Transcatheter aortic valve replacement in patients with anomalous left circumflex coronary artery.

The anomalous left circumflex artery can be a risk for coronary stenosis or obstruction during transcatheter aortic valve replacement; however, the best procedural management has not been clarified. We describe three patients with severe aortic valve stenosis as well as anomalous left circumflex artery. In the first patient, a coronary guidewire with balloon was placed before deploying a SAPIEN 3 transcatheter heart valve, as protection from the coronary occlusion or stenosis. For the second and third patients, no coronary protection was used. All procedures were completed safely and no complications were detected at one-year follow-up.

Inhibition of late sodium current attenuates ionic arrhythmia mechanism in ventricular myocytes expressing LaminA-N195K mutation.

BACKGROUND: Lamin A and C are nuclear filament proteins encoded by the LMNA gene. Mutations in the LMNA gene cause many congenital diseases known as laminopathies, including Emery-Dreifuss muscular dystrophy, Hutchinson-Gilford progeria syndrome, and familial dilated cardiomyopathy (DCM) with conduction disease. A missense mutation (N195K) in the A-type lamins results in familial DCM and sudden arrhythmic death. OBJECTIVE: The purpose of this study was to investigate the ion current mechanism of arrhythmia and DCM caused by the LaminA-N195K variant. METHODS: A homozygous mouse line expressing the Lmna-N195K mutation (LmnaN195K/N195K) that exhibited arrhythmia, DCM, and sudden death was used. Using whole cell patch-clamp technique, we measured action potential duration (APD), Na+ currents (INa) in ventricular myocytes isolated from LmnaN195K/N195K, and wild-type mice. RESULTS: Both peak and late INa were significantly (P <.05) increased in LmnaN195K/N195K ventricular myocytes. Similarly, LmnaN195K/N195K ventricular myocytes exhibited significant (P <.005) prolongation of APD (time to 50% [APD50] and 90% [APD90] repolarization) and triggered activity. Acute application of ranolazine inhibited late INa, shortened APD, and abolished triggered activity in LmnaN195K/N195K ventricular myocytes. CONCLUSION: Inhibition of late INa may be an effective therapy in preventing arrhythmia in patients with LmnaN195K mutation-related DCM.

The immediate impact of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial on the management of stable angina.

BACKGROUND: The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial confirmed that percutaneous coronary intervention is no better than optimal medical therapy for the prevention of major adverse cardiac events in patients with stable angina. The impact of these findings on clinical practice remains unknown. HYPOTHESIS: Clinicians may more frequently opt for medical rather than procedural therapy of stable angina in response to the COURAGE trial. METHODS: Clinical information was collected from patients with stable angina referred to our hospital for cardiac catheterization between January 1, 2007 and June 18, 2007 (n = 332). Catheterization referral volume and the use of medications and coronary revascularization were compared before and after the release of the COURAGE trial. RESULTS: There was a significant increase in anti-ischemia medication use prior to catheterization referral following the COURAGE trial (mean = 1.31 [SD 0.83] medications pre-COURAGE, mean = 1.54 [SD 0.84] medications post-COURAGE, P = 0.012). Among 217 patients with coronary disease on catheterization, treatment with medication rather than percutaneous or surgical revascularization increased after COURAGE (11.1% pre-COURAGE vs 23.0% post-COURAGE, P = 0.03). There was also a significant decrease in referral volume following the COURAGE trial (3.12 referrals/day pre-COURAGE vs 2.51 referrals/day post-COURAGE, P = 0.034). CONCLUSIONS: The COURAGE trial immediately impacted the management of stable angina. Catheterization referral volume decreased, medication use increased, and the use of medical therapy rather than revascularization increased among patients with coronary disease.

Hemodynamically supported percutaneous coronary revascularization improves left ventricular function in patients with ischemic dilated cardiomyopathy at very high risk for surgery: a single-center experience.

