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Cardiovascular Health in Turner Syndrome: A Scientific Statement From the American Heart Association
- Michael Silberbach,
- Jolien W. Roos-Hesselink,
- Niels H. Andersen,
- Alan C. Braverman,
- Nicole Brown,
- R. Thomas Collins,
- Julie De Backer,
- Kim A. Eagle,
- Loren F. Hiratzka,
- Walter H. Johnson,
- Daniella Kadian-Dodov,
- Leo Lopez,
- Kristian H. Mortensen,
- Siddharth K. Prakash,
- Elizabeth V. Ratchford,
- Arwa Saidi,
- Iris van Hagen,
- Luciana T. Young and
Circulation: Genomic and Precision Medicine Volume 11, Issue 101 October 2018

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Girls and women with Turner syndrome face a lifelong struggle with both congenital heart disease and acquired cardiovascular conditions. Bicuspid aortic valve is common, and many have left-sided heart obstructive disease of varying severity, from hypoplastic left-sided heart syndrome to minimal aortic stenosis or coarctation of the aorta. Significant enlargement of the thoracic aorta may progress to catastrophic aortic dissection and rupture. It is becoming increasingly apparent that a variety of other cardiovascular conditions, including early-onset hypertension, ischemic heart disease, and stroke, are the major factors reducing the life span of those with Turner syndrome. The presentations and management of cardiovascular conditions in Turner syndrome differ significantly from the general population. Therefore, an international working group reviewed the available evidence regarding the diagnosis and treatment of cardiovascular diseases in Turner syndrome. It is recognized that the suggestions for clinical practice stated here are only the beginning of a process that must also involve the establishment of quality indicators, structures and processes for implementation, and outcome studies.
Investigating the Genetic Architecture of the PR Interval Using Clinical Phenotypes
- Jonathan D. Mosley,
- M. Benjamin Shoemaker,
- Quinn S. Wells,
- Dawood Darbar,
- Christian M. Shaffer,
- Todd L. Edwards,
- Lisa Bastarache,
- Catherine A. McCarty,
- Will Thompson,
- Christopher G. Chute,
- Gail P. Jarvik,
- David R. Crosslin,
- Eric B. Larson,
- Iftikhar J. Kullo,
- Jennifer A. Pacheco,
- Peggy L. Peissig,
- Murray H. Brilliant,
- James G. Linneman,
- John S. Witte,
- Josh C. Denny and
- Dan M. Roden
Circulation: Cardiovascular Genetics Volume 10, Issue 21 April 2017

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Background—One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability.Methods and Results—We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities; n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics; n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=−0.88; P=0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47; P=0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change; 95% confidence interval, 0.83–0.95; P=0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=−0.03 [0.16]).Conclusions—The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity.
P‐Wave Amplitude and PR Changes in Patients With Inappropriate Sinus Tachycardia: Findings Supportive of a Central Mechanism
- Michael E. Field,
- Paolo Donateo,
- Nicola Bottoni,
- Matteo Iori,
- Michele Brignole,
- Ryan T. Kipp,
- Douglas E. Kopp,
- Miguel A. Leal,
- Lee L. Eckhardt,
- Jennifer M. Wright,
- Kathleen E. Walsh,
- Richard L. Page and
- Mohamed H. Hamdan
Journal of the American Heart Association Volume 7, Issue 9

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BackgroundThe mechanism of inappropriate sinus tachycardia (IST) remains incompletely understood.Methods and ResultsWe prospectively compared 3 patient groups: 11 patients with IST (IST Group), 9 control patients administered isoproterenol (Isuprel Group), and 15 patients with cristae terminalis atrial tachycardia (AT Group). P‐wave amplitude in lead II and PR interval were measured at a lower and higher heart rate (HR1 and HR2, respectively). P‐wave amplitude increased significantly with the increase in HR in the IST Group (0.16±0.07 mV at HR1=97±12 beats per minute versus 0.21±0.08 mV at HR2=135±21 beats per minute, P=0.001). The average increase in P‐wave amplitude in the IST Group was similar to the Isuprel Group (P=0.26). PR interval significantly shortened with the increases in HR in the IST Group (146±15 ms at HR1 versus 128±16 ms at HR2, P<0.001). A similar decrease in the PR interval was noted in the Isuprel Group (P=0.6). In contrast, patients in the atrial tachycardia Group experienced PR lengthening during atrial tachycardia when compared with baseline normal sinus rhythm (153±25 ms at HR1=78±17 beats per minute versus 179±29 ms at HR2=140±28 beats per minute, P<0.01).ConclusionsWe have shown that HR increases in patients with IST were associated with an increase in P‐wave amplitude in lead II and PR shortening similar to what is seen in healthy controls following isoproterenol infusion. The increase in P‐wave amplitude and absence of PR lengthening in IST support an extrinsic mechanism consistent with a state of sympatho‐excitation with cephalic shift in sinus node activation and enhanced atrioventricular nodal conduction.
The PR Interval is a Heritable Quantitative Trait with Evidence for Linkage to Chromosome 4 in a Genome-Wide Scan: the Framingham Heart Study
Circulation Volume 103, Issue suppl_11 March 2001

