- Fragmented QRS as a Marker of Conduction Abnormality and a Predictor of Prognosis of Brugada Syndrome
- Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid: Determinants and Effect on Cardiovascular Risk
- Adenosine A3 Receptor Deficiency Exerts Unanticipated Protective Effects on the Pressure-Overloaded Left Ventricle
- Complication Rate of Right Ventricular Endomyocardial Biopsy via the Femoral Approach: A Retrospective and Prospective Study Analyzing 3048 Diagnostic Procedures Over an 11-Year Period
- Chronic Actions of a Novel Oral B-Type Natriuretic Peptide Conjugate in Normal Dogs and Acute Actions in Angiotensin II–Mediated Hypertension
- Local Tenomodulin Absence, Angiogenesis, and Matrix Metalloproteinase Activation Are Associated With the Rupture of the Chordae Tendineae Cordis
- Dialysis Accelerates Medial Vascular Calcification in Part by Triggering Smooth Muscle Cell Apoptosis
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Fragmented QRS as a Marker of Conduction Abnormality and a Predictor of Prognosis of Brugada Syndrome
Brugada syndrome is characterized by coved-type ST elevation (type I ECG described in the consensus report on Brugada syndrome) in the right precordial leads, which represents abnormal repolarization in the right ventricle. Spontaneous type I ECGs and a history of syncope have been reported as prognostic indicators. Patients with Brugada syndrome also have a depolarization abnormality that can be detected as right bundle-branch block, HV-interval prolongation, late potentials by signal-averaged electrogram, and delayed potentials at the epicardium. The contribution of these abnormal depolarization indices to prognosis is controversial, and indeed, the existence of late potentials did not predict prognosis in the present study. We focused on a new marker of depolarization abnormality, fragmented QRS (f-QRS), which is the presence of multiple spikes within the QRS complex. f-QRS has been reported in patients with myocardial infarction and can detect myocardial damage and arrhythmia occurrence. Of 115 patients with Brugada syndrome, f-QRS existed in 43%, more frequently in patients with prior ventricular fibrillation (VF) than in patients with syncope or asymptomatic patients. Patients with f-QRS who had prior episodes of VF or syncope without detected VF often experienced recurrent VF within 4 years. These results suggest that patients who experienced syncope without detected VF who had f-QRS were at increased risk for a subsequent arrhythmic event and should be considered for an implantable cardioverter defibrillator. In patients with prior VF, the existence of f-QRS also indicates a risk of recurrent VF, including arrhythmic storm. See p 1697.
Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid: Determinants and Effect on Cardiovascular Risk
Acetylsalicylic acid is effective for preventing major cardiovascular events in a broad range of high-risk patients, but there is emerging evidence of variable response. The present analyses demonstrate that incomplete suppression of thromboxane with usual doses of aspirin, as measured by elevated concentrations of 11-dehydro thromboxane B2 in the urine, is associated with an increased risk of subsequent serious vascular events. Increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher urinary concentrations of 11-dehydro thromboxane B2, whereas aspirin dose ≥150 mg/d, history of treatment with nonsteroidal antiinflammatory drugs, history of hypercholesterolemia, and statin therapy were associated with lower concentrations. These findings validate the role of urinary 11-dehydro thromboxane B2 concentrations as a predictor of cardiovascular risk in aspirin-treated patients and raise the potential for higher aspirin doses and statin therapy to modify risk through reductions in thromboxane concentrations. See p 1705.
Adenosine A3 Receptor Deficiency Exerts Unanticipated Protective Effects on the Pressure-Overloaded Left Ventricle
Adenosine A3 receptors (A3R) participate in cardioprotection against ischemia/reperfusion injury and are involved in regulation of cell growth, neutrophil chemotaxis, and activation of inflammatory cells. We examined whether the A3R can facilitate the adaptation of the left ventricle to pressure overload produced by transverse aortic constriction. Contrary to our expectation, mice with genetic ablation of the A3R developed less severe myocardial hypertrophy and left ventricular dysfunction in response to transverse aortic constriction than did wild-type mice, implying that A3R activation during pressure overload has a deleterious effect on the heart. In support of these functional data, A3R deletion decreased myocardial oxidative stress and the expression of proinflammatory cytokines. The findings suggest that selective A3R inhibition might have potential for treatment of pressure overload–induced left ventricular hypertrophy and dysfunction. See p 1713.
Complication Rate of Right Ventricular Endomyocardial Biopsy via the Femoral Approach: A Retrospective and Prospective Study Analyzing 3048 Diagnostic Procedures Over an 11-Year Period
The diagnosis of myocarditis and viral persistence, based on histological, immunohistological, and molecular biological analyses of endomyocardial biopsies (EMBs), has prognostic and crucial therapeutic implications for the selection of immunosuppressive or antiviral treatment in patients with unexplained left ventricular dysfunction. Nevertheless, EMB procedures have not yet gained widespread acceptance because of concerns about possible complications, which are still not well defined. Therefore, this retrospective and prospective single-center study, the largest of its kind with 2415 patients subjected to 3048 EMB procedures, evaluated the incidence of major and minor complications associated with right ventricular EMB procedures to assess unexplained left ventricular dysfunction. EMB procedures were performed via the right femoral approach under biplane fluoroscopic guidance by senior cardiologists and 4 interventional fellows using a flexible modified Cordis bioptome. No patient died or required emergency cardiac surgery. Other major complications like cardiac tamponade requiring pericardiocentesis or complete atrioventricular block requiring permanent pacing were very rare: 0.12% in the retrospective and 0% in the prospective trial. Minor complications such as pericardial effusion, conduction abnormalities, or arrhythmias occurred in 0.20% of the EMB procedures in the retrospective trial and 5.5% in the prospective trial. Patients with preexisting left bundle-branch block had a higher risk for complete atrioventricular block requiring temporary pacing, whereas patients with left ventricular enlargement had no increased risk of conduction abnormalities. In summary, the femoral approach to EMB procedures with a modified Cordis bioptome enables the safe utilization of recent knowledge about the clinical benefit arising from EMB-based differential therapies of heart failure. See p 1722.
