Christian Zellner

Identification of Four Gene Variants Associated with Myocardial Infarction

Family history is a major risk factor for myocardial infarction (MI). However, known gene variants associated with MI cannot fully explain the genetic component of MI risk. We hypothesized that a gene-centric association study that was not limited to candidate genes could identify novel genetic associations with MI. We studied 11,053 single-nucleotide polymorphisms (SNPs) in 6,891 genes, focusing on SNPs that could influence gene function to increase the likelihood of identifying disease-causing gene variants. To minimize false-positive associations generated by multiple testing, two studies were used to identify a limited number of nominally associated SNPs; a third study tested the hypotheses that these SNPs are associated with MI. In the initial study (of 340 cases and 346 controls), 637 SNPs were associated with MI (P<.05); these were evaluated in a second study (of 445 cases and 606 controls), and 31 of the 637 SNPs were associated with MI (P<.05) and had the same risk allele as in the first study. For each of these 31 SNPs, we tested the hypothesis that it is associated with MI, using a third study (of 560 cases and 891 controls). We found that four of these gene variants were associated with MI (P<.05; false-discovery rate <10%) and had the same risk allele as in the first two studies. These gene variants encode the cytoskeletal protein palladin (KIAA0992 [odds ratio (OR) 1.40]), a tyrosine kinase (ROS1 [OR 1.75]), and two G protein-coupled receptors (TAS2R50 [OR 1.58] and OR13G1 [OR 1.40]); all ORs are for carriers of two versus zero risk alleles. These findings could lead to a better understanding of MI pathophysiology and improved patient risk assessment.

Coronary vasodilator effects of BNP: mechanisms of action in coronary conductance and resistance arteries

Brain natriuretic peptide (BNP), a hormone secreted predominantly in ventricular myocytes, may influence coronary vascular tone. We studied the coronary vasodilatory response to BNP under physiological conditions and after preconstriction with endothelin-1 (ET-1) in anesthetized pigs. Average peak-flow velocity (APV) was measured using intracoronary Doppler, and cross-sectional area (CSA) was measured using intravascular ultrasound. Coronary blood flow (CBF) was calculated. Intracoronary BNP induced dose-dependent increases in CSA, APV, and CBF similar in magnitude to those induced by nitroglycerin (NTG). The magnitude of BNP-induced vasodilation was accentuated after preconstriction with ET-1. Pretreatment with either the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester or the cyclooxygenase inhibitor indomethacin attenuated the coronary vasodilator effect of BNP in resistance arteries without influencing epicardial vasodilation. Pretreatment with the ATP-sensitive potassium-channel blocker glibenclamide enhanced epicardial vasodilation in response to BNP. We conclude that BNP exerts coronary vasodilator effects, predominantly in epicardial conductance vessels. An accentuated vasodilatory response to BNP occurs in ET-1-preconstricted arteries. BNP-induced vasodilation in coronary resistance arteries may be partially mediated via nitric oxide and/or prostaglandin release.Brain natriuretic peptide (BNP), a hormone secreted predominantly in ventricular myocytes, may influence coronary vascular tone. We studied the coronary vasodilatory response to BNP under physiological conditions and after preconstriction with endothelin-1 (ET-1) in anesthetized pigs. Average peak-flow velocity (APV) was measured using intracoronary Doppler, and cross-sectional area (CSA) was measured using intravascular ultrasound. Coronary blood flow (CBF) was calculated. Intracoronary BNP induced dose-dependent increases in CSA, APV, and CBF similar in magnitude to those induced by nitroglycerin (NTG). The magnitude of BNP-induced vasodilation was accentuated after preconstriction with ET-1. Pretreatment with either the nitric oxide synthase inhibitor N ω-nitro-l-arginine methyl ester or the cyclooxygenase inhibitor indomethacin attenuated the coronary vasodilator effect of BNP in resistance arteries without influencing epicardial vasodilation. Pretreatment with the ATP-sensitive potassium-channel blocker glibenclamide enhanced epicardial vasodilation in response to BNP. We conclude that BNP exerts coronary vasodilator effects, predominantly in epicardial conductance vessels. An accentuated vasodilatory response to BNP occurs in ET-1-preconstricted arteries. BNP-induced vasodilation in coronary resistance arteries may be partially mediated via nitric oxide and/or prostaglandin release.