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P19Introduction: Delayed atrioventricular conduction on the electrocardiogram (ECG), manifested by PR interval prolongation, can progress to heart block. Both heart-rate slowing drugs and environmental factors may lead to PR interval prolongation; however, the heritability of the PR interval has not been studied in the general population and genetic variants in the regulation of PR duration have not been characterized. Methods: We examined the heritability of the PR interval and we tested for evidence of linkage of the PR interval to chromosomal regions in a large population-based cohort. 12-lead ECGs were obtained routinely in adult Framingham Heart Study participants as part of the clinic examination. The PR interval was measured using digital calipers. We conducted a 10 cM genome wide scan in 328 extended families (1688 genotyped subjects, 2257 phenotyped subjects, 2028 phenotyped sibling pairs). Variance component methods were used to estimate heritability and to perform linkage analysis. Results: The PR interval (adjusted for age and RR-interval) was heritable [h² 0.32 (95% confidence interval 0.26-0.37)]. The highest multipoint LOD score for the adjusted PR interval was found on chromosome 4 (LOD score was 2.16 at 123 cM). The next highest LOD score was 1.88 (chromosome 17 at 59 cM). Conclusion: These results suggest there are influential genetic regions contributing to variability in PR interval in the general population. Defining genetic determinants of PR duration may provide insights into the pathophysiology of heart block and may help identify persons with a high susceptibility to drug-induced heart block.
Alternating QRS Morphologies and PR Intervals in a Desperately Ill Woman
- Blake G. Smith,
- Jonathan Kalehoff and
- G. Neal Kay
Circulation Volume 140, Issue 927 August 2019

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Abstract 19011: Is It Necessary to Pre-Stent Right Ventricular Outflow Tract Prior to Percutaneous Pulmonary Valve Implantation in All Patients?
- Daniel R Turner,
- Nikhil M Thatte,
- Pooja Gupta,
- Sanjeev Aggarwal,
- Harinder Singh,
- Thomas J Forbes and
- Srinath T Gowda
Circulation Volume 128, Issue suppl_2226 November 2013

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Background: Bare metal stent placement prior to Melody valve insertion (MVI) is common. We analyzed acute and short-term outcome following MVI with and without pre-stenting (PS) the conduit.Methods: This is a retrospective single-center study. Patients (pts) were divided into two groups, with and without PS. The conduits were divided into homograft (HG) and valve with supporting ring (VSR) groups.Results: From June 2010 to May 2013, 49 pts underwent MVI. Conduits were HG in 24 (49%) and VSR in 25 (51%). Primary indication was stenosis in 20 and regurgitation in 29 pts. PS was performed in 16 (33%) vs. no PS in 33 (67%) pts. Major procedural complication included conduit (HG) rupture requiring covered stent placement in 1 pt. In the entire cohort, baseline peak RVOT gradient at cath was 27.14 ± 14.55 vs. 14.82 ± 9.83 mmHg post-implantation (p < 0.0001). Baseline pulmonary regurgitation (PR) was moderate to severe in 36/40 (90%). Only 2 had moderate or greater PR post-implant. Freedom from Melody stent fracture was 95.83% (in 23/24) at 9.85 months and freedom from melody valve dysfunction was 93.7% (45/48) at median 16.5 months of follow up. The pre- and immediate post-implantation RVOT gradient (12.81 ± 14.14 mmHg vs. 12.09 ± 11.88 mmHg, p=0.852) and degree of PR were not significantly different between the PS and no PS group. At follow-up, Melody valve dysfunction and freedom from stent fracture were not significantly different between the groups. In pts with VSR, RVOT gradient post-implant was not significantly different between the PS and no PS groups; however pts with no PS showed a trend towards lower post-implant RVOT gradient (20.38 ± 10.72 vs. 12.76 ± 10.23, p=0.059). There were no VSR pts with stent fracture and only 1 had moderate PR on follow-up.Conclusion: We demonstrated excellent procedural and short term success in all pts despite absence of pre-stenting in the majority of pts. Patients with VSR and no pre-stenting had better or comparable hemodynamic results and no stent fractures at short term follow-up. Pts with VSR may not require pre-stenting prior to MVI.
Stroke Genetics: Turning Discoveries into Clinical Applications
Stroke Volume 52, Issue 91 September 2021

