Mark Kozak

Sterile Inflammation Associated With Transradial Catheterization and Hydrophilic Sheaths

In 1999, we noted the development of inflammation and/or abscesses at the site of radial access in a group of patients. Over a 3‐year period, we noted this inflammation in 33 patients out of 2,038 (1.6%) who had catheterization via the radial approach. The radial abscesses occurred in 30 patients out of 1,063 (2.8%) in whom we could confirm the use of a hydrophilic‐coated sheath, but in no patient for whom we can document that an uncoated sheath was used. No infectious agent could be implicated, and the time course for the development of the abscess, typically 2 to 3 weeks, seemed long for a bacterial infection. Later patients had biopsies, and granulomatous reactions were seen in most. Additionally, a few of the biopsies showed an amorphous extravascular substance consistent with the catheter coating. All patients had good long‐term outcomes. Cathet Cardiovasc Intervent 2003;59:207–213.

Cardiac catheterization in morbidly obese patients

The safety and findings of cardiac catheterization and coronary angiography in morbidly obese patients with suspected coronary heart disease (CHD) have not been fully examined in the modern era. From a database of 4,978 patients undergoing diagnostic cardiac catheterization, we identified 110 with morbid obesity (body mass ≥ 145 kg and body mass index ≥ 40 kg/m2). Relative to all the other patients in this database, morbidly obese patients had a lower prevalence of CHD (45% vs. 72%; P < 0.05), reflecting a higher prevalence of false positive noninvasive tests. Overall, noninvasive tests were only 75% sensitive and 39% specific for CHD in this group. Use of radial access (66%) and femoral closure devices (24%) was much more frequent in the morbidly obese cohort. Complications were no more frequent in the morbidly obese group, with major (0 vs. 0.9%) and minor (4.7% vs. 3.5%) adverse outcomes being similar to the rest of the database. We conclude that cardiac catheterization using the radial artery or a femoral closure device is a safe and effective method of evaluating CHD in morbidly obese patients. In contrast, noninvasive testing is frequently not definitive and may be misleading. Cathet Cardiovasc Intervent 2002;56:174–177.

PDGF-induced vascular smooth muscle cell proliferation is associated with dysregulation of insulin receptor substrates

In vascular smooth muscle cells (VSMCs), platelet-derived growth factor (PDGF) plays a major role in inducing phenotypic switching from contractile to proliferative state. Importantly, VSMC phenotypic switching is also determined by the phosphorylation state/expression levels of insulin receptor substrate (IRS), an intermediary signaling component that is shared by insulin and IGF-I. To date, the roles of PDGF-induced key proliferative signaling components including Akt, p70S6kinase, and ERK1/2 on the serine phosphorylation/expression of IRS-1 and IRS-2 isoforms remain unclear in VSMCs. We hypothesize that PDGF-induced VSMC proliferation is associated with dysregulation of insulin receptor substrates. Using human aortic VSMCs, we demonstrate that prolonged PDGF treatment led to sustained increases in the phosphorylation of protein kinases such as Akt, p70S6kinase, and ERK1/2, which mediate VSMC proliferation. In addition, PDGF enhanced IRS-1/IRS-2 serine phosphorylation and downregulated IRS-2 expression in a time- and concentration-dependent manner. Notably, phosphoinositide 3-kinase (PI 3-kinase) inhibitor (PI-103) and mammalian target of rapamycin inhibitor (rapamycin), which abolished PDGF-induced Akt and p70S6kinase phosphorylation, respectively, blocked PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. In contrast, MEK1/ERK inhibitor (U0126) failed to block PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. PDGF-induced IRS-2 downregulation was prevented by lactacystin, an inhibitor of proteasomal degradation. Functionally, PDGF-mediated IRS-1/IRS-2 dysregulation resulted in the attenuation of insulin-induced IRS-1/IRS-2-associated PI 3-kinase activity. Pharmacological inhibition of PDGF receptor tyrosine kinase with imatinib prevented IRS-1/IRS-2 dysregulation and restored insulin receptor signaling. In conclusion, strategies to inhibit PDGF receptors would not only inhibit neointimal growth but may provide new therapeutic options to prevent dysregulated insulin receptor signaling in VSMCs in nondiabetic and diabetic states.

