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Genome Screen to Detect Linkage to Common Susceptibility Genes for Intracranial and Aortic Aneurysms
- Bradford B. Worrall,
- Tatiana Foroud,
- Robert D. Brown,
- E. Sander. Connolly,
- Richard W. Hornung,
- John Huston,
- Dawn Kleindorfer,
- Daniel L. Koller,
- Dongbing Lai,
- Charles J. Moomaw,
- Laura Sauerbeck,
- Daniel Woo,
- Joseph P. Broderick
Stroke Volume 40, Issue 11 January 2009

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Background and Purpose— Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is thought to be heritable with mounting evidence for genetic predisposition. The concept of shared risk for these conditions is challenged by differences in age of diagnosis and demographic characteristics. We performed a genomewide linkage analysis in multiplex families with both IA and AA from the Familial Intracranial Aneurysm study.Methods— Available medical records of subjects who reported IA or abdominal/thoracic AA were reviewed with adjudication as definite/probable, possible, or not a case. To identify genes contributing to the susceptibility for IA and AA, genomewide linkage analysis was performed in the 26 multiplex IA families who had members who also had thoracic or abdominal AA. Individuals (n=91) were defined as affected if they had an IA (definite/probable) or an aortic or thoracic AA (definite/probable).Results— Maximum logarithm of odds (LOD) scores were found on chromosomes 11 (144 cM; LOD=3.0) and 6 (33 cM; LOD=2.3). In both chromosomal regions, analyses of these same 26 families considering only IA as the disease phenotype produced LOD scores of 1.8 and 1.6, respectively.Conclusions— Our linkage analysis in these 26 families using the broadest disease phenotype, including IA, abdominal AA, and thoracic AA, supports the concept of shared genetic risk. The chromosome 11 locus appears to confirm earlier independent associations in IA and AA. The chromosome 6 finding is novel. Both warrant further investigation.
Genome Screen to Detect Linkage to Intracranial Aneurysm Susceptibility Genes: The Familial Intracranial Aneurysm (FIA) Study
- Tatiana Foroud,
- Laura Sauerbeck,
- Robert Brown,
- Craig Anderson,
- Daniel Woo,
- Dawn Kleindorfer,
- Matthew L. Flaherty,
- Ranjan Deka,
- Richard Hornung,
- Irene Meissner,
- Joan E. Bailey-Wilson,
- Guy Rouleau,
- E. Sander Connolly,
- Dongbing Lai,
- Daniel L. Koller,
- John Huston,
- Joseph P. Broderick and
Stroke Volume 39, Issue 51 May 2008

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Background and Purpose— Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA.Methods— Multiplex families having at least 2 individuals with “definite” or “probable” IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a gene×smoking (pack-years) interaction.Results— The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P=0.03), 7 (LOD=4.1; P=0.01) and 12 (LOD=3.6; P=0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking.Conclusions— We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a gene×smoking interaction with 3 of the loci.
Familial Intracranial Aneurysms: Is Anatomic Vulnerability Heritable?
- Jason Mackey,
- Robert D. Brown,
- Charles J. Moomaw,
- Richard Hornung,
- Laura Sauerbeck,
- Daniel Woo,
- Tatiana Foroud,
- Dheeraj Gandhi,
- Dawn Kleindorfer,
- Matthew L. Flaherty,
- Irene Meissner,
- Craig Anderson,
- Guy Rouleau,
- E. Sander Connolly,
- Ranjan Deka,
- Daniel L. Koller,
- Todd Abruzzo,
- John Huston,
- Joseph P. Broderick and
Stroke Volume 44, Issue 11 January 2013

