinko , Slama Michel , Frohlich Edward D.
Published: June 2007

Background: Omapatrilat has potent enzymatic inhibitory effects on the angiotensin-converting enzyme and neutral endopeptidase. The prolonged effects of this inhibition on systemic and regional hemodynamics, cardiovascular mass, and hydroxyproline concentration in spontaneously hypertensive rats were studied. The contribution of endogenous bradykinin on the cardiovascular actions of omapatrilat in this genetic model of hypertension was also investigated.Methods and Results: Systemic and regional hemodynamics (radionuclide-labeled microspheres), left and right ventricular and aortic masses, and hydroxyproline concentration were determined in 35-week-old spontaneously hypertensive rats after 12 weeks of treatment with omapatrilat (40 mg/kg/day), with and without the bradykinin receptor antagonist icatibant (500,ug/kg/day). Omapatrilat decreased mean arterial pressure, reducing total peripheral resistance as well as decreased left ventricular and aortic mass indices. It also induced a profound renovasodilation associated with a decrease renal vascular resistance that markedly increased renal blood flow. Coronary hemodynamics and left ventricular hydroxyproline concentration remained unaltered. Concomitant blockade of bradykinin receptors partially attenuated the hypotensive effect of omapatrilat and its effect on aortic mass; and icatibant did not influence the renovasodilation.Conclusion: Omapatrilat produced profoundly beneficial effects on systemic and renal hemodynamics, as well as on left ventricular and aortic masses, without any effect on coronary hemodynamics. These effects of omapatrilat on arterial pressure and aortic mass, but not on renal hemodynamics and left ventricular mass, may have been at least partially mediated through the action of bradykinin.
Reversal of Refractory Congestive Heart Failure after Thiamine Supplementation: Report of a Case and Review of Literature
Authors: Mendoza Cesar E. , Rodriguez Francisco , Rosenberg Donald G.
Published: June 2007

Patients with refractory heart failure comprise a very important subgroup of patients with congestive heart failure. Before assuming that this condition simply reflects advanced, perhaps terminal, myocardial dysfunction, potentially reversible factors should be sought carefully. We describe a 58-year-old Hispanic man with a diagnosis of idiopathic dilated cardiomyopathy who presented with symptoms of severe congestive heart failure, glossitis, and peripheral neuropathy. His hemodynamic profile was characterized by refractory low-output cardiac failure and decreased vascular resistance. Thiamine deficiency was documented by a high thiamine pyrophosphate effect. His clinical condition was quickly reversed with thiamine administration. This response to thiamine administration supports the diagnosis and indicates that thiamine deficiency may play an important etiologic role in the deterioration of cardiac function in some patients with congestive heart failure.
Rosiglitazone and Heart Failure: Long-Term Vigilance
Authors: Singh Nalini
Published: June 2007

Thiazolidinediones have become a powerful tool for lowering insulin resistance. In many short-term clinical studies, many patients taking thiazolidinediones experience significant improvement in glycemic control and lipid profiles without any adverse effects. Health care providers should be aware that, in long-term follow-up, peripheral edema and congestive heart failure may occur in patients with multiple comorbidities more than 26 weeks after starting thiazolidinediones. This article reports two patients who developed congestive heart failure 6 to 12 months after starting rosiglitazone, in combination with insulin. The patients' glycemic control improved over the first 3 to 6 months of therapy. When edema and congestive heart failure occurred later, they recovered only after medical therapy (diuretics, afterload reduction) was titrated and the rosiglitazone was withdrawn.
Tumor Necrosis Factor-α-Induced Apoptosis of Human Coronary Artery Endothelial Cells: Modulation by the Peroxisome Proliferator-Activated Receptor-γ Ligand Pioglitazone
Authors: Chen Jiawei , Li Dayuan , Zhang Xingjian , Mehta Jawahar L.
Published: June 2007

