Beta-blockade for patients undergoing vascular surgery.
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Adrenergic beta-Antagonists↗
Biomedical subjects
D M Gilligan
Publications and source records attributed to D M Gilligan.
Frequency of anticoagulation for atrial fibrillation and reasons for its non-use at a Veterans Affairs medical center.
Randomized clinical trials have led to guidelines for anticoagulation in atrial fibrillation (AF). However, it is unclear how successfully these guidelines are being implemented in clinical practice and there is concern that anticoagulation is underused. Therefore, we examined the rate of anticoagulation in 998 patients with AF who attended a Veterans Affairs Medical Center over a 2-year period. Warfarin was prescribed for 504 patients (51%) and not prescribed for 494 patients (49%). Of these 494 patients, 446 had sufficient data for further assessment. Warfarin was judged not indicated in 200 because AF was transient or lone. Warfarin was indicated in 246 patients, 63% having > or =3 risk factors for thromboembolism. However, 184 of these patients also had at least 1 contraindication to anticoagulation. Thus, warfarin was prescribed to 67% of patients with AF in whom anticoagulation was indicated and to 89% of such patients in whom it was indicated and who had no contraindications. However, 25% of AF patients with strong indications for anticoagulation had concomitant contraindications, which precluded its use. We conclude that the use of warfarin for AF in this setting is higher than previously reported and approaching ideal levels. However, there remains a large, problematic subgroup of patients with AF in whom indications for and contra-indications to anticoagulation coexist.
Aged↗
The mouse adducin gene family: alternative splicing and chromosomal localization.
Mouse cDNA sequences encoding alpha, beta, and gamma adducins were cloned from a mouse reticulocyte cDNA library. The purified clones contain alternatively spliced exons from all three adducin genes. In the case of alpha and beta, the inclusion of the alternatively spliced exons results in truncated polypeptide isoforms (called alpha-2 and beta-2). The mouse predicted amino acid sequences are compared with published rat and human sequences. For completion of this comparison, cDNA encoding the rat beta-1 carboxy terminus was cloned by PCR. The carboxy terminal region containing MARCKS homology, calmodulin-binding region-2, and spectrin-actin-binding site, is conserved among alpha-1, beta-1, and gamma-1 isoforms in mouse, rat, and humans. We also report here the localization of the gene encoding gamma adducin (Add3) to murine Chr 19, in a region that shows conserved synteny with human Chr 10.
Alternative Splicing↗
Dual-chamber pacing in hypertrophic cardiomyopathy.
This review focuses on recent developments in the field of pacing in hypertrophic cardiomyopathy (HCM). Regarding mechanisms of action, recent data indicates that pacing acts by inducing dysynchronous left ventricular activation, thus reducing contractility and increasing end-systolic volume. Following several positive uncontrolled studies, three randomized crossover trials, with a total of approximately 140 patients, have now confirmed that gradients are on average halved with pacing but the reduction in symptoms has been modest and maximum exercise capacity has not been improved. These studies have identified a placebo effect from pacemaker implantation in HCM and have questioned the efficacy of pacing as a symptomatic therapy for HCM. There is probably a subgroup of patients with HCM who respond to permanent dual-chamber pacing but their precise identification is not yet clear. Permanent pacing should continue to be considered as one option in the management of the patient with drug refractory, symptomatic obstructive HCM.
Cardiac Pacing, Artificial↗
Catheter ablation of ventricular tachycardia in patients with structural heart disease using cooled radiofrequency energy: results of a prospective multicenter study. Cooled RF Multi Center Investigators Group.
OBJECTIVES: The purpose of this multicenter study was to evaluate the safety and efficacy of a radiofrequency (RF) catheter ablation system with internal saline irrigation. BACKGROUND: Catheter ablation of ventricular tachycardia (VT) associated with structural heart disease is more difficult than ablation of idiopathic VT. The larger size of responsible reentrant circuits contributes to the difficulty in achieving an adequate ablation lesion with conventional techniques. Recently, cooling of the ablation electrode by saline irrigation has been shown to increase RF lesion size. METHODS: The patient population included 146 patients who participated in the Cooled RF Ablation System clinical trial and underwent an attempt at ablation of VT occurring in the presence of structural heart disease. The duration of follow-up was 243 +/- 153 days. RESULTS: Catheter ablation was acutely successful, as defined by elimination of all mappable VTs, in 106 patients (75%). In 59 patients (41%), no VT of any type was inducible after ablation. Twelve patients (8%) experienced a major complication. After catheter ablation, 66 patients (46%) developed one or more episodes of a sustained ventricular arrhythmia. CONCLUSIONS: The results of this study demonstrate that catheter ablation of all mappable forms of sustained VT can be performed with high initial success and a moderate incidence of major complications (8%).