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The field of medical and population genetics in stroke is moving at a rapid pace and has led to unanticipated opportunities for discovery and clinical applications. Genome-wide association studies have highlighted the role of specific pathways relevant to etiologically defined subtypes of stroke and to stroke as a whole. They have further offered starting points for the exploration of novel pathways and pharmacological strategies in experimental systems. Mendelian randomization studies continue to provide insights in the causal relationships between exposures and outcomes and have become a useful tool for predicting the efficacy and side effects of drugs. Additional applications that have emerged from recent discoveries include risk prediction based on polygenic risk scores and pharmacogenomics. Among the topics currently moving into focus is the genetics of stroke outcome. While still at its infancy, this field is expected to boost the development of neuroprotective agents. We provide a brief overview on recent progress in these areas.
Abstract 17817: Does a Repaired Type A Dissection Turn into a Medical Type B Dissection? Lessons From IRAD
- Kevin K Varughese,
- Magnus Larsen,
- Kevin M Harris,
- Mark D Peterson,
- Rossella Fattori,
- Stuart Hutchison,
- Gilbert R Upchurch,
- Marek P Ehrlich,
- Reed E Pyeritz,
- Daniel G Montgomery,
- Santi Trimarchi,
- Christoph A Nienaber,
- Eric M Isselbacher,
- Kim A Eagle and
- Truls Myrmel
Circulation Volume 128, Issue suppl_2226 November 2013

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Background: Following complete arch replacement, many Type A acute aortic dissection (TAAAD) patients exhibit a residual false lumen in their descending and/or abdominal aorta. Medically-managed Type B (TBAAD) patients with descending thoracic involvement resemble these post-operative TAAAD cases. We sought to examine whether outcomes differed between these two groups with anatomically-similar remaining dissection flaps.Methods: We analyzed 1017 patients enrolled in the International Registry of Acute Aortic Dissection. Of these, 241 (23.7%) had TAAAD with complete arch replacement; 776 (76.3%) were medically-managed TBAAD patients with most proximal extension in the descending aorta.Results: TAAAD patients were younger (58.0 ± 13.2 v. 64.9 ± 13.7 years, p<0.001) and more often male (80.1% v. 60.3%, p<0.001). Of the 418 (45.4%) with intimal tear identified, the tear was located in the descending aorta and therefore not resected in 4.1% of TAAAD patients, versus 39.9% of their TBAAD counterparts. Additionally, Type A patients had larger descending aortic diameters on presentation (5.0 ± 6.4 v. 4.8 ± 5.3 cm, p<0.001) but smaller abdominal aortic dimensions (2.4 ± 0.6 v. 3.0 ± 1.0 cm, p<0.001). In-hospital mortality was higher in the TAAAD cohort (24.9% v. 8.9%, p<0.001). However, a Kaplan-Meier analysis of five-year mortality showed no significant difference between groups.Conclusions: The increased in-hospital mortality of Type A patients likely reflects the higher risks and more complicated clinical course associated with surgical repair. No long-term differences in mortality were seen between groups, despite the younger age of Type A patients and lower prevalence of a prevailing intimal tear. Further studies are warranted to determine whether aortic growth or other post-discharge outcomes differ between cohorts.
Unravelling Atrioventricular Block Risk in Inflammatory Diseases: Systemic Inflammation Acutely Delays Atrioventricular Conduction via a Cytokine‐Mediated Inhibition of Connexin43 Expression
Journal of the American Heart Association Volume 10, Issue 212 November 2021