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Background and Purpose—Previous studies have suggested that family members with intracranial aneurysms (IAs) often harbor IAs in similar anatomic locations. IA location is important because of its association with rupture. We tested the hypothesis that anatomic susceptibility to IA location exists using a family-based IA study.Methods—We identified all affected probands and first-degree relatives (FDRs) with a definite or probable phenotype in each family. We stratified each IA of the probands by major arterial territory and calculated each family’s proband-FDR territory concordance and overall contribution to the concordance analysis. We then matched each family unit to an unrelated family unit selected randomly with replacement and performed 1001 simulations. The median concordance proportions, odds ratios (ORs), and P values from the 1001 logistic regression analyses were used to represent the final results of the analysis.Results—There were 323 family units available for analysis, including 323 probands and 448 FDRs, with a total of 1176 IAs. IA territorial concordance was higher in the internal carotid artery (55.4% versus 45.6%; OR, 1.54 [1.04–2.27]; P=0.032), middle cerebral artery (45.8% versus 30.5%; OR, 1.99 [1.22–3.22]; P=0.006), and vertebrobasilar system (26.6% versus 11.3%; OR, 2.90 [1.05–8.24], P=0.04) distributions in the true family compared with the comparison family. Concordance was also higher when any location was considered (53.0% versus 40.7%; OR, 1.82 [1.34–2.46]; P<0.001).Conclusions—In a highly enriched sample with familial predisposition to IA development, we found that IA territorial concordance was higher when probands were compared with their own affected FDRs than with comparison FDRs, which suggests that anatomic vulnerability to IA formation exists. Future studies of IA genetics should consider stratifying cases by IA location.
The Relationship Between Smoking and Replicated Sequence Variants on Chromosomes 8 and 9 With Familial Intracranial Aneurysm
- Ranjan Deka,
- Daniel L. Koller,
- Dongbing Lai,
- Subba Rao Indugula,
- Guangyun Sun,
- Daniel Woo,
- Laura Sauerbeck,
- Charles J. Moomaw,
- Richard Hornung,
- E. Sander Connolly,
- Craig Anderson,
- Guy Rouleau,
- Irene Meissner,
- Joan E. Bailey-Wilson,
- John Huston,
- Robert D. Brown,
- Dawn O. Kleindorfer,
- Matthew L. Flaherty,
- Carl D. Langefeld,
- Tatiana Foroud,
- Joseph P. Broderick and
Stroke Volume 41, Issue 61 June 2010

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Background and Purpose— The purpose of this study was to replicate the previous association of single nucleotide polymorphisms (SNPs) with risk of intracranial aneurysm (IA) and to examine the relationship of smoking with these variants and the risk of IA.Methods— White probands with an IA from families with multiple affected members were identified by 26 clinical centers located throughout North America, New Zealand, and Australia. White control subjects free of stroke and IA were selected by random digit dialing from the Greater Cincinnati population. SNPs previously associated with IA on chromosomes 2, 8, and 9 were genotyped using a TaqMan assay or were included in the Affymetrix 6.0 array that was part of a genomewide association study of 406 IA cases and 392 control subjects. Logistic regression modeling tested whether the association of replicated SNPs with IA was modulated by smoking.Results— The strongest evidence of association with IA was found with the 8q SNP rs10958409 (genotypic P=9.2×10⁻⁵; allelic P=1.3×10⁻⁵; OR=1.86, 95% CI: 1.40 to 2.47). We also replicated the association with both SNPs on chromosome 9p, rs1333040 and rs10757278, but were not able to replicate the previously reported association of the 2 SNPs on chromosome 2q. Statistical testing showed a multiplicative relationship between the risk alleles and smoking with regard to the risk of IA.Conclusion— Our data provide complementary evidence that the variants on chromosomes 8q and 9p are associated with IA and that the risk of IA in patients with these variants is greatly increased with cigarette smoking.
Association of the Vitamin D Metabolism Gene CYP24A1 With Coronary Artery Calcification
- Haiqing Shen,
- Lawrence F. Bielak,
- Jane F. Ferguson,
- Elizabeth A. Streeten,
- Laura M. Yerges-Armstrong,
- Jie Liu,
- Wendy Post,
- Jeffery R. O'Connell,
- James E. Hixson,
- Sharon L.R. Kardia,
- Yan V. Sun,
- Min A. Jhun,
- Xuexia Wang,
- Nehal N. Mehta,
- Mingyao Li,
- Daniel L. Koller,
- Hakan Hakonarson,
- Brendan J. Keating,
- Daniel J. Rader,
- Alan R. Shuldiner,
- Patricia A. Peyser,
- Muredach P. Reilly and
- Braxton D. Mitchell
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 30, Issue 121 December 2010