Adult↗
The acute effects of biatrial pacing on atrial depolarization and repolarization.
Permanent biatrial and/or multisite atrial pacing may prevent atrial fibrillation (AF), but the effects on atrial electrophysiology remain incompletely understood. Acute biatrial pacing was studied in 20 patients with and 28 without (controls) a history of atrial fibrillation and/or flutter. Twelve-lead electrocardiograms were recorded during pacing from the high right atrium (RA), from the distal coronary sinus (LA), and biatrial pacing. P wave duration was measured in each lead and the difference between maximum and minimum P duration was termed P wave dispersion. Effective refractory periods (ERPs) were measured during each pacing mode. The dispersion of P wave duration was 35 +/- 14 ms in controls and 40 +/- 29 ms in AF patients (P = 0.17). Compared to RA pacing, LA pacing shortened P duration in controls (127 +/- 18 to 107 +/- 16 ms, P < 0.05) and biatrial pacing markedly shortened P duration in controls (127 +/- 18 to 93 +/- 14 ms, P < 0.05) and AF patients (114 +/- 43 to 97 +/- 21 ms, P < 0.05). P wave dispersion was unaffected. In controls, the LA ERP was longer than the RA ERP. This phenomenon was not present in AF patients, whose LA ERP was shorter than that of controls. Biatrial pacing had no effect on atrial ERPs or the dispersion of atrial refractoriness. In conclusion, acute biatrial pacing does not affect atrial repolarization but it does cause a marked shortening of global biatrial depolarization. Distal coronary sinus pacing produces a shorter P wave than RA pacing. There is substantial dispersion in the surface P wave of the electrocardiogram, the significance of which awaits further study.
Atrial Fibrillation↗
Diagnostic utility of mechanical, pharmacological and orthostatic stimulation of the carotid sinus in patients with unexplained syncope.
OBJECTIVES: The purpose of the present study was to systematically evaluate the diagnostic utility of mechanical, pharmacological and orthostatic stimulation of the carotid sinus in a consecutive series of patients with recurrent unexplained syncope. BACKGROUND: Carotid sinus hypersensitivity (CSH) is an infrequently recognized cause of recurrent unexplained syncope usually diagnosed by carotid sinus massage (CSM) in the supine position. The diagnostic utility of systematic assessment of mechanical, pharmacological and orthostatic stimulation of the carotid sinus has not been clearly established. METHODS: Eighty consecutive patients (63 +/- 12 years) with a history of recurrent unexplained syncope (mean episodes: 6 +/- 3); 30 age-matched controls (65 +/- 14 years) and 16 patients (59 +/- 12 years) with syncope not related to CSH were studied. Pharmacological stimulation of the carotid sinus was achieved by randomly administering bolus injections of nitroprusside and phenylephrine. Mechanical stimulation of the carotid sinus was performed by CSM applied for 5 s in the supine position and after 2 min at 60 degrees. A 60 degree low-dose isoproterenol head-up tilt test (HUTT) was also performed for a total duration of 30 min. RESULTS: Carotid sinus hypersensitivity was elicited by CSM in the supine position in seven (8.7%) patients, two (6.6%) controls and one (6.3%) patient with syncope unrelated to CSH, compared with 48 (60%) patients, two (6.6%) controls and one (6.3%) syncope unrelated to CSH patient after 60 degree HUTT, increasing the diagnostic yield by 51%. Baroreceptor gain was significantly reduced in the CSH group. Head-up tilt test was positive in 12 (25%) patients with CSH, two (6.6%) controls and two (12%) with documented syncope but not positive in any of the patients in which syncope remained unexplained. Diagnostic accuracy was enhanced by 38% (31% supine vs. 69% upright) when CSM was performed at 60 degrees. CONCLUSIONS: CSH was documented in 68% of patients, 8.7% in the supine position and 60% in the upright position. Sensitivity was increased by 51%, and diagnostic accuracy was enhanced by 38% by performing CSM in the upright position. Decreased baroreceptor gain was documented and may play a role in the pathophysiology of CSH.
Aged↗
Targeted disruption of the beta adducin gene (Add2) causes red blood cell spherocytosis in mice.
Adducins are a family of cytoskeleton proteins encoded by three genes (alpha, beta, gamma). In a comprehensive assay of gene expression, we show the ubiquitous expression of alpha- and gamma-adducins in contrast to the restricted expression of beta-adducin. beta-adducin is expressed at high levels in brain and hematopoietic tissues (bone marrow