The cytokine tumor necrosis factor-a (TNF-α) plays an important role in endothelial injury, which is associated with the release of reactive oxygen species and the induction of apoptosis. We report on our study of TNF-α-induced apoptosis in human coronary artery endothelial cells and its modulation by the peroxisome proliferator-activated receptor-γ (PPAR-γ) ligand pioglitazone. Treatment of cells with TNF-α (40 ng/mL) resulted in apoptosis as measured by DNA laddering and caspase-3 activation. TNF-α treatment decreased the expression of antiapoptotic protein Bcl-2 (P < .05 vs control), but not the expression of Fas or FLIP, in human coronary artery endothelial cells. Treatment of cells with TNF-α also enhanced lipid peroxidation (P < .01 vs control). Pretreatment of cells with the PPAR-γ ligand pioglitazone blocked TNF-α-mediated apoptosis, caspase-3 activation, expression of Bcl-2, and lipid peroxidation (P < .01 vs TNF-α alone). These results indicate that TNF-α induces oxidative stress in human coronary artery endothelial cells, resulting in apoptosis through a reduction in Bcl-2 expression and the subsequent activation of caspase-3. The PPAR-γ ligand pioglitazone modulates lipid peroxidation, alters Bcl-2 expression and caspase-3 activation, and finally reduces apoptosis. The antioxidant and antiapoptotic effects of pioglitazone may be the mechanism by which this agent reduces endothelial injury.
Clopidogrel Resistance: Myth or Reality?
Authors: Barsky Aron A. , Arora Rohit R.
Published: June 2007

Platelets have a central role in the development of arterial thrombosis and subsequent cardiovascular events. An appreciation of this complex process has made antiplatelet therapy the cornerstone of cardiovascular disease management. Dual antiplatelet therapy with aspirin and clopidogrel has been approved for the secondary prevention of cardiovascular events and is currently part of the postpercutaneous coronary intervention treatment regimen. However, subacute stent thrombosis continues to occur in 1% to 2% of patients despite dual antiplatelet therapy. Studies have shown interindividual variations in response to clopidogrel, where a cohort of patients seems to be resistant to the antithrombotic effects of clopidogrel. Furthermore, there is an apparent link between clopidogrel resistance and clinical outcomes. Currently, there is neither a universally accepted definition of clopidogrel resistance nor an agreement on the phenomenon's mechanism. This review highlights the origins of clopidogrel resistance, the current problems that exist with its definition, and discusses the future implications and relevant challenges it poses for the clinician.
Adaptive-Outward and Maladaptive-Inward Arterial Remodeling Measured by Intravascular Ultrasound in Hyperhomocysteinemia and Diabetes
Authors: Reddy Hanumanth K. , Koshy Santhosh K. G. , Wasson Sanjeev , Quan Edwin E. , Pagni Sebastian , Roberts Andrew M. , Joshua Irving G. , Tyagi Suresh C.
Published: June 2007

Background: Coronary artery remodeling implies structural changes in the vessel wall in response to various pathophysiologic conditions. However, the classification of remodeling is unclear. We hypothesized that the adaptive, positive-outward remodeling is a reactive and compensatory response to the stress. The maladaptive negative-inward constrictive remodeling is a passive atherosclerotic condition in which the vessel becomes stiffer.

Methods: Patients with atherosclerotic lesions underwent intravascular ultrasound (IVUS) scans. The size of the vessels distal to and proximal to plaques were analyzed by IVUS. Diabetes was created in mice by an intraperitoneal injection of alloxan (65 mg/kg). To reduce remodeling, mice received ciglitazone, an agonist of peroxisome proliferators activated receptor-g (PPARg) in drinking water. After 8 weeks, atherosclerotic vessels were analyzed for collagen and elastin.

Results: IVUS data suggest an adaptive coronary arterial remodeling was a positive compensatory response to various pathologic stimuli; for example, with the deposition of atherosclerotic plaque, coronary arterial segments enlarged to maintain luminal area. This phenomenon was commonly observed during the initial phases of the development of atherosclerosis. However, negative coronary artery remodeling, or a decrease in vessel area with the formation of atherosclerotic plaque, was maladaptive and was associated with smoking, hypertension, hyperhomocysteinemia, diabetes mellitus, and also after percutaneous coronary interventions (restenosis). In diabetic mice, there was increased collagen and decreased elastin contents; however, treatment with ciglitazone ameliorated the decrease in elastin contents.