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BackgroundRecent data suggest that systemic inflammation can negatively affect atrioventricular conduction, regardless of acute cardiac injury. Indeed, gap‐junctions containing connexin43 coupling cardiomyocytes and inflammation‐related cells (macrophages) are increasingly recognized as important factors regulating the conduction in the atrioventricular node. The aim of this study was to evaluate the acute impact of systemic inflammatory activation on atrioventricular conduction, and elucidate underlying mechanisms.Methods and ResultsWe analyzed: (1) the PR‐interval in patients with inflammatory diseases of different origins during active phase and recovery, and its association with inflammatory markers; (2) the existing correlation between connexin43 expression in the cardiac tissue and peripheral blood mononuclear cells (PBMC), and the changes occurring in patients with inflammatory diseases over time; (3) the acute effects of interleukin(IL)‐6 on atrioventricular conduction in an in vivo animal model, and on connexin43 expression in vitro. In patients with elevated C‐reactive protein levels, atrioventricular conduction indices are increased, but promptly normalized in association with inflammatory markers reduction, particularly IL‐6. In these subjects, connexin43 expression in PBMC, which is correlative of that measured in the cardiac tissue, inversely associated with IL‐6 changes. Moreover, direct IL‐6 administration increased atrioventricular conduction indices in vivo in a guinea pig model, and IL‐6 incubation in both cardiomyocytes and macrophages in culture, significantly reduced connexin43 proteins expression.ConclusionsThe data evidence that systemic inflammation can acutely worsen atrioventricular conduction, and that IL‐6‐induced down‐regulation of cardiac connexin43 is a mechanistic pathway putatively involved in the process. Though reversible, these alterations could significantly increase the risk of severe atrioventricular blocks during active inflammatory processes.
Associations Between Ambient Particle Radioactivity and Blood Pressure: The NAS (Normative Aging Study)
- Marguerite M. Nyhan,
- Brent A. Coull,
- Annelise J. Blomberg,
- Carol L.Z. Vieira,
- Eric Garshick,
- Abdulaziz Aba,
- Pantel Vokonas,
- Diane R. Gold,
- Joel Schwartz and
- Petros Koutrakis
Journal of the American Heart Association Volume 7, Issue 6

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BackgroundThe cardiovascular effects of low‐level environmental radiation exposures are poorly understood. Although particulate matter (PM) has been linked to cardiovascular morbidity and mortality, and elevated blood pressure (BP), the properties promoting its toxicity remain uncertain. Addressing a knowledge gap, we evaluated whether BP increased with higher exposures to radioactive components of ambient PM, herein referred to as particle radioactivity (PR).Methods and ResultsWe performed a repeated‐measures analysis of 852 men to examine associations between PR exposure and BP using mixed‐effects regression models. As a surrogate for PR, we used gross β activity, measured by the US Environmental Protection Agency's radiation monitoring network. Higher PR exposure was associated with increases in both diastolic BP and systolic BP, for exposures from 1 to 28 days. An interquartile range increase in 28‐day PR exposure was associated with a 2.95–mm Hg increase in diastolic BP (95% confidence interval, 2.25–3.66; P<0.001) and a 3.94–mm Hg increase in systolic BP (95% confidence interval, 2.62–5.27; P<0.001). For models including both PR and PM ≤2.5 µm, the PR‐BP associations remained stable and significant. For models including PR and black carbon or PR and particle number, the PR‐BP associations were attenuated; however, they remained significant for many exposure durations.ConclusionsThis is the first study to demonstrate the potential adverse effects of PR on both systolic and diastolic BPs. These were independent and similar in magnitude to those of PM ≤2.5 µm, black carbon, and particle number. Understanding the effects of particle‐bound radionuclide exposures on BP may have important implications for environmental and public health policy.
Increased Airway Pressure and Simulated Branch Pulmonary Artery Stenosis Increase Pulmonary Regurgitation After Repair of Tetralogy of Fallot: Real-Time Analysis With a Conductance Catheter Technique
- Rajiv R. Chaturvedi,
- Philip J. Kilner,
- Paul A. White,
- Andrew Bishop,
- Richard Szwarc and
- Andrew N. Redington
Circulation Volume 95, Issue 34 February 1997