Endotheliopathy: A continuum of hemolytic uremic syndrome due to mitomycin therapy

Hemolytic uremic syndrome (HUS) is a rare, often fatal complication of mitomycin C therapy. It is generally accepted that HUS is, in part, caused by endothelial cell dysfunction. Endothelial cells modulate blood flow, blood pressure, and myointimal proliferation. Endothelial cells synthesize and release products that modulate vascular tone and regulate vascular smooth muscle cell growth. We describe a patient who developed HUS secondary to mitomycin C, resulting in end-stage renal disease and necessitating chronic hemodialysis. Over several months, the patient subsequently developed multisystem organ failure involving the heart, liver, and intestine that was associated with angiographically documented small, distal vessel occlusive disease and ultrasonographically identified coronary artery intimal hyperplasia. We propose that a diffuse ongoing endothelial cell dysfunction (ie, endotheliopathy) is the putative mechanism for this patients clinical course. To our knowledge, this continuum of HUS presenting as a multisystem, progressive disorder has not been previously reported.

New Strategies to Prevent Restenosis

The Holy Grail of cardiovascular pharmacology has been the search for an effective therapy targeting restenosis after angioplasty and/or intra-arterial stenting. The failure of promising therapeutics in clinical trials underscores the complexity and redundancy of the signaling cascades regulating mitogenesis and fibrogenesis. Novel therapeutic modalities have potential to target dysfunctional signaling elements directly in vascular smooth muscle cells. Significant progress in the treatment against restenosis will require the exploitation and cross-fertilization of developments in the fields of pharmacology, bioengineering, genetics, and molecular biology. Collaboration among researchers in these fields will be essential.

Altered energy state reversibly controls smooth muscle contractile function in human saphenous vein during acute hypoxia–reoxygenation: Role of glycogen, AMP-activated protein kinase, and insulin-independent glucose uptake

Hypoxia is known to promote vasodilation of coronary vessels through several mediators including cardiac-derived adenosine and endothelium-derived prostanoids and nitric oxide. To date, the impact of endogenous glycogen depletion in vascular smooth muscle and the resultant alterations in cellular energy state (e.g., AMP-activated protein kinase, AMPK) on the contractile response to G protein-coupled receptor agonists (e.g., serotonin, 5-HT) has not yet been studied. In the present study, ex vivo exposure of endothelium-denuded human saphenous vein rings to hypoxic and glucose-deprived conditions during KCl-induced contractions for 30 min resulted in a marked depletion of endogenous glycogen by ∼80% (from ∼1.78 μmol/g under normoxia to ∼0.36 μmol/g under hypoxia). Importantly, glycogen-depleted HSV rings, which were maintained under hypoxia/reoxygenation and glucose-deprived conditions, exhibited significant increases in basal AMPK phosphorylation (∼6-fold ↑) and 5-HT-induced AMPK phosphorylation (∼19-fold ↑) with an accompanying suppression of 5-HT-induced maximal contractile response (∼68% ↓), compared with respective controls. Exposure of glycogen-depleted HSV rings to exogenous D-glucose, but not the inactive glucose analogs, prevented the exaggerated increase in 5-HT-induced AMPK phosphorylation and restored 5-HT-induced maximal contractile response. In addition, the ability of exogenous D-glucose to rescue cellular stress and impaired contractile function occurred through GLUT1-mediated but insulin/GLUT4-independent mechanisms. Together, the present findings from clinically-relevant human saphenous vein suggest that the loss of endogenous glycogen in vascular smooth muscle and the resultant accentuation of AMPK phosphorylation by GPCR agonists may constitute a yet another mechanism of metabolic vasodilation of coronary vessels in ischemic heart disease.