Chronic Actions of a Novel Oral B-Type Natriuretic Peptide Conjugate in Normal Dogs and Acute Actions in Angiotensin II–Mediated Hypertension
Although B-type natriuretic peptide (BNP) has been approved as an intravenous agent for acute heart failure, increasing research suggests that an additional prime clinical target may be human hypertension to complement its therapeutic use in heart failure in which molecular forms with reduced biological actions have been reported. Several lines of investigation support a strategy for the therapeutic use of BNP or other natriuretic peptides for hypertension. The evidence includes relative deficiency of biologically active BNP in the early stages of hypertension, the ability to chronically enhance sodium excretion and reduce blood pressure as demonstrated in the current studies, potent antifibrotic and prolusitropic actions, and the ability to suppress aldosterone synthesis and release. Importantly, in hypertension, we take advantage of the blood pressure–lowering effects that characterize the inherent properties of the natriuretic peptides, although this effect is a potential limitation for their indiscriminate use in heart failure patients. What is lacking in clinical practice, however, is the ability to chronically deliver peptides by means other than subcutaneous injections. Our report ushers in a new day in protein therapeutics in which we see the ability of advanced alkylPEGylation that modifies the hydrophilicity/hydrophobicity of BNP, permitting its chronic oral delivery. As stated in population studies from Canada, the rise in hypertension prevalence will likely far exceed the predicted prevalence for 2025, and strategies to manage hypertension and its sequelae are urgently needed. We advance here the concept for cardiovascular disease that the chronic use of natriuretic peptides like oral BNP as therapeutic agents will prove highly attractive. See p 1729.
Local Tenomodulin Absence, Angiogenesis, and Matrix Metalloproteinase Activation Are Associated With the Rupture of the Chordae Tendineae Cordis
Valvular heart disease is a life-threatening disease. Although the overall incidence of rheumatic valvular heart disease has been decreasing continuously in developed countries, it has increased with respect to patient age. Rupture of the chordae tendineae cordis (CTC) is a well-known cause of mitral regurgitation, although its etiology remains unknown and surgical procedures have focused exclusively on treatment. Cardiac valves and the CTC are avascular tissues, and we have recently reported that cardiac valves express chondromodulin-I, which is an angioinhibitory factor purified from cartilage that plays a pivotal role in the maintenance of normal valvular function by preventing angiogenesis. In the present study, we show that tenomodulin, which is a chondromodulin-I–related antiangiogenic factor isolated from tendons, is concentrically expressed in normal CTC. Conditioned medium from cultured CTC interstitial cells showed a strong angioinhibitory effect, and the immunohistochemical analysis of human surgical samples showed that tenomodulin was locally absent in the ruptured areas of the CTC, in which abnormal vessel formation, strong expression of vascular endothelial growth factor-A and matrix metalloproteinases, and infiltration of inflammatory cells were observed, whereas these features were not observed in the normal or nonruptured areas. The tenomodulin layers of the tricuspid CTC of dogs were surgically filed, the animals were euthanized after several months, and immunohistological analyses were performed. Angiogenesis and the expression of vascular endothelial growth factor-A and matrix metalloproteinases in the core layer were observed in a time-dependent manner. The present findings support tenomodulin and unknown proteins of similar function as therapeutic agents for the prevention of CTC rupture. Understanding these mechanisms should form the basis for new therapeutic regimens for the treatment of valvular heart disease. See p 1737.
Dialysis Accelerates Medial Vascular Calcification in Part by Triggering Smooth Muscle Cell Apoptosis
The present study, for the first time, provides quantitative evidence that calcium (Ca) accumulation in the vessel wall begins predialysis and that factors specific to the dialysis milieu trigger accelerated calcification. We found that the vessel Ca load is strongly correlated with the mean serum Ca × phosphate (P) product, suggesting that stringent measures to control the serum P levels and also to limit the Ca load to patients (from P binders and dialysate) should be practiced, beginning from the predialysis stages. The currently available clinical measures of vascular damage and calcification (carotid intima-media thickness, pulse wave velocity, and multi-slice computed tomography scan) are not sensitive enough to detect early stages of calcification, and a normal/negative test should be interpreted with caution. Importantly, although Ca accumulation begins predialysis, it progresses extremely rapidly on dialysis: a dialysis vintage of even 2 months was sufficient to induce overt calcification. Histologically, vessels from dialysis patients showed apoptotic vascular smooth muscle cell damage, osteo/chondrocytic conversion, and vesicle release, suggesting that in the dialysis milieu, damage-inducing agents in addition to continued exposure to high and possibly worsening Ca and P lead to progressive vascular smooth muscle cell damage and calcification. Thus this study further emphasizes the need to avoid dialysis and perform preemptive renal transplantation wherever possible. See p 1748.
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