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Background Pulmonary regurgitation (PR) is an important determinant of outcome after repair of tetralogy of Fallot. Baseline PR was measured by magnetic resonance (MR) phase velocity mapping and from real-time right ventricular pressure-volume loops with a conductance catheter. Subsequently, the impact of two loading maneuvers (increased airway pressure, simulated branch pulmonary artery stenosis) on PR was assessed by the conductance catheter method.Methods and Results Thirteen patients, 3 to 35 years after tetralogy of Fallot repair or pulmonary valvotomy, had PR measured by MR phase velocity mapping while breathing spontaneously. During catheterization under general anesthesia, PR was estimated from right ventricular pressure-volume loops generated by conductance and microtip pressure catheters. The effect of increased airway pressure (continuous positive airway pressure, 20 cm H₂O; n=12) and simulated branch pulmonary artery stenosis (transient balloon occlusion of a branch pulmonary artery, n=7) was measured. Basal PR fraction derived by MR and from right ventricular pressure-volume loops had a correlation coefficient of .76 and mean of differences of 2.0±18.2% (95% limits of agreement). Increased airway pressure increased PR (16.3±11.4% to 25.7±17.3%, P<.01). Simulated branch pulmonary artery stenosis increased right ventricular end-systolic pressure (69.1±21.4 to 78.7±23.1 mm Hg, P<.05) and PR (27.5±11.3% to 36.9±12.8%, P<.05).Conclusions There was reasonable agreement between MR phase velocity–derived PR fraction and that obtained from right ventricular pressure-volume loops generated by use of conductance and pressure-microtip catheters. Exacerbation of PR by increased airway pressure and branch pulmonary stenosis may be relevant to the acute postoperative and long-term management, respectively, of patients after repair of tetralogy of Fallot.
From Mouse to Whale: A Universal Scaling Relation for the PR Interval of the Electrocardiogram of Mammals
- Sami F. Noujaim,
- Elena Lucca,
- Viviana Muñoz,
- Dharmendra Persaud,
- Omer Berenfeld,
- Frits L. Meijler and
- José Jalife
Circulation Volume 110, Issue 182 November 2004

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Background— On the ECG, the PR interval measures the time taken by an electrical impulse generated in the sinoatrial node to propagate from atria to ventricles. From mouse to whale, the PR interval increases ≈10¹, whereas body mass (BM) augments ≈10⁶. Scaling of many biological processes (eg, metabolic rate, life span, aortic diameter) is described by the allometric equation Y=Y₀ · BM^b, where Y is the biological process and b is the scaling exponent that is an integer multiple of 1/4. Hierarchical branching networks have been proposed to be the underlying mechanism for the 1/4 power allometric law.Methods and Results— We first derived analytically the allometric equation for the PR interval. We assumed that the heart behaves as a set of “fractal-like” networks that tend to minimize propagation time across the conducting system while ensuring a hemodynamically optimal atrioventricular activation sequence. Our derivation yielded the relationship PR∝BM^1/4. We subsequently obtained previously published values of PR interval, heart rate, and BM of 541 mammals representing 33 species. Double-logarithmic analysis demonstrates that PR interval increases as heart rate decreases, and both variables relate to BM following the 1/4 power law. Most important, the best fit for PR versus BM is described by the equation PR=53 · BM^0.24. Hence, the empirically determined exponent (0.24) is close to 1/4, as predicted.Conclusions— We have demonstrated that the PR interval of mammals scales as the 1/4 power of the BM, following the universal law for allometric scaling to ensure an optimal atrioventricular activation sequence.
Lipoprotein(a) Particle Production as a Determinant of Plasma Lipoprotein(a) Concentration Across Varying Apolipoprotein(a) Isoform Sizes and Background Cholesterol‐Lowering Therapy
- Dick C. Chan,
- Gerald F. Watts,
- Blai Coll,
- Scott M. Wasserman,
- Santica M. Marcovina and
- P. Hugh R. Barrett
Journal of the American Heart Association Volume 8, Issue 72 April 2019

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BackgroundElevated lipoprotein(a) (Lp(a)), a low‐density lipoprotein‐like particle bound to the polymorphic apolipoprotein(a) (apo(a)), may be causal for cardiovascular disease. However, the metabolism of Lp(a) in humans is poorly understood.Methods and ResultsWe investigated the kinetics of Lp(a)‐apo(a) and low‐density lipoprotein‐apoB‐100 in 63 normolipidemic men. The fractional catabolic rate (FCR) and production rate PR) were studied. Plasma apo(a) concentration was significantly and inversely associated with apo(a) isoform size (r=−0.536, P<0.001) and apo(a) FCR (r=−0.363, P<0.01), and positively with apo(a) PR (r=0.877, P<0.001). There were no significant associations between the FCRs of apo(a) and low‐density lipoprotein‐apoB‐100. Subjects with smaller apo(a) isoform sizes (≤22 kringle IV repeats) had significantly higher apo(a) PR (P<0.05) and lower apo(a) FCR (P<0.01) than those with larger sizes. Plasma apo(a) concentration was significantly associated with apo(a) PR (r=0.930, P<0.001), but not with FCR (r=−0.012, P>0.05) in subjects with smaller apo(a) isoform size. In contrast, both apo(a) PR and FCR were significantly associated with plasma apo(a) concentrations (r=0.744 and −0.389, respectively, P<0.05) in subjects with larger isoforms. In multiple regression analysis, apo(a) PR and apo(a) isoform size were significant predictors of plasma apo(a) concentration independent of low‐density lipoprotein‐apoB‐100 FCR and background therapy with atorvastatin and evolocumab.ConclusionsIn normolipidemic men, the plasma Lp(a) concentration is predominantly determined by the rate of production of Lp(a) particles, irrespective of apo(a) isoform size and background therapy with a statin and a proprotein convertase subtilisin‐kexin type 9 inhibitor. Our findings underscore the importance of therapeutic targeting of the hepatic synthesis and secretion of Lp(a) particles. Lp(a) particle catabolism may only play a modest role in determining Lp(a) concentration in subjects with larger apo(a) isoform size.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT02189837.
Abstract 2998: Aortic Root Dilatation in Children with Systemic Hypertension
- Monesha Gupta-Malhotra,
- Archana Dave,
- Brian Sturhan and
- Ronald Portman
Circulation Volume 114, Issue suppl_1831 October 2006