BACKGROUND: Coronary artery bypass grafting is often considered for patients with ischemic cardiomyopathy, but age, comorbidities and depressed left ventricular function can increase surgical risk. Percutaneous left ventricular assist devices (pLVAD) may facilitate complex percutaneous coronary interventions (PCI) in the setting of severely impaired left ventricular function, thus providing a possible alternative to thoracotomy in high-risk patients. The long-term effects of hemodynamically-supported PCI on left ventricular function and clinical outcome in these patients are poorly understood. OBJECTIVE: To determine the effect of hemodynamically-supported multivessel PCI on left ventricular ejection fraction (LVEF) in patients with severe ischemic cardiomyopathy at very high operative risk. METHODS: Retrospective case-series analysis of patients with ischemic cardiomyopathy at very high surgical risk who underwent prophylactic pLVAD implantation for hemodynamic support during complex PCI between January 2004 and February 2007. The main outcome variable was change in LVEF assessed by echocardiography 90 days or more after PCI. Major in-hospital adverse cardiovascular events (MACE), vascular complications and all-cause mortality were secondary endpoints. RESULTS: Eleven patients with prior myocardial infarction and ischemic cardiomyopathy (mean age 73 +/- 14 years) underwent TandemHeart-supported PCI. The indications for prophylactic support were depressed LVEF and a large myocardial mass at risk. Baseline LVEF was 25 +/- 8%, increasing to 41 +/- 9% at a mean follow-up time of 15 +/- 15 months (p = 0.0004). There were no in-hospital MACE and only 1 vascular complication requiring blood transfusion. CONCLUSIONS: PLVAD-supported PCI in patients with ischemic cardiomyopathy at very high risk for surgery is feasible and relatively safe. In combination with medical therapy, it results in significant improvement in LVEF by echocardiography.

Fulminant myopericarditis from phenytoin-induced systemic lupus erythematosus.

Myocarditis and pericarditis are identified at autopsy in up to 50% of patients with systemic lupus erythematosus. However, clinical symptoms of heart failure are unusual, occurring in only 5%-7% of patients. Drug-induced lupus is rare and typically causes classic lupus symptoms of rash, fever, pleuritis, renal insufficiency, and arthritis. We present an unusual case of drug-induced lupus from chronic phenytoin use in a man who presented with symptoms of fulminant myopericarditis. To our knowledge, this is the first such case reported in English.

Left atrial volume is associated with inflammation and atherosclerosis in patients with kidney disease.

BACKGROUND: Left atrial volume (LAV) is an independent echocardiographic predictor of cardiovascular events in the general population. We evaluated predictors of LAV in patients with advanced chronic kidney disease (CKD). HYPOTHESIS: Increasing LAV identifies increased cardiovascular risk in patients with CKD. METHODS: Transthoracic echocardiography was performed in CKD patients undergoing cardiovascular evaluation prior to listing for renal transplantation. LAV was measured using the biplane area-length formula and indexed for body surface area. Carotid intima-media thickness was assessed by B-mode ultrasound. Lipoproteins were measured by nuclear magnetic resonance spectroscopy. Values are presented as mean (standard deviation). Relationships with LAV were evaluated using univariate and multivariable regression analyses. RESULTS: There were 99 participants (80% white, 68% male). Their mean age was 55.7 (9.3) years. Significant correlates of LAV were systolic blood pressure (r = 0.24), C-reactive protein (r = 0.29), carotid intima-media thickness (r = 0.29), peak transmitral E-wave (r = 0.38), and severity of mitral regurgitation (r = 0.23, P < 0.05 for all). LAV also was higher among individuals with a history of stroke (45 mL/m2 vs 36.3 mL/m2, P = 0.04) and with >75% stenosis on coronary angiography (38.4 mL/m2 vs 31.8 mL/m2, P = 0.03). In regression models, high sensitivity CRP (hs-CRP), the transmitral E-wave velocity, and a history of stroke independently predicted LAV (P < or = 0.05). CONCLUSION: In individuals with advanced CKD, LAV is associated with inflammation, increased early transmitral filling velocities, and atherosclerosis. These findings may indicate increased cardiovascular risk with increasing LAV in patients with CKD.

Mitral annular calcification is associated with reduced left ventricular function and inflammation in patients with chronic kidney disease.