Conclusion: Global enlargement of the coronary vascular tree occurs during pressure and volume overload associated with ventricular hypertrophic states such as athletic conditioning, hypertensive heart disease, and dilated cardiomyopathy. On the other hand, maladaptive coronary arterial remodeling occurs in patients with severe deconditioning, diabetes mellitus, after coronary artery bypass surgery, and in some instances, postintervention.
Resistant Hypertension: Diagnosis and Management
Authors: Papadopoulos Dimitris P. , Papademetriou Vasilios
Published: June 2007

The incidence of resistant hypertension, the failure to reduce blood pressure below 140/90 mm Hg, despite the use of 3 antihypertensive medications at optimal doses including a diuretic, is estimated to be less than 5% of the hypertensive population. Resistant hypertension increases the risk of stroke, myocardial infarction, congestive heart failure, and renal failure. Evaluation of the patient with resistant hypertension should include 24-hour ambulatory blood pressure monitoring or home measurements and a limited search for secondary causes. Treatment should focus on optimizing the drug regimen in a logical way, based on the patient’s comorbidities and tolerability. Long-acting, well-tolerated once-daily medications are preferred, and the regimen should include in sequence a diuretic, β-blocker, angiotensin-converting enzyme/angiotensin receptor-blocker inhibitors, and a calcium-channel blocker. This article reviews the definitions and causes and provides specific recommendations for the evaluation and management of patients with this life-threatening condition
The In Vitro Effects of a Novel Vascular Protectant, AGI-1067, on Platelet Aggregation and Major Receptor Expression in Subjects With Multiple Risk Factors for Vascular Disease
Authors: Serebruany Victor , Malinin Alex , Scott Robert
Published: June 2007

Oxidation-sensitive signals are important in platelet activation. The novel, phenolic, intracellular and extra-cellular antioxidant AGI-1067 inhibits the expression of a number of proinflammatory genes involved in atherosclerosis. The effect of AGI-1067 on human platelets was evaluated. Blood obtained from 20 aspirin-naïve volunteers with multiple risk factors for vascular disease was preincubated with escalating concentrations of AGI-1067 for the assessment of its ex vivo effects on platelet aggregation and expression of major surface receptors flow cytometry, evaluated by flow cytometry. AGI-1067 resulted in significant inhibition of a variety of activation-dependent platelet biomarkers in healthy volunteers, including adenosine diphosphate-induced platelet aggregation and decreased surface platelet expression of glycoprotein IIb/IIIa antigen, activity with PAC-1 antibody, and glycoprotein Ib (CD42b). The effect of AGI-1067 differs from other known antiplatelet agents, suggesting opportunities for therapeutic combination. These data need to be confirmed in subjects receiving orally dosed AGI-1067 to be clinically relevant.
Dose-Dependent Effects of Oral Dronedarone on the Circadian Variation of RR and QT Intervals in Healthy Subjects: Implications for Antiarrhythmic Actions
Authors: Wadhani Nitin , Sarma Jonnalagedda SM , Singh Bramah N. , Radzik David , Gaud Christine
Published: June 2007

Dronedarone, a non-iodinated benzofuran derivative, was developed as a potentially less toxic alternative to amiodarone. This study describes Holter data of dronedarone in humans. Five groups of healthy subjects were given 1 of 5 oral doses of dronedarone in a twice-daily regimen or placebo. Holter recordings of circadian rhythmicity of RR and QT intervals were evaluated. Dronedarone prolonged RR and QT intervals as a function of dose, without effect on circadian patterns. The relative prolongation of QT, QTc, and RR by dronedarone was significant. The QTc interval did not exhibit a clearly recognizable circadian pattern, suggesting that the circadian pattern of the QT interval was mostly a reflection of circadian changes in the RR interval in the study population. Dronedarone resembled amiodarone in class III and sympatholytic effects, indicating its potential as a unique antiarrhythmic compound seemingly devoid of the side effects mediated by iodine in amiodarone.
Dose of Aspirin in the Treatment and Prevention of Cardiovascular Disease: Current and Future Directions
Authors: Hennekens Charles H. , Sechenova Oksana , Hollar Danielle , Serebruany Victor L.
Published: June 2007