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Objective—The vitamin D endocrine system is essential for calcium homeostasis, and low levels of vitamin D metabolites have been associated with cardiovascular disease risk. We hypothesized that DNA sequence variation in genes regulating vitamin D metabolism and signaling pathways might influence variation in coronary artery calcification (CAC).Methods and Results—We genotyped single-nucleotide polymorphisms (SNPs) in GC, CYP27B1, CYP24A1, and VDR and tested their association with CAC quantity, as measured by electron beam computed tomography. Initial association studies were carried out in a discovery sample comprising 697 Amish subjects, and SNPs nominally associated with CAC quantity (4 SNPs in CYP24A1, P=0.008 to 0.00003) were then tested for association with CAC quantity in 2 independent cohorts of subjects of white European ancestry (Genetic Epidemiology Network of Arteriopathy study [n=916] and the Penn Coronary Artery Calcification sample [n=2061]). One of the 4 SNPs, rs2762939, was associated with CAC quantity in both the Genetic Epidemiology Network of Arteriopathy (P=0.007) and Penn Coronary Artery Calcification (P=0.01) studies. In all 3 populations, the rs2762939 C allele was associated with lower CAC quantity. Metaanalysis for the association of this SNP with CAC quantity across all 3 studies yielded a P value of 2.9×10⁻⁶.Conclusion—A common SNP in the CYP24A1 gene was associated with CAC quantity in 3 independent populations. This result suggests a role for vitamin D metabolism in the development of CAC quantity.
Genome-Wide Association Study of Intracranial Aneurysms Confirms Role of Anril and SOX17 in Disease Risk
- Tatiana Foroud,
- Daniel L. Koller,
- Dongbing Lai,
- Laura Sauerbeck,
- Craig Anderson,
- Nerissa Ko,
- Ranjan Deka,
- Thomas H. Mosley,
- Myriam Fornage,
- Daniel Woo,
- Charles J. Moomaw,
- Richard Hornung,
- John Huston,
- Irene Meissner,
- Joan E. BaileyWilson,
- Carl Langefeld,
- Guy Rouleau,
- E. Sander Connolly,
- Bradford B. Worrall,
- Dawn Kleindorfer,
- Matthew L. Flaherty,
- Sharyl Martini,
- Jason Mackey,
- Felipe De Los Rios La Rosa,
- Robert D. Brown,
- Joseph P. Broderick and
Stroke Volume 43, Issue 111 November 2012

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Background—Genomewide association studies have identified novel genetic factors that contribute to intracranial aneurysm (IA) susceptibility. We sought to confirm previously reported loci, to identify novel risk factors, and to evaluate the contribution of these factors to familial and sporadic IA.Method—We utilized 2 complementary samples, one recruited on the basis of a dense family history of IA (discovery sample 1: 388 IA cases and 397 controls) and the other without regard to family history (discovery sample 2: 1095 IA cases and 1286 controls). Imputation was used to generate a common set of single nucleotide polymorphisms (SNP) across samples, and a logistic regression model was used to test for association in each sample. Results from each sample were then combined in a metaanalysis.Results—There was only modest overlap in the association results obtained in the 2 samples. In neither sample did results reach genomewide significance. However, the metaanalysis yielded genomewide significance for SNP on chromosome 9p (CDKN2BAS; rs6475606; P=3.6 × 10⁻⁸) and provided further evidence to support the previously reported association of IA with SNP in SOX17 on chromosome 8q (rs1072737; P=8.7 × 10⁻⁵). Analyses suggest that the effect of smoking acts multiplicatively with the SNP genotype, and smoking has a greater effect on risk than SNP genotype.Conclusion—In addition to replicating several previously reported loci, we provide further evidence that the association on chromosome 9p is attributable to variants in CDKN2BAS (also known as ANRIL, an antisense noncoding RNA).
Genome-Wide Association Study of Intracranial Aneurysm Identifies a New Association on Chromosome 7
- Tatiana Foroud,
- Dongbing Lai,
- Daniel Koller,
- Femke van’t Hof,
- Mitja I. Kurki,
- Craig S. Anderson,
- Robert D. Brown,
- Edward Sander Connolly,
- Johan G. Eriksson,
- Matthew Flaherty,
- Myriam Fornage,
- Mikael von und zu Fraunberg,
- Emília I. Gaál,
- Aki Laakso,
- Juha Hernesniemi,
- John Huston,
- Juha E. Jääskeläinen,
- Lambertus A. Kiemeney,
- Riku Kivisaari,
- Dawn Kleindorfer,
- Nerissa Ko,
- Hanna Lehto,
- Jason Mackey,
- Irene Meissner,
- Charles J. Moomaw,
- Thomas H. Mosley,
- Marek Moskala,
- Mika Niemelä,
- Aarno Palotie,
- Joanna Pera,
- Gabriel Rinkel,
- Stephan Ripke,
- Guy Rouleau,
- Ynte Ruigrok,
- Laura Sauerbeck,
- Agnieszka Słowik,
- Sita H. Vermeulen,
- Daniel Woo,
- Bradford B. Worrall and
- Joseph Broderick
and for the Familial Intracranial Aneurysm Study Investigators

Stroke Volume 45, Issue 111 November 2014

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Background and Purpose—Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk.Methods—Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest.Results—Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0×10⁻¹¹), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14×10⁻⁸). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91×10⁻¹⁰).Conclusions—We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA.
Letter Regarding Article by Koller et al, “Altered Dynamics of Action Potential Restitution and Alternans in Humans With Structural Heart Disease”
- Arthur M. Yue
Circulation Volume 113, Issue 1121 March 2006

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Impaired nitric oxide-mediated flow-induced dilation in arterioles of spontaneously hypertensive rats.
- A Koller and
- A Huang
Circulation Research Volume 74, Issue 31 March 1994