Nitrite consumption in ischemic rat heart catalyzed by distinct blood-borne and tissue factors

Nitric oxide (NO) may limit myocardial ischemia-reperfusion injury by slowing the mitochondrial metabolism. We examined whether rat heart contains catalysts potentially capable of reducing nitrite to NO during an episode of regional myocardial ischemia produced by temporary coronary artery occlusion. In intact Sprague-Dawley rats, a 15-min coronary occlusion lowered the nitrite concentration of the myocardial regions exhibiting ischemic glucose metabolism to approximately 50% that of nonischemic regions (185 +/- 223 vs. 420 +/- 203 nmol/l). Nitrite was rapidly repleted during subsequent reperfusion. The heart tissue tested in vitro acquired a substantial ability to consume nitrite when made hypoxic at neutral pH, and this ability was slightly enhanced by simultaneously lowering the pH to 5.5. More than 70% of this activity could be abolished by flushing the coronary circulation with crystalloid to remove trapped erythrocytes. Correspondingly, erythrocytes demonstrated the ability to reduce exogenous nitrite to NO under hypoxic conditions in vitro. In erythrocyte-free heart tissue, the nitrite consumption increased fivefold when the pH was lowered to 5.5. Approximately 40% of this pH-sensitive increase in nitrite consumption could be blocked by the xanthine oxidoreductase inhibitor allopurinol, whereas lowering the Po(2) sufficiently to desaturate myoglobin accelerated it further. We conclude that rat heart contains several factors capable of catalyzing ischemic nitrite reduction; the most potent is contained within erythrocytes and activated by hypoxia, whereas the remainder includes xanthine oxidoreductase and other pH-sensitive factors endogenous to heart tissue, including deoxymyoglobin.

C6-Ceramide-Coated Catheters Promote Re-Endothelialization of Stretch-Injured Arteries

OBJECTIVE: Drug eluting stents have recently been associated with the increased risk of adverse thrombogenic events and/or late luminal loss, which is highly associated with incomplete re-endothelialization. The increased risks behoove the design of alternative delivery modalities and/or drugs that do not compromise the re-endotheliaization process. The objective of the present study is to elucidate the biological mechanism(s) by which non-stent-based delivery modalities for the anti-proliferative lipid metabolite, C(6)-ceramide, could lead to a reduction in arterial injury after angioplasty. RESULTS: Immunohistochemical studies in rabbit and porcine models suggest that C(6)-ceramide-coated balloon catheters limit arterial stenosis without inhibiting endothelial wound healing responses. Specifically, C(6)-ceramide-coated balloon catheters reduce internal elastica injury with a corresponding reduction in medial fracture length in a 28-day porcine coronary artery stretch model. In addition, C(6)-ceramide decreases the formation of the fibrin matrix to possibly augment the subsequent wound healing response. We hypothesized that differential metabolism of exogenous ceramide by coronary endothelial and smooth muscle cells could explain the apparent discrepancy between the anti-proliferative actions of ceramide and the pro-wound healing responses of ceramide. Human coronary artery endothelial cells (HCAEC), in contrast to human coronary artery smooth muscle cells (HCASMC), preferentially express ceramide kinase and form ceramide-1-phosphate, which promotes endothelial cell survival. CONCLUSION: Differential metabolism of ceramide between HCASMC and HCAEC offers a mechanism by which ceramide preferentially limits smooth muscle cell growth, in the presence of active wound healing. The combinatorial ability of ceramide to limit vascular smooth muscle proliferation and promote re-endothelialization, offers the potential for C(6)-ceramide-coated catheters to serve as adjuncts to stent-based modalities or as a stand-alone treatment.

Hydrophilic-Coated Radial Sheaths: A Leap Forward, But Watch Where You Land

Radial artery spasm is one of the impediments to transradial cardiac catheterization. Although the incidence of spasm as a reason for procedural failure appears to markedly decrease with operator experience, it never completely disappears. In addition to preventing the completion of the procedure,

High Numbers of False-Positive Stress Tests Are the Result of Inappropriate Testing

Patients who underwent coronary angiography preceded by stress testing during the period January 2009 through March 2012 were evaluated using the CathPCI database. The predictive accuracy of stress echocardiography (SE) and single-photon emission computed tomography (SPECT) were determined and used to back calculate the pretest probability of the population being tested. In total, 2662 catheterizations were performed, 866 (33%) of which were preceded by stress imaging. Overall, the positive predictive values of SE and SPECT did not differ significantly (61% and 66%, P = .15) and were much lower in certain subgroups. The overall pretest probabilities of patients without a documented history of coronary artery disease undergoing SE and SPECT in the study population were estimated to be 18% and 27%, respectively. This study shows that stress testing is performed too often in low-risk patients in whom it is unlikely to improve clinical decision making.