In meta-analyses of randomized trials of aspirin among patients with prior occlusive vascular disease events (secondary prevention), doses from 75 mg to more than 1500 mg daily provide similar benefits on myocardial infarction, stroke, and cardiovascular death. In acute myocardial infarction and during acute occlusive stroke, a loading dose of 162.5 to 325 mg is necessary to achieve a rapid clinical antithrombotic effect. In primary prevention trials, predominantly among men, aspirin (75 mg daily to 325 mg on alternate days) reduced the risk of a first myocardial infarction. In a large-scale trial in women, aspirin (100 mg on alternate days) reduced risk of a first stroke. In subgroup analyses of women older than age 65, aspirin significantly reduced first myocar-dial infarction and ischemic stroke. Direct comparisons of higher doses may yield additional cardiovascular benefits. At present, daily doses of 75 to 325 mg aspirin are sufficient for long-term treatment and prevention of cardiovascular disease.
Transmyocardial Revascularization: Peril and Potential
Authors: Tasse Jordan , Arora Rohit
Published: June 2007

Transmyocardial laser revascularization is a technique for the treatment of patients with chronic angina pectoris that is refractory to medical therapy and who are not eligible for surgical intervention. Percutaneous myocardial revascularization is a less-invasive catheter-based procedure that has been adapted from transmyocardial laser revascularization. Six prospective randomized clinical trials have been performed with transmyocardial laser revascularization and 5 have been performed using percutaneous myocardial revascularization. All of the transmyocardial laser revascularization and 4 of the percutaneous myocardial revascularization studies showed a significant improvement in angina class; however, results for improved survival, increased exercise tolerance, improved ejection fraction, and improved myocardial perfusion were less definitive. Transmyocardial laser revascularization has significant potential for morbidity and mortality. This article summarizes the results of the randomized trials, explains the current theories for the mechanism of transmyocardial laser revascularization, and discusses its current role in treatment for patients, considering the evidence that currently exists.
Lipid-Lowering Therapy and Outcomes in Heart Failure
Authors: Ray Joel G. , Norris Colleen M. , Udell Jacob A. , Tsuyuki Ross T. , McAlister Finlay A. , Knudtson Merril L. , Ghali William A.
Published: June 2007

Lipid-lowering therapy, particularly with statins, reduces the risk of cardiovascular mortality; however, there is uncertainty about their efficacy in patients with heart failure, including those without coronary artery stenosis. A clinical database was studied to determine whether lipid-lowering therapy is associated with improved survival in persons with heart failure—with or without concomitant coronary artery stenosis. During an 8-year period, 6060 people with a history of heart failure underwent coronary angiography. At the time of angiography, 1216 received a lipid-lowering agent. During a median follow-up of 4.7 years, 7.1 deaths per 100 person-years occurred among users of lipid-lowering therapy, compared with 7.8 per 100 person-years among nonusers (adjusted hazard ratio 0.87, 95% confidence interval 0.77-0.97). Use of lipid-lowering therapy was associated with a reduced risk of death in patients with heart failure. Current evidence supports statin use in individuals with recognized heart failure and concomitant coronary heart disease, dyslipidemia, or diabetes mellitus. More data are needed before statins can be recommended in those with isolated heart failure.
The Search for Social Safety and Comfort in Families Raising Children With Complex Chronic Conditions
Authors: Rehm Roberta S. , Bradley Joan F.
Published: June 2007

Social consequences of raising children who were medically fragile and developmentally delayed (MF/DD) were explored in an ethnographic study of 20 families with school-age children. The overarching theme was the families’ search for safety and comfort in social situations. Major categories comprising this theme included the need to anticipate and plan for the child’s care; overcoming environmental, child-related, and attitudinal barriers; and finding social activities that were comfortable for all members of the family. When this search was successful, families could relax, and all members could participate in a variety of social encounters and activities; but when safety and comfort could not be achieved, families were likely to limit social activities or split the family so that the child who was MF/DD could be cared for while other family members participated in social events.
Are Antiphospholipid Antibodies an Independent Risk Factor for Atherosclerosis?
Authors: Bilora Franca , Boccioletti Veronica , Girolami Bruno , Zanon Ezio , Armani Mario , Petrobelli Francesco , Girolami Antonio
Published: June 2007