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We tested the hypothesis that impairment of flow-dependent dilator mechanisms of skeletal muscle arterioles is one of the underlying reasons for the increased peripheral resistance in hypertension. Isolated, cannulated arterioles (approximately 55 microns) of gracilis muscle of 12-week-old spontaneously hypertensive (SH) and normotensive Wistar (NW) rats were investigated. At a constant perfusion pressure (80 mm Hg), the active diameters of NW and SH arterioles were 57.7 +/- 1.9 and 51.5 +/- 3.2 microns, whereas their passive diameters (Ca(2+)-free solution) were 113.6 +/- 2.9 and 101.7 +/- 2.9 microns, respectively. Flow-induced dilation was elicited by increases in flow of the perfusion solution from 0 to 25 microL/min in 5-microL/min steps. This response was significantly less in arterioles of SH compared with NW rats. For example, at 25-microL/min flow, the diameter of arterioles of SH rats was approximately 56% less (P < .05) than those of NW rats. Indomethacin, an inhibitor of prostaglandin synthesis, significantly attenuated the flow-diameter curve in both strains of rats. In contrast, N omega-nitro-L-arginine, a nitric oxide synthase inhibitor, significantly shifted the flow-diameter curve to the right in NW rats, but it did not affect the flow-diameter curve in SH rats. Thus, the present findings demonstrate that in gracilis muscle arterioles of normotensive rats in response to increases in flow (shear stress), prostaglandins and nitric oxide are co-released, resulting in a dilation. In early hypertension, however, there is a reduced arteriolar dilation to increases in flow that is due to the impairment of the nitric oxide-mediated portion of the flow-dependent arteriolar dilation.
Prostaglandins mediate arteriolar dilation to increased blood flow velocity in skeletal muscle microcirculation.
- A Koller and
- G Kaley
Circulation Research Volume 67, Issue 21 August 1990

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In cremaster muscle of pentobarbital-anesthetized rats, temporary occlusion of an arteriole increased red blood cell velocity (mean increase, 8.2 +/- 1.0 mm/sec from a control velocity of 7.9 +/- 0.7 mm/sec) in proximal parallel arteriolar branches (mean control diameter, 19.4 +/- 0.6 microns). Increases in flow velocity were consistently followed by proportional delayed (6-15 seconds) increases in arteriolar diameter (5.8 +/- 0.7 microns). Administration of NG-monomethyl-L-arginine (200 microM), an inhibitor of the synthesis of endothelium-derived relaxing factor that blocked the arteriolar responses to acetylcholine (1 microM) but not to arachidonic acid (10 microM), did not affect the dilation (mean increase, 8.9 +/- 1.1 microns) due to increases in red blood cell velocity (13.4 +/- 1.5 mm/sec). However, the cyclooxygenase inhibitor indomethacin (or meclofenamate), which completely blocked the dilator response to arachidonic acid but did not change the response to acetylcholine, inhibited the arteriolar dilation (mean increase, 0.3 +/- 0.2 micron) due to increases in red blood cell velocity (9.3 +/- 1.0 mm/sec). Inhibition of prostaglandin synthesis also reduced the increase in calculated blood flow by 57% during occlusion. These results suggest that the arterioles are sensitive to increases in blood flow velocity (wall shear stress), in response to which they release prostaglandins, eliciting vasodilation. The existence of this phenomenon in the skeletal muscle microcirculation suggests a new regulatory mechanism that, by modulation of vascular resistance in the microvascular network, has the role of normalizing wall shear stress and providing for substantial increases in tissue blood flow.
Role of shear stress and endothelial prostaglandins in flow- and viscosity-induced dilation of arterioles in vitro.
- A Koller,
- D Sun and
- G Kaley
Circulation Research Volume 72, Issue 61 June 1993

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We have studied the effect of changes in shear stress on diameter of isolated arterioles of rat cremaster muscle. The steady-state active diameter of arterioles at a constant perfusion pressure (60 mm Hg) was 80 +/- 1.2 microns. The vessels' passive diameter (Ca(2+)-free solution) was 156 +/- 1.8 microns. Changes in shear stress were induced either by an increase in flow (velocity) or by an increase in viscosity of the perfusion solution. At a constant perfusion pressure, the stepwise increase in perfusion flow (0-80 microliters/min in 10-microliters/min steps) elicited, with a delay of approximately 20 seconds, a gradual increase in diameter up to 46%. At a constant 20-microliters/min flow rate, increases in viscosity of the perfusate (2%, 4%, and 6% dextran [molecular weight, 77,800]) caused a gradual vasodilation up to 22%. Varying flow and viscosity of the perfusate simultaneously resulted in an upward shift of the flow-diameter curve. Both flow- and viscosity-induced dilations were eliminated by the removal of the endothelium of arterioles (by air) or were inhibited by indomethacin (10(-5) M). The efficacy and specificity of these inhibitory treatments were assessed with vasoactive agents whose action, with regard to endothelial mediation, has been determined previously. The arteriolar dilation maintained calculated wall shear stress close to control values during increases in flow and/or viscosity of the perfusate, but when the dilation was inhibited by removal of the endothelium or by indomethacin, wall shear stress increased significantly in a cumulative manner.(ABSTRACT TRUNCATED AT 250 WORDS)
Molecular biology of the natriuretic peptides and their receptors.
- K J Koller and
- D V Goeddel
Circulation Volume 86, Issue 41 October 1992