Physiological Concentrations of Estradiol Attenuate Endothelin 1–Induced Coronary Vasoconstriction In Vivo

BACKGROUND Estrogens are cardioprotective hormones and are reported to have antianginal properties. We examined the effect of physiological concentrations of 17beta-estradiol on coronary reactivity in anesthetized female farm pigs. METHODS AND RESULTS Epicardial coronary cross-sectional area (CSA) was assessed by two-dimensional intravascular ultrasound, average coronary peak flow velocity (APV) by intravascular Doppler velocimetry, and coronary blood flow (CBF) was calculated. Dose-response curves to intracoronary endothelin-1 (ET-1, 1 pmol/L to 10 nmol/L), the selective ET(B) receptor agonist sarafotoxin (1 pmol/L to 10 nmol/L), and serotonin (0.1 nmol/L to 1 micromol/L) were assessed before and after a 10-minute infusion of intracoronary estradiol (1 nmol/L). Before estradiol administration, ET-1 induced significant dose-dependent decreases in CSA, APV, and CBF. Estradiol attenuated ET-1-induced epicardial vasoconstriction (P<.001) as well as ET-1-induced decreases in APV (P=.05) and CBF (P=.012). In an additional five pigs, vehicle (DMSO) had no effect on ET-1-induced coronary vasoconstriction. Before estradiol administration, sarafotoxin induced no net change in CSA but induced increases in APV and CBF, the extent of which did not change significantly after estradiol. Serotonin induced small decreases in CSA but increased APV and CBF. Estradiol did not influence serotonin-induced changes in CSA, APV, or CBF. CONCLUSIONS We conclude that estradiol attenuates ET-1-induced vasoconstriction, possibly through effects on the ET(A) receptor, because selective ET(B) receptor-induced stimulation with sarafotoxin remained unchanged. Such an effect on the ET(A) receptor may relate to the antianginal properties of estrogens.

Relation of Increased Prebeta-1 High-Density Lipoprotein Levels to Risk of Coronary Heart Disease

Preβ-1 high-density lipoprotein (HDL) plays a key role in reverse cholesterol transport by promoting cholesterol efflux. Our aims were (1) to test previous associations between preβ-1 HDL and coronary heart disease (CHD) and (2) to investigate whether preβ-1 HDL levels also are associated with risk of myocardial infarction (MI). Plasma preβ-1 HDL was measured by an ultrafiltration-isotope dilution technique in 1,255 subjects recruited from the University of California-San Francisco Lipid and Cardiovascular Clinics and collaborating cardiologists. Preβ-1 HDL was significantly and positively associated with CHD and MI even after adjustment for established risk factors. Inclusion of preβ-1 HDL in a multivariable model for CHD led to a modest improvement in reclassification of subjects (net reclassification index 0.15, p = 0.01; integrated discrimination improvement 0.003, p = 0.2). In contrast, incorporation of preβ-1 HDL into a risk model of MI alone significantly improved reclassification of subjects (net reclassification index 0.21, p = 0.008; integrated discrimination improvement 0.01, p = 0.02), suggesting that preβ-1 HDL has more discriminatory power for MI than for CHD in our study population. In conclusion, these results confirm previous associations between preβ-1 HDL and CHD in a large well-characterized clinical cohort. Also, this is the first study in which preβ-1 HDL was identified as a novel and independent predictor of MI above and beyond traditional CHD risk factors.

Safety of cardiac catheterization in patients with end-stage liver disease awaiting liver transplantation.