The purpose of this study was to check whether antiphospholipid antibodies (aPL) could be an independent risk factor for atherosclerosis. Eighty-five subjects were studied: 45 with primitive antiphospholipid antibody syndrome and 40 controls affected by deep vein thrombosis secondary to known causes. The two groups were homogeneous for age, sex, and risk factors for atherosclerosis. All the subjects submitted to echo-color doppler of the carotid arteries, femoral arteries, and abdominal aorta. The cases were then subdivided into three subgroups on the basis of the positivity to the three subpopulations of aPL. Results demonstrate that there is no correlation between aPL and atherosclerosis. The different positivity to aPL does not modify this conclusion.
Is Family History Sufficient to Identify Women with Risk of Venous Thromboembolism Before Commencing the Contraceptive Pill?
Authors: Aznar Justo , Mira Yolanda , Vayá Amparo , Ferrando Fernando , Villa Piedad
Published: June 2007

Oral contraceptives (OCs) increase risk of venous thromboembolic disease (VTE). The incidence of thomboembolic disease in healthy young women who are not taking OCs is 0.4-0.8/10,000, and in healthy young women using OCs, it is 3-4/10,000. To assess whether a family history of thromboembolism is a suitable tool to identify women who should not be given OCs, 50 women who suffered a VTE while taking OCs were studied. Only 16% of these women had family history which is why in our opinion, it is not a sufficient safeguard to recommending the use of OCs.
Oral Contraceptives and Venous Thromboembolism: Which Are the Safest Preparations Available?
Authors: Girolami A. , Spiezia L. , Rossi F. , Zanon E.
Published: June 2007

Oral contraceptive therapy is associated with a fourfold increased risk of venous thromboembolism as compared with agematched non-users. The composition of oral contraceptives has varied considerably during the past two to three decades. The estrogen content (ethinylestradiol) has decreased and is now less than 0.03 mg/pill. This was done on the assumption that estrogen was the main culprit for thrombotic complications. Subsequently it was found that the progestins contained in the pill could also play a thrombogenic role. This was particularly maintained to be so for the third-generations progestins, namely gestodene or desogestrel. These gonane progestins have been widely used since the early 1990s, because they appeared to have a lesser androgenic effect. A careful and impartial evaluation of the literature seems to indicate that third-generation progestins are associated with a slight increase in thrombotic risk. However, the significance of this difference remains to be proven. In fact, a relative risk of only two in retrospective studies may have limited effect and disappear in prospectives studies. The role of associated risk factors, both congenital and acquired, has been often overlooked in most of the papers dealing with the subject. This may be important. Preparations containing third-generation progestins are probably associated with a slight increase in thrombosis risk. It is the responsibility of the physician to select the preparation most suited for a given patient. As a general rule it may be safe to start with a preparation containing second-generation progestins. However there is no need for “a pill scare” and it does not seem justified to have women already taking pills containing third-generation progestins to switch to other preparations. If a woman taking preparations containing third-generation progestins experience symptoms, it is probably safe to advise that patient not to take any oral contraceptive pill in the future, regardless of the type. The same is true for women who experience symptoms while taking second-generation progestins preparations.
Effect of Clopidogrel on Platelet Aggregation and Plasma Concentration of Fibrinogen in Subjects with Cerebral or Coronary Atherosclerotic Disease
Authors: Izaguirre-Avila R. , Peñia-Díaz A. De la , Barinagarrementería-Aldatz F. , Gonzáilez-Pacheco H. , Ramírez-Gutierrez A. E. , Ruiz-Sandoval J. L. , Quiroz-Martínez A. , Cantú-Brito C.
Published: June 2007