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After the description in the past 5 years of BNP and CNP, interest in the natriuretic peptide family has dramatically increased. Molecular characterization of the receptors for this hormone family has identified a heterogeneity in the receptor subtypes not previously alluded to by pharmacological or biochemical studies. Much has been published on the physiology of ANP, but the major roles for BNP and CNP remain to be elucidated. Some experiments indicate that ANP and BNP may act synergistically, especially during cardiac stress; however, the high level of structural diversity of BNP among species and the ability of porcine BNP, but not human BNP, to activate human NPR-B suggest that an as yet unidentified receptor may exist that specifically recognizes BNP. Localization studies have implied that CNP is the most prominent neuropeptide in the natriuretic peptide family, and the restriction of its receptor, NPR-B, to the nervous system suggests that CNP and NPR-B may act in the brain to coordinate the central aspects of body fluid homeostasis. Of the three known NPRs, two, NPR-A and NPR-B, are capable of synthesizing their own second messenger, cGMP. The domain within these receptors that has high homology to protein kinases has been demonstrated to be essential for regulating this activity. No kinase activity has been measured in these proteins, but it is possible that this region is important for ATP regulation of guanylyl cyclase activity. This possibility raises interesting parallels with receptor-mediated cAMP signaling within cells. Seven transmembrane receptors, once activated by ligand, associate with G proteins to affect the activity of adenylyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
Reduction of lipid peroxidation in reperfused isolated rabbit hearts by diltiazem.
- P T Koller and
- S R Bergmann
Circulation Research Volume 65, Issue 31 September 1989

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The calcium-channel inhibiting agent, diltiazem, has been shown to enhance salvage of reperfused myocardium independent of effects on coronary blood flow or myocardial work. Because lipid peroxidation may be a mediator of reperfusion injury and modifiable by calcium-sensitive pathways, we evaluated the effects of diltiazem on the formation of malondialdehyde (MDA), a product of lipid peroxidation, in isolated rabbit hearts perfused with buffer under control conditions or after 60 minutes of ischemia with or without 3 minutes of reperfusion. Diltiazem (5 x 10(-7)M) reduced tissue MDA content in seven reperfused hearts compared with levels measured in 14 hearts reperfused without drug (1.54 +/- 1.09 [SD] compared with 3.57 +/- 1.88 nmol/g, p less than 0.05). Superoxide dismutase and catalase were ineffective in reducing tissue MDA content in reperfused hearts (n = 8; MDA concentration, 3.88 +/- 2.82 nmol/g) although they were effective in preventing lipid peroxidation in separate studies in which oxygen-centered free radicals were generated directly by an infusion of xanthine oxidase and hypoxanthine. These results suggest that the salutary effects of diltiazem in the setting of reperfusion may be mediated by reduction of lipid peroxidation at a locus not accessible to scavengers of oxygen-centered free radicals or by a mechanism not mediated by free radical pathways.
Abstract 187: Preshock Pause Intervals and Rearrest After Resuscitation from Out-of-Hospital Cardiac Arrest
- Allison C Koller,
- David Salcido and
- James J Menegazzi
Circulation Volume 124, Issue suppl_2122 November 2011