Patients with end-stage liver disease (ESLD) are predisposed to bleeding complications due to thrombocytopenia, reduced synthesis of coagulation factors, and increased fibrinolytic activity. The exact incidence of vascular access site and bleeding complications related to cardiac catheterization in this group remains unknown. Eighty-eight consecutive patients with ESLD who underwent left-sided cardiac catheterization from August 2004 to February 2007 were identified. Eighty-one patients without known liver disease matched for age, gender, and body mass index who underwent left-sided cardiac catheterization during the same period were chosen as the control group. Vascular complications were defined as hematoma >5 cm, pseudoaneurysm, arteriovenous fistula, or retroperitoneal bleeding. Patients with ESLD had lower baseline mean hematocrit (32.3 +/- 6.0% vs 39.2 +/- 6.2%, p <0.001) and mean platelet count (90.1 +/- 66.3 vs 236.1 +/- 77.1 x 10(9)/L, p <0.001) compared with controls. They also had higher mean serum creatinine (1.9 +/- 1.7 vs 1.2 +/- 0.8 mg/dl, p = 0.002) and mean international normalized ratio (1.6 +/- 0.7 vs 1.1 +/- 0.2, p <0.001). There were more complicated pseudoaneurysms in the patients with liver failure (5.7% [5 of 88]), compared with 0% in controls (p = 0.029). Patients with ESLD had lower starting hemoglobin levels and greater reductions in hemoglobin after cardiac catheterization, resulting in greater need for packed red blood cell transfusion (16% vs 4%, p = 0.008), fresh frozen plasma (51.7% vs 1.2%, p <0.001), and platelet transfusions (48.3% vs 1.2%, p <0.001). Major bleeding was higher in the ESLD group (14.8% vs 3.7%, p = 0.014), driven mainly by the need for blood transfusion. In conclusion, despite severe coagulopathy, left-sided cardiac catheterization may be performed safely in this patient population, with correction of coagulopathy and meticulous attention to procedural technique.

Genetic variation of PLTP modulates lipoprotein profiles in hypoalphalipoproteinemia

Phospholipid transfer protein (PLTP) participates in key processes in lipoprotein metabolism, including interparticle phospholipid transfer, remodeling of HDL, cholesterol and phospholipid efflux from peripheral tissues, and the production of hepatic VLDL. The impact of PLTP on reverse cholesterol transport suggests that the gene may harbor sequence anomalies that contribute to disorders of HDL metabolism. The human PLTP gene was screened for sequence anomalies by DNA melting analysis in 276 subjects with hypoalphalipoproteinemia (HA) and 364 controls. The association with plasma lipid parameters was evaluated. We discovered 18 sequence variations, including four missense mutations and a novel polymorphism (c.-34G>C). In healthy controls, the c.-34G>C minor allele was associated with higher high density lipoprotein-cholesterol (HDL-C) and was depleted in subjects with HA. Linear regression models predict that possession of the rare allele decreases plasma triglyceride (TG) and TG/HDL-C and increases HDL-C independent of TG. Decreased PLTP activity was observed in one (p.R235W) of four (p.E72G, p.S119A, p.S124Y, and p.R235W) mutations in an in vitro activity assay. These findings indicate that PLTP gene variation is an important determinant of plasma lipoproteins and affects disorders of HDL metabolism.

Teleconferencing with dynamic medical images

Dynamic images, a sequence of static images displayed in rapid succession and perceived as a continuous motion by the human eye, are widely used in medicine. One of the primary objectives of telemedicine is the transmission of such images to a distant location to manage clinical problems remotely. A broad variety of methods is available to acquire, store, transmit and display these images. However, the context of the clinical problem determines which of these methods can be deployed in a telemedicine solution. This paper discusses the advantages and disadvantages of the different technologies and presents an example of a teleconferencing system for interventional cardiology. This system acquires cardiac angiography and intravascular ultrasound images and transmits them over an existing Internet connection to a distant location. It is specifically optimized for clinical conferencing, where time is limited for each case presentation during the conference, compared to the relatively long time available for the conference preparation. The system takes advantage of this characteristic by transmitting the images well in advance of the clinical conference and displaying them synchronously at both locations during the conference. This allows for the preservation of the original image quality.