Acetylsalicylic acid inhibits thromboxane A2 production and reduces the risk of vascular occlusive events by 20% to 25%. Ticlopidine inhibits ADP-dependent platelet aggregation and reduces the same risk by 30% to 35%, but produces some adverse effects. Clopidogrel is a ticlopidin-related antiplatelet drug, with the same mechanism of action; it reduces the expression of the glycoprotein Ilb/Illa, the fibrinogen receptor on the platelet surface. Clopidogrel has the same clinical efficacy of ticlopidin and has a decreased incidence of adverse effects. The effect of one daily dose of 75 mg of clopidogrel on platelet function in 90 subjects was evaluated; 41 with coronary artery disease and 49 with cerebral vascular disease. Before treatment and after 6 and 12 weeks, bleeding time and fibrinogen plasma concentration were also evaluated. There was a reduction in 5-μM ADP-induced platelet aggregation of 38% ± 27% at 6 weeks and 44% ± 29% at 12 weeks in patients with coronary artery disease; 35% ± 41%, 29% ± 59% in the cerebral vascular disease group; and 36% ± 36% and 35% ± 49% in the total group. Reduction of 20,ug/mL collagen-induced platelet aggregation was not significant in any group. Plasma fibrinogen levels did not vary during treatment. Bleeding time was significantly prolonged in all studied groups. There were no hemorrhagic complications; only digestive discomfort in less than 3% of patients. Clopidogrel efficiently reduces ADP-induced platelet aggregation and prolongs bleeding time and is a safe and efficacious antiplatelet drug.
Ticlopidine-Induced Marrow Aplasia Treated with Cyclosporine
Authors: Ertorer M. Eda , Gokcel Adnan , Savaş Lutfu , Kocak Rikkat
Published: June 2007

A 50-year-old diabetic and hypertensive male patient is reported who had ticlopidine-induced marrow aplasia partially responsive to colony-stimulating factors and corticosteroids, but experienced complete recovery with cyclosporine. There is no consensus on the treatment of ticlopidine-induced marrow aplasia. Although many cases are reported to recover with colony-stimulating factors and corticosteroids, others are unresponsive or partially responsive. Our patient also did not completely respond to these medications, but was successfully treated with cyclosporine alone. Alone or in combination with corticosteroids, cyclosporine is an effective drug of choice for the resistant patients.
Seasonal Variation in the Incidence of Deep Vein Thrombosis in Patients With Deficiency of Protein C or Protein S
Authors: Bilora F. , Boccioletti V. , Manfredini E. , Petrobelli F. , Tormene, D. , Simioni P. , Girolami A.
Published: June 2007

An attempt was made to identify circaseptanal or seasonal variation of deep vein thrombosis (DVT) in a population with protein C or protein S deficit. Forty-four patients with DVT and protein C or protein S deficit were studied for 1 year. A significant circannual rhythm was found for the total population that peaked during winter. There was also a significant falling circaseptanal rhythm on Fridays. These observations may optimize an adequate and precise anticoagulant therapy in patients witi protein C or protein S deficits.
Effect of Hemodialysis on Plasma Levels of Vascular Endothelial Markers
Authors: Naumnik Beata , Borawski Jacek , Pawlak Krystyna , Myśliwiec Michal
Published: June 2007

Vascular endothelial cell dysfunction is linked to hemostatic abnormalities and accelerated atherosclerosis in patients receiving maintenance hemodialysis (HD). The relationships between pre-dialysis plasma levels of immunoreactive thrombomodulin, von Willebrand factor, tissue factor and its inhibitor were studied, and the effects of HD procedure on these endothelial markers were observed. All the markers were higher in 39 HD patients than in 15 healthy controls (p<0.0001). HD treatment resulted in a 50% increase in tissue factor pathway inhibitor (p<0.0001), but did not influence the other markers. This increment directly correlated with the post-dialysis decrease in diastolic (p=0.011) and mean arterial blood pressure (p=0.039), and the surface area of the dialysis membrane (p=0.007). There were no associations between the increase in tissue factor pathway inhibitor and the amount of fluid removed, dose of enoxaparin, or other HD-specific factors. In conclusion, HD is responsible for an increase in plasma tissue pathway factor inhibitor level. The release of tissue factor pathway inhibitor during HD is not only due to heparin injection but also to the contact between blood and artificial dialysis membrane, and to HD-activated hemodynamic forces.