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Background: Systemic hypertension (HTN) is associated with target organ damage and aortic root dilatation has been described in adults with HTN with a prevalence of 4–10%. The aim of the study was to determine the prevalence of aortic root dilatation in children with uncomplicated HTN.Methods: Children aged 1 to 19 years (mean 12.4 years, n = 143, males 77) previously untreated for the HTN underwent a pediatric echocardiogram for evaluation of end-organ damage and size of their aorta per standard protocol. Infants and preterm children were excluded from the study. HTN was defined as blood pressure above the 95th percentile based on the Fourth Working Group criteria confirmed by 24-hour ambulatory BP monitoring. The aorta was measured by a transthoracic echocardiogram in the parasternal long-axis view at the sinus of Valsalva, supra-aortic ridge and the ascending aorta. The dilation was based on the normative data (Roman MJ, et al) available in children for the given body surface area.Results: Aortic root dilatation was detected in 3 (2.1%, all females, mean age 16.7 years) of the 143 consecutive children evaluated. The ascending aorta in the 3 patients measured 30–35mm, the supra-aortic ridge was 27–30mm and the sinus of Valsalva was 31–33 mm in diameter. All 3 children with aortic root dilatation had a normal aortic valve apparatus without any stenosis as determined by an echocardiogram. Trace aortic insufficiency was seen in 6 (4.2%) children with HTN of which one had a dilated aortic root. None had a positive family history of Marfan syndrome, aneurysm or sudden death. One child had Turner syndrome and the other 2 were non-syndromic females.Conclusions: Aortic root dilatation was seen in 2.1% children with HTN. Children with HTN who undergo evaluation for end-organ damage by an echocardiogram may also benefit from routine measurements of their aortic root. Aortic root dilatation has been reported in children with Turners syndrome without the presence of hypertension. In the other 2 girls, the cause of the dilatation remains unknown at present. Controlling the blood pressure may be beneficial in preventing further stress on the dilated aortas.
Endothelin-Converting Enzyme : Ultrastructural Localization and Its Recycling From the Cell Surface
- Kay Barnes,
- Carolyn Brown and
- Anthony J. Turner
Hypertension Volume 31, Issue 11 January 1998

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Abstract—The potent vasoconstrictor endothelin-1 (ET-1) is secreted constitutively by endothelial cells and has been implicated in the pathophysiology of several cardiovascular diseases. It is generated from its inactive intermediate, big ET-1, through the action of endothelin-converting enzyme (ECE). Using several complementary techniques, we have demonstrated that ECE is present at the cell surface and on intracellular vesicles and that it recycles from the cell surface in endothelial cells. This is the first ultrastructural localization of ECE in lung and the first time big ET-1 and ECE have been colocalized by immunogold in a vesicular population, 50 to 100 nm in diameter. In addition, by double immunogold staining of ultrathin cryosections, we have localized ECE together with angiotensin-converting enzyme on the luminal membrane of endothelial cells. With cell surface biotinylation of a transformed rat endothelial cell line and of human umbilical vein endothelial cells, we have confirmed the presence of ECE on the plasma membrane. After treatment of endothelial cells with chloroquine, ECE and trans-Golgi network 38 protein were shown by immunofluorescence staining to localize to the same intracellular compartment.
TRL, IDL, and LDL Apolipoprotein B-100 and HDL Apolipoprotein A-I Kinetics as a Function of Age and Menopausal Status
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 25, Issue 81 August 2005