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Background: Loss of pulses after successful return of spontaneous circulation (ROSC) during resuscitation from out-of-hospital cardiac arrest (OHCA) is known as re-arrest (RA). Recent studies have provided estimates of the rate occurrence of re-arrest - as high as 38% -, but the causes and characteristics of RA are not yet fully understood. One plausible contributor to RA is the pre-shock pause (PSP) interval - the time interval between the last chest compression and a defibrillating shock - which has been shown to predict survival to hospital discharge.Objective: Measure the PSP time interval in cases of OHCA with and without RA in order to: a) provide an estimate of the PSP in cases with RA, and b) compare the PSP of cases with RA to cases without PSP.Methods: Case data for emergency medical services (EMS)-treated OHCA were obtained from the Pittsburgh site of the multi-center Resuscitation Outcomes Consortium (ROC) and were part of a previously identified dataset (n = 113) used to compare ECG characteristics of RA cases to those without RA. A subset of these cases was identified that received at least one shock during treatment by EMS. Time-coded impedance, compression force, compression depth, or audio recordings accompanying each ECG trace were used to calculate the PSP to the nearest second for each shock in each case. The PSP for shocks that followed ROSC without preceding compressions were calculated as the interval between loss of pulses and the shock. All other PSP were calculated as the difference between the time of the final pre-shock compression and shock delivery. The kruskal-wallis test was used to compare the medians of RA and no-RA PSP with an alpha level of 0.05.Results: Fifty-six cases were identified with at least 1 EMS-delivered defibrillating shock. Of these, 27 (48%) cases had at least one instance of RA. For a total of 159 shocks in both RA and no-RA groups, the median (IQR) PSP was 16s (12.75). The median (IQR) PSP for the RA group (n = 101) was 16s (14), while the median (IQR) PSP for the no-RA group (n = 58) was 14s (11). The median PSP of RA and no-RA groups were not significantly different (p = 0.15).Conclusion: The PSP for EMS-treated cases of OHCA with RA had a median duration of 16s. In this limited study, PSP were not different between groups with and without RA.
Abstract 225: Healthcare Provider Perspectives on Resuscitation of Drug-Related Out-of-Hospital Cardiac Arrest
- Allison Koller,
- David D Salcido,
- Clifton W Callaway and
- James J Menegazzi
Circulation Volume 128, Issue suppl_2226 November 2013

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Introduction: Out-of-hospital cardiac arrest from drug overdose (OD-OHCA) caused over 38,000 deaths in 2010. A preliminary study in Pittsburgh found that OD-OHCA patients differed demographically and in the resuscitation treatments they received, despite identical American Heart Association (AHA) resuscitation guidelines. We hypothesized that physician and non-physician healthcare provider perceptions affect decision-making in the treatment of OD-OHCA versus non-OD OHCA.Methods: A handwritten survey was administered at the National Association of EMS Physicians 2013 Scientific Assembly between January 9 and 12, 2013. Participants were asked about their affiliated EMS agencies, perceptions of OD-OHCA incidence and abused drugs, and perspectives on and knowledge of the treatment of OD-OHCA during resuscitation. Participants were instructed to complete only one survey.Results: In sum, 193 respondents participated in this survey: 144 (75%) were physicians and 49 (25%) were non-physician healthcare providers. Of the physicians, 79% identified current status as a medical director and 76% of non-physicians identified as a paramedic. Eighty-three percent of physicians and 65% of non-physicians indicated that OD-OHCA patients had different demographics than non-OD OHCA; 64% all respondents felt that OD-OHCA patients should be treated differently. Of those respondents who believed that OD-OHCA patients should be treated differently, 47% believed there were differences in the AHA guidelines, while only 27% of those respondents who believed that OD-OHCA patients should not be treated differently believed that AHA guidelines recommended differential treatment. Fifty-four percent of all respondents reported that they or their paramedics make different decisions when treating OD-OHCA patients, regardless of protocol. Seventy-eight percent of respondents indicated the use of naloxone during OD-OHCA resuscitation while 12% reported administering naloxone during non-OD OHCA resuscitations.Conclusions: Physicians and non-physicians report perceiving OD-OHCA patients differently than non-OD and making different treatment decisions based on these perceptions. This may result in etiology-oriented resuscitation for OD-OHCA.
Adjusted hypervolemic hemodilution in acute ischemic stroke.
- M Koller,
- P Haenny,
- K Hess,
- D Weniger and
- P Zangger
Stroke Volume 21, Issue 101 October 1990

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We prospectively randomized 47 patients with acute ischemic stroke of the middle cerebral artery of less than 24 hours' duration to either adjusted hypervolemic hemodilution or control treatment and followed them up for 90 days. Rapid hemodilution to a target hematocrit of 30-35% as monitored with bedside determinations was achieved by using infusions of dextran 40, venesections, and infusions of additional crystalloid solution when necessary. There was no difference in the death rate between the two treatment groups. Of these 47 patients, 37 (19 in the hemodilution group and 18 in the control group) could be followed up for the entire study period of 3 months. The relative improvement in neurologic function from day 1 to days 8, 21, and 90 was significantly better in the hemodilution group than in the control group. In accordance, special tests for fine motor control of the paretic arm disclosed better performance in the hemodilution group. The frequency of patients with severe disability was significantly lower in the hemodilution group on days 8 and 21. Plasma viscosity (measured in 11 patients) was not affected by infusions of dextran 40. Vigorous hypervolemic hemodilution in patients with acute ischemic stroke is well tolerated and improves early neurologic outcome with an effect lasting at least 3 months.
Abstract 209: Time Intervals and Rearrest After Out-of-Hospital Cardiac Arrest
- Allison C Koller,
- David D Salcido,
- Clifton W Callaway and
- James J Menegazzi
Circulation Volume 126, Issue suppl_2120 November 2012