BACKGROUND: Mitral annular calcification (MAC) is prevalent in patients with chronic kidney disease (CKD); however, it is not known whether the increased cardiovascular risk observed in patients with CKD and MAC is related to atherosclerotic burden, because they share common risk factors. METHODS: Transthoracic echocardiography was performed in patients with CKD undergoing pre-kidney transplantation evaluation. Fasting lipids, high-sensitivity C-reactive protein, parathyroid hormone, calcium, and creatinine levels were measured. RESULTS: Of 99 participants, the 31 with MAC had higher carotid intima-media thickness (P = .004), lower left ventricular ejection fraction (P = .016), and higher high-sensitivity C-reactive protein (P = .01). MAC was predicted independently by increasing high-sensitivity C-reactive protein, decreasing left ventricular ejection fraction, and not being on dialysis (likelihood ratio 21.8, P < .001). Models were not affected significantly by the addition of age, carotid intima-media thickness, and other laboratory tests. CONCLUSIONS: In patients with CKD, MAC is associated with inflammation, reduced left ventricular function, and treatment with dialysis, independent of the degree of subclinical atherosclerosis.

Platelet-derived growth factor receptor antagonist STI571 (imatinib mesylate) inhibits human vascular smooth muscle proliferation and migration in vitro but not in vivo.

BACKGROUND: Cell-specific inhibition of vascular smooth muscle cells, the primary constituent of neointima following arterial injury, without deleterious effects on vascular endothelial cell function may be a critical requirement for drug-eluting stents that are not prone to excess late thrombosis. We hypothesized that imatinib mesylate (Gleevec, Glivec, formerly known as STI571), a relatively selective inhibitor of protein tyrosine kinases including platelet-derived growth factor receptor (PDGFR), would inhibit hCASMC proliferation and migration in vitro with little effect on endothelial cell proliferation and prevent restenosis in a swine balloon injury model. METHODS: Proliferation and migration of stimulated human vascular smooth muscle and endothelial cells were quantified in cell culture in the presence of imatinib (0.001 to 10 M). Imatinib-loaded drug-eluting stents were implanted in swine coronary arteries after predilatation with an oversized balloon, and neointimal proliferation was measured by quantitative angiography and histopathology. RESULTS: Increasing doses of imatinib-inhibited autophosphorylation of the PDGFR and its downstream effects of proliferation and migration of human CASMC in a dose-responsive manner, yet had no effect on stimulated human aortic endothelial cells. However, imatinib-eluting stents had no effect on neointimal proliferation and restenosis in a standard porcine in-stent restenosis model compared to bare-metal or unloaded polymer-coated stents. CONCLUSION: We conclude that imatinib is a potent inhibitor of proliferation and migration of human vascular smooth muscle cells in vitro, but has no effect on human vascular endothelial cell proliferation. However, the lack of an in vivo effect on neointimal proliferation in a standard porcine coronary overstretch model does not support the use of imatinib mesylate for localized drug delivery in the prevention of in-stent restenosis.

Release of plasmid DNA from intravascular stents coated with ultrathin multilayered polyelectrolyte films.

Materials that permit control over the release of DNA from the surfaces of topologically complex implantable devices, such as intravascular stents, could contribute to the development of new approaches to the localized delivery of DNA. We report the fabrication of ultrathin, multilayered polyelectrolyte films that permit both the immobilization and controlled release of plasmid DNA from the surfaces of stainless steel intravascular stents. Our approach makes use of an aqueous-based, layer-by-layer method for the assembly of nanostructured thin films consisting of alternating layers of plasmid DNA and a hydrolytically degradable polyamine. Characterization of coated stents using scanning electron microscopy (SEM) demonstrated that stents were coated uniformly with an ultrathin film ca. 120 nm thick that adhered conformally to the surfaces of stent struts. These ultrathin films did not crack, peel, or delaminate substantially from the surface after exposure to a range of mechanical challenges representative of those encountered during stent deployment (e.g., balloon expansion). Stents coated with eight bilayers of degradable polyamine and a plasmid encoding enhanced green fluorescent protein (EGFP) sustained the release of DNA into solution for up to four days when incubated in phosphate buffered saline at 37 degrees C, and coated stents were capable of mediating the expression of EGFP in a mammalian cell line without the aid of additional transfection agents. The approach reported here could, with further development, contribute to the development of localized gene-based approaches to the treatment of cardiovascular diseases or related conditions.

Use of a percutaneous vascular suture device for closure of an inadvertent subclavian artery puncture.

A well-known complication of central venous catheterization is inadvertent arterial sheath placement. Sheath removal from noncompressible arteries has the potential for severe complications. We report a case of inadvertent subclavian arterial sheath placement during an attempted internal jugular venous catheterization. This was successfully removed using a percutaneous vascular suture device.

Abnormal Ca2+ release, but normal ryanodine receptors, in canine and human heart failure.