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Objective— To determine mechanisms contributing to the altered lipoprotein profile associated with aging and menopause, apolipoprotein B-100 (apoB-100) and apoA-I kinetic behavior was assessed.Methods and Results— Eight premenopausal (25±3 years) and 16 postmenopausal (65±6 years) women consumed for 6 weeks a standardized Western diet, at the end of which a primed-constant infusion of deuterated leucine was administered in the fed state to determine the kinetic behavior of triglyceride-rich lipoprotein (TRL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB-100, and high-density lipoprotein (HDL) apoA-I. Data were fit to a multicompartmental model using SAAM II to calculate fractional catabolic rate (FCR) and production rate (PR). Total cholesterol, LDL cholesterol (LDL-C), TRL-C, and triglyceride levels were higher (50%, 55%, 130%, and 232%, respectively) in the postmenopausal compared with the premenopausal women, whereas HDL-C levels were similar. Plasma TRL, IDL, and LDL-apoB-100 levels and pool sizes (PS) were significantly higher in the postmenopausal than premenopausal women. These differences were accounted for by lower TRL, IDL, and LDL apoB-100 FCR (P<0.05), with no difference in PR. There was no significant difference between groups in HDL-C levels or apoA-I kinetic parameters. Plasma TRL-C concentrations were negatively correlated with TRL apoB-100 FCR (r=−0.46; P<0.05) and positively correlated with PR (r=0.62; P<0.01). Plasma LDL-C concentrations were negatively correlated with LDL apoB-100 FCR (r=−0.70; P<0.001) but not PR.Conclusions— The mechanism for the increase in TRL and LDL apoB-100 PS observed in the postmenopausal women was determined predominantly by decreased TRL and LDL catabolism rather than increased production. No differences were observed in HDL apoA-I kinetics between groups.Postmenopausal women have higher VLDL-C and LDL-C levels compared with premenopausal women. To determine mechanism, apolipoprotein kinetic studies were conducted in 24 women. Postmenopausal women had higher TRL and LDL pool sizes, which were accounted for by lower TRL and LDL apoB-100 catabolic rates. No significant difference in plasma HDL-C levels or apoA-I kinetics parameters were observed between groups.
Measurement of Local Cerebral Blood Flow in the Unanesthetized Rat Using a Hydrogen Clearance Method
- JOSEPH L. HAINING,
- M. Don TURNER and
- RALPH M. PANTALL
Circulation Research Volume 23, Issue 21 August 1968

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The hydrogen clearance method for measuring local tissue blood flow was adapted for use in the brain of the unanesthetized rat by means of a stainless steel plate screw mounted in the skull as the reference electrode instead of a calomel electrode. Blood flow was measured at 3 sites in the brains of 5 three-month-old rats over a 6-week period. Blood flow in the frontal cortex and the cerebellum for all the animals averaged 79 ± 22 (SD) and 81 ± 25 ml/min/100 g tissue, respectively. The other site, supposedly the hippocampus, exhibited a two-component clearance curve in most cases. The initial rapid component was of questionable validity; the second slow component averaged 110 ± 23 ml/min/100 g. Autopsy revealed that the hippocampal electrode was actually positioned in more than one type of tissue or proximal to an interspace.Hypoxia (Po₂ = 50 mm Hg) and hypercapnia (produced by inhalation of 10% CO₂) increased the clearance rates two- to four-fold. The rate of local blood flow and its variability were affected by the state of the animal; anesthesia (sodium pentobarbital) decreased the rate of blood flow as anticipated, and markedly reduced the variation in rate seen in the conscious state.
Systems Genetics Approaches in Rat Identify Novel Genes and Gene Networks Associated With Cardiac Conduction
- Michiel E. Adriaens,
- Elisabeth M. Lodder,
- Aida Moreno‐Moral,
- Jan Šilhavý,
- Matthias Heinig,
- Charlotte Glinge,
- Charly Belterman,
- Rianne Wolswinkel,
- Enrico Petretto,
- Michal Pravenec,
- Carol Ann Remme and
- Connie R. Bezzina
Journal of the American Heart Association Volume 7, Issue 216 November 2018