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Background: Re-arrest (RA) occurs when a patient loses pulses following return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA), but the exact causes of RA are not fully understood. Time-to-treatment intervals may affect patient outcome and could be a plausible contributor to RA.Objectives: To compare emergency medical services (EMS) time intervals between cases with and without RA. We hypothesized that RA cases will have significantly longer time intervals than no-RA cases.Methods: The Institutional Review Board of the University of Pittsburgh approved this study. Cases of EMS-treated, non-traumatic OHCA from 2006 to 2011 with at least one instance of prehospital ROSC were retrospectively gathered from the Pittsburgh site of the Resuscitation Outcomes Consortium. Prehospital event times were derived from computer assisted dispatch records. We calculated time intervals to the nearest minute, including 911 call to EMS arrival, arrival to first EMS CPR, EMS CPR to ROSC, and 911 call to arrival at the emergency department (ED). RA status was determined from electronic defibrillator downloads and patient care reports. We used logistic regression to examine the association between RA and each time interval while controlling for patient demographic and clinical variables with alpha = 0.05.Results: Two-hundred and thirty-five cases were analyzed, and 79 (34%) cases had an instance of RA. Mean time intervals and patient demographics are in Table 1. The RA group had a significantly higher proportion of males and shocked cases than the non-RA group. Odds ratios for the outcome of RA by time interval are as follows: 911 to arrival: 1.09 (CI: .98 - 1.21, p = 0.10); arrival to CPR: 1.02 (CI: 0.89 - 1.19, p = 0.74); CPR to ROSC: 0.99 (CI: 0.96 - 1.02, p = 0.86); 911 to ED: 0.99 (CI: 0.96 - 1.01, p = 0.35).Conclusion: EMS time intervals for OHCA were not predictive of RA.
Abstract 52: CPR Quality and Outcomes in Resuscitation of Suspected Drug-Related Cardiac Arrests
- Allison C Koller,
- David D Salcido,
- Clifton W Callaway and
- James J Menegazzi
Circulation Volume 126, Issue suppl_2120 November 2012

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Introduction: Cardiac arrest resulting from drug overdose (OD) is a significant public health issue and is the cause of many preventable deaths each year. Little is known about actual resuscitation process parameters of ODs and such arrests are often excluded from out-of-hospital cardiac arrest (OHCA) studies. We sought to investigate the characteristics of emergency medical services (EMS)-treated OHCA cases resulting from suspected OD.Methods: The University of Pittsburgh Institutional Review Board approved this study. Data from EMS-treated non-traumatic OHCAs were obtained from the Pittsburgh site of the Resuscitation Outcomes Consortium, a multi-center clinical research consortium with 10 sites across North America. Cases from 2006-2011 were analyzed. Case definition for OD was naloxone administration or drug overdose indicated on the patient care report. Resuscitation parameters including chest compression fraction, compression rate, and compression depth, shock delivery and the administration of resuscitation drugs were collected and compared between OD and non-OD groups. Demographic and outcome variables including age, sex, EMS- or bystander-witnessed status, return of spontaneous circulation and survival to hospital discharge were also compared by OD status. Resuscitation parameters were compared between groups using logistic regression or t-tests with alpha = 0.05.Results: We identified 180 OD cases and compared them to 2,162 non-OD OHCAs. Both groups were predominantly male (OD: 66%, non-OD: 59%; p = 0.0498). OD OHCAs were on average 20 years younger than non-OD OHCAs (45 vs. 65 years, p < 0.001). OD cases were associated with higher overall CPR fraction than non-OD (66% vs. 63%, p = 0.0158) and survival (19%, vs.11%; OR: 1.82, CI: 1.12 - 2.94, p = 0.015). OD cases were also associated with higher probability of epinephrine (OR: 2.05, CI: 1.33 - 3.15, p < 0.001) and sodium bicarbonate administration (OR: 2.70, CI: 1.98 - 3.68, p < 0.001). Other variables did not differ.Conclusion: Patients with OD-related OHCA were more likely to receive resuscitation drugs, receive higher CPR fraction, and survive than non-OD OHCAs.
Relation Between Repolarization and Refractoriness During Programmed Electrical Stimulation in the Human Right Ventricle : Implications for Ventricular Tachycardia Induction
- Bettina S. Koller,
- Pamela E. Karasik,
- Allen J. Solomon and
- Michael R. Franz
Circulation Volume 91, Issue 91 May 1995