Genetic variation in phospholipid transfer protein modulates lipoprotein profiles in hyperalphalipoproteinemia

We previously demonstrated the role of a phospholipid transfer protein (PLTP) gene variation (rs2294213) in determining levels of high-density lipoprotein cholesterol (HDL-C) in hypoalphalipoproteinemia (HypoA). We have now explored the role of PLTP in hyperalphalipoproteinemia (HyperA). The human PLTP gene was screened for sequence anomalies by DNA melting in 107 subjects with HyperA. The association with plasma lipoprotein levels was evaluated. We detected 7 sequence variations: 1 previously reported variation (rs2294213) and 5 novel mutations including 1 missense mutation (L106F). The PLTP activity was unchanged in the p.L106F mutation. The frequency of the rs2294213 minor allele was markedly increased in the HyperA group (7.0%) in comparison with a control group (4.3%) and the hypoalphalipoproteinemia group (2.2%). Moreover, rs2294213 was strongly associated with HDL-C levels. Linear regression models predict that possession of the rs2294213 minor allele increases HDL-C independent of triglycerides. These findings extend the association of rs2294213 with HDL-C levels into the extremes of the HDL distribution.

Dehydroepiandrosterone sulfate induces acute vasodilation of porcine coronary arteries in vitro and in vivo.

Although an inverse relationship between dehydroepiandrosterone sulfate (DHEAS) and coronary artery disease has been demonstrated in men, the vascular effects of DHEAS are not well defined. The vasoactive effects of intracoronary DHEAS and testosterone (0.1 nM to 1 μM) were examined in vivo in 24 pigs. Epicardial cross-sectional area was measured by intravascular ultrasound, and coronary flow velocity by intravascular Doppler velocimetry. We also examined the effects of antagonism of the androgen receptor, nitric oxide synthase, and potassium channels on DHEAS-induced vasodilation in vitro in coronary rings from male and female pig hearts. DHEAS and testosterone induced increases in cross-sectional area, average peak velocity, and coronary blood flow. The maximal increase in coronary blood flow in response to testosterone was 1.26-fold (P = 0.02), and in average peak velocity 1.43-fold (P = 0.05), greater than that to DHEAS, whereas increases in cross-sectional area were similar. Vasodilation to both hormones was rapid, with maximal responses occurring <10 minutes after administration. In vitro, DHEAS and testosterone induced vasodilation in coronary rings, greater with testosterone. At doses of 0.1 and 1 μM, the vasodilator effects of DHEAS and testosterone were inhibited by the androgen receptor antagonist flutamide but not the estrogen receptor antagonist ICI 182,780. At 10 μM, neither DHEAS- nor testosterone-induced vasorelaxation was inhibited by flutamide, ICI 182,780, L-NAME, or deendothelialization, but both were attenuated by pretreatment with glibenclamide. No gender differences were observed in any of the responses examined. In conclusion, DHEAS is an acute coronary artery vasodilator, but less potent than testosterone. Its effect might be mediated via androgen receptors and may involve ATP-sensitive potassium channels.

Sterile radial artery granuloma after transradial procedures: a unique and avoidable complication.

Trans‐radial cardiac catheterization has lower rates of arterial access site complications. Hydrophilic‐coated sheaths designed specifically for trans‐radial procedures have resulted in numerous reports of a foreign body reaction to retained material. Although this is a self‐limited condition that should be managed expectantly, it is often confused with an infected pseudoaneurysm, resulting in unnecessary surgery. We searched the FDA MAUDE (Manufacturer and User Facility Device Experience) database to determine which brands of sheath have been associated with this complication. In addition, we performed a literature search for all reported cases of this complication. Only one brand of sheath has been associated with this condition. As trans‐radial procedures become more common in the US, knowledge of such complications, which appear to be specific to the Cook radial hydrophilic‐coated sheaths, is imperative for all radial interventionalists to prevent unnecessary surgical procedures.