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BackgroundElectrocardiographic (ECG) parameters are regarded as intermediate phenotypes of cardiac arrhythmias. Insight into the genetic underpinnings of these parameters is expected to contribute to the understanding of cardiac arrhythmia mechanisms. Here we used HXB/BXH recombinant inbred rat strains to uncover genetic loci and candidate genes modulating ECG parameters.Methods and ResultsRR interval, PR interval, QRS duration, and QTc interval were measured from ECGs obtained in 6 male rats from each of the 29 available HXB/BXH recombinant inbred strains. Genes at loci displaying significant quantitative trait loci (QTL) effects were prioritized by assessing the presence of protein‐altering variants, and by assessment of cis expression QTL (eQTL) effects and correlation of transcript abundance to the respective trait in the heart. Cardiac RNA‐seq data were additionally used to generate gene co‐expression networks. QTL analysis of ECG parameters identified 2 QTL for PR interval, respectively, on chromosomes 10 and 17. At the chromosome 10 QTL, cis‐eQTL effects were identified for Acbd4, Cd300lg, Fam171a2, and Arhgap27; the transcript abundance in the heart of these 4 genes was correlated with PR interval. At the chromosome 17 QTL, a cis‐eQTL was uncovered for Nhlrc1 candidate gene; the transcript abundance of this gene was also correlated with PR interval. Co‐expression analysis furthermore identified 50 gene networks, 6 of which were correlated with PR interval or QRS duration, both parameters of cardiac conduction.ConclusionsThese newly identified genetic loci and gene networks associated with the ECG parameters of cardiac conduction provide a starting point for future studies with the potential of identifying novel mechanisms underlying cardiac electrical function.
Human Apolipoprotein (Apo) B-48 and ApoB-100 Kinetics With Stable Isotopes
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 19, Issue 121 December 1999

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Abstract—The kinetics of apolipoprotein (apo) B-100 and apoB-48 within triglyceride-rich lipoproteins (TRLs) and of apoB-100 within IDL and LDL were examined with a primed-constant infusion of (5,5,5-²H₃) leucine in the fed state (hourly feeding) in 19 subjects after consumption of an average American diet (36% fat). Lipoproteins were isolated by ultracentrifugation and apolipoproteins by SDS gels, and isotope enrichment was assessed by gas chromatography/mass spectrometry. Kinetic parameters were calculated by multicompartmental modeling of the data with SAAM II. The pool sizes (PS) of TRL apoB-48, VLDL apoB-100, and LDL apoB-100 were 17±10, 273±167, and 3325±1146 mg, respectively. There was a trend toward a faster fractional catabolic rate (FCR) for VLDL apoB-100 than for TRL apoB-48 (6.73±3.48 versus 5.02±2.07 pools/d, respectively, P=0.06). The mean FCRs for IDL and LDL apoB-100 were 10.07±7.28 and 0.27±0.08 pools/d, respectively. The mean production rate (PR) of TRL apoB-48 was 6.5% of VLDL apoB-100 (1.3±0.90 versus 20.06±6.53 mg · kg⁻¹ · d⁻¹, P<0.0001). TRL apoB-48 PS was correlated with apoB-48 PR (r=0.780, P<0.0001) but not FCR (r=−0.1810, P=0.458). VLDL apoB-100 PS was correlated with both PR (r=0.713, P=0.0006) and FCR (r=−0.692, P=0.001) of VLDL apoB-100 and by apoB-48 PR (r=0.728, P=0.0004). LDL apoB-100 PS was correlated with FCR (r=−0.549, P=0.015). These data indicate that (1) the FCRs of TRL apoB-48 and VLDL apoB-100 are similar in the fed state, (2) TRL apoB-48 PS is correlated with TRL apoB-48 PR, (3) VLDL apoB-100 PS is correlated with both PR and FCR of VLDL apoB-100 and PR of TRL apoB-48, and (4) LDL apoB-100 PS is correlated with LDL FCR.
The cardiac effects of d- and l-disopyramide in normal subjects: a noninvasive study.
- C Pollick,
- K M Giacomini,
- T F Blaschke,
- W L Nelson,
- K Turner-Tamiyasu,
- V Briskin and
- R L Popp
Circulation Volume 66, Issue 21 August 1982

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Commercially available disopyramide is a racemic mixture of equal parts of dextrorotatory (d-) and levorotatory (l-) optical isomers. We studied the cardiac effects of i.v. administration of each isomer and the racemic mixture (dl-) in six normal males by digitized echocardiography, systolic time intervals and ECG. Both isomers and the racemic mixture produced equally marked dose-dependent negative inotropic effects (28.1 +/- 11.8% mean maximal reduction in fractional shortening of left ventricular dimension) and diastolic effects (28.6 +/- 24.1% mean maximal reduction in peak left ventricular filling rate). However, only the d-isomer prolonged QTc duration (by 13.6 +/- 5.2% at maximum, p less than 0.001 vs l-isomer). We conclude that disopyramide, in the doses used, produces marked adverse effects on left ventricle systolic and diastolic function in normal subjects independent of optical rotation. The production of these effects by the l-isomer without affecting QTc duration suggests different subcellular mechanisms for the myocardial depressant effects and some of the electrophysiologic effects of disopyramide.

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