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Background Although programmed electrical stimulation is widely used for provoking sustained ventricular tachycardia (VT), the mechanism by which repetitive extrastimulation evokes VT is still little understood. Specifically, it is not clear why several closely coupled extrastimuli are frequently required to induce VT. Although regularly paced human ventricular myocardium exhibits a near constant relation between myocardial repolarization and refractoriness, the effect of repetitive extrastimulation on the relation between repolarization and excitability in the human heart and its relevance for arrhythmia induction by programmed stimulation are unknown. We hypothesized that the induction of VT by repetitive extrastimulation is facilitated by an altered relation between repolarization and refractoriness, and this leads to disturbances in ventricular impulse propagation, which trigger the onset of VT. Methods and Results Twenty-one patients undergoing routine electrophysiological study were paced from the right ventricular apex and outflow tract endocardium with monophasic action potential–pacing catheters placed at both sites simultaneously. Monophasic action potential durations (APDs) and effective refractory periods (ERPs) were measured simultaneously at each site, during regular stimulation (S1-S1) at 400-ms cycle length and during three consecutive extrastimuli (S2 through S4) at the closest coupling intervals at which all three extrastimuli still resulted in capture. Measurements further included the repolarization level at which the earliest capture occurred, the ratio between ERP and APD, and the propagation time between the pacing and distant recording site. APD and ERP both shortened progressively with each extrastimulus. APD at 90% repolarization decreased from a baseline (S1) of 238.1±19.7 ms by 14.9% at S2, 18.9% at S3, and 22.9% at S4 (P<.0001, S1 versus S4). ERP decreased from 233.1±19.7 ms (S1) to 180.0±41.9 ms (S3) (P<.0001, S1 versus S3). While ERP shortening occurred mainly on the basis of APD shortening, there was an additional factor that contributed to ERP shortening independent of APD shortening. Each consecutive extrastimulus was able to elicit a propagated response at earlier repolarization levels than the previous one: the earliest capture for S2 occurred at 85.5±10.2% of complete repolarization, for S3 at 83.9±10.5%, and for S4 at 78.4±11.2% (P<.05 for S2 versus S3; P<.05 for S3 versus S4; P<.01 for S2 versus S4). This progressive “encroachment” of the earliest capture stimulus onto the preceding repolarization phase (at progressively less repolarized levels) correlated with a progressive delay of impulse propagation between the pacing site and the second recording site: propagation time increased from baseline (S1) by 10.5±1.3% with S2 to 19.0±1.6% with S3 and to 22.5±2.8% with S4 (P<.05, S4 versus S1). VT was induced in 11 of 21 patients. Nine of these had VT induced only when significant encroachment of extrastimuli on the preceding repolarization phase (<81.3±7.0%) and associated conduction slowing (>16.6±1.8%) were present. Conclusions Repetitive extrastimulation not only shortens APD and subsequently ERP but also alters the ERP/APD relation by allowing capture to occur at progressively less complete repolarization levels. This progressive encroachment onto the preceding repolarization phase is associated with impaired impulse propagation and a high incidence of VT induction. This may help explain how repetitive, closely coupled extrastimulation induces ventricular tachycardia in the human heart.
Endothelin and Prostaglandin H₂ Enhance Arteriolar Myogenic Tone in Hypertension
- An Huang and
- Akos Koller
Hypertension Volume 30, Issue 51 November 1997

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Abstract We hypothesized that endothelin in addition to prostaglandin (PG)H₂ may also contribute to the enhanced myogenic tone of skeletal muscle arterioles of spontaneously hypertensive (SH) rats. Changes in the diameter of isolated, cannulated arterioles (≈60 μm) from cremaster muscles of 30-week-old normotensive Wistar Kyoto (WKY) and SH rats were measured as a function of perfusion pressure (20 to 140 mm Hg). Pressure-induced constrictions were significantly enhanced between 60 to 140 mm Hg in arterioles of SH rats compared with those of WKY rats; at 80 and 140 mm Hg the normalized diameter of arterioles (expressed as a percentage of corresponding passive diameter) of SH rats was 11.0% and 15.4% less (P<.05) than that of WKY rats. After inhibition of thromboxane A₂–PGH₂ receptors by SQ 29,548 (10⁻⁶ mol/L), the still enhanced myogenic response of SH arterioles was eliminated by the removal of endothelium or the administration of BQ-123 (10⁻⁷ mol/L), an endothelin A (ET-A) receptor blocker, which also inhibited constrictions to exogenous ET-1 (10⁻¹¹ to 5×10⁻¹⁰ mol/L). ET-1 elicited comparable responses in arterioles of SH and WKY rats. Thus, in SH rats the enhanced arteriolar constriction to increases in intravascular pressure seems to be due to the production of endothelium-derived constrictor factors PGH₂ and endothelin.

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