Sarcoplasmic reticulum (SR) Ca2+ transport proteins, especially ryanodine receptors (RyR) and their accessory protein FKBP12.6, have been implicated as major players in the pathogenesis of heart failure (HF), but their role remain controversial. We used the tachycardia-induced canine model of HF and human failing hearts to investigate the density and major functional properties of RyRs, SERCA2a, and phospholamban (PLB), the main proteins regulating SR Ca2+ transport. Intracellular Ca2+ is likely to play a role in the contractile dysfunction of HF because the amplitude and kinetics of the [Ca2+]i transient were reduced in HF. Ca2+ uptake assays showed 44+/-8% reduction of Vmax in canine HF, and Western blots demonstrated that this reduction was due to decreased SERCA2a and PLB levels. Human HF showed a 30+/-5% reduction in SERCA2a, but PLB was unchanged. RyRs from canine and human HF displayed no major structural or functional differences compared with control. The P(o) of RyRs was the same for control and HF over the range of pCa 7 to 4. Subconductance states, which predominate in FKBP12.6-stripped RyRs, were equally frequent in control and HF channels. An antibody that recognizes phosphorylated RyRs yields equal intensity for control and HF channels. Further, phosphorylation of RyRs by PKA did not appear to change the RyR/FKBP12.6 association, suggesting minor beta-adrenergic stimulation of Ca2+ release through this mechanism. These results support a role for SR in the pathogenesis of HF, with abnormal Ca2+ uptake, more than Ca2+ release, contributing to the depressed and slow Ca2+ transient characteristic of HF.

Maximal ATPase activity and calcium sensitivity of reconstituted myofilaments are unaltered by the fetal troponin T re-expressed during human heart failure.

Re-expression of a fetal isoform of troponin T (TnT(4)) has been demonstrated in failing human ventricular myocardium and associated with a decrease in myofibrillar ATPase activity. In order to elucidate the regulatory role of the re-expressed TnT(4) in the failing human heart, we measured ATPase activity in reconstituted cardiac myofilaments prepared with recombinant human TnT(4) or the adult human isoform of troponin T (TnT(3)). Neither the maximal calcium-activated ATPase activity nor the calcium sensitivity of this biochemical assay was significantly different between reconstituted myofilaments containing adult TnT(3) or fetal TnT(4). Our results suggest that the re-expressed fetal TnT(4) is not responsible for the depressed ATPase activity of failing ventricular myofibrils. The increased expression of the fetal isoform of this thin filament regulatory protein in the failing ventricle may be a consequence of a programmed change in gene expression occurring in response to hemodynamic stress, but probably does not contribute to depressed ventricular function characteristic of dilated cardiomyopathies.

Age-associated changes in function, structure and mitochondrial genetic and enzymatic abnormalities in the Fischer 344 x Brown Norway F(1) hybrid rat heart.

We hypothesized that cardiac aging in the rat involves mitochondrial genetic damage and mitochondrial enzymatic dysfunction of individual cardiomyocytes as has been demonstrated previously only in primate myocardium. Myocardium from Fischer 344 x Brown Norway F(1)hybrid rats of ages 5, 18 and 36-38 months was examined for mitochondrial genetic and enzymatic abnormalities. In-vivo hemodynamic measurements revealed age-related changes of left ventricular function while histological evaluation demonstrated an increase in percent area fibrosis from 7%+/-5 in the 5-month-old hearts to 38%+/-2 in the subendocardium of the left ventricle of 38-month-old rats. Mitochondrial genomes lacking 8000 to 9000 bp of primary sequence were detected in tissue homogenates from right and left ventricular myocardium and the abundance of these deleted genomes increased with age. In-situ histochemical staining of serial cryomicrotome sections of myocardial tissue revealed individual cardiomyocytes displaying abnormal, primarily absent, activities of cytochrome c oxidase and succinate dehydrogenase. The area density of histochemically-abnormal cardiomyocytes increased from 0.05 per mm(2)to 0.3 per mm(2)between 5 and 36-38 months of age in the left ventricle, and they were localized primarily to the left ventricular subendocardium. The presence of age-related mitochondrial genetic and enzymatic abnormalities in the Fischer 344 x Brown Norway F(1)hybrid rat heart suggests the role of mitochondrial dysfunction, secondary to mtDNA mutations, in age-related cardiomyocyte loss and subsequent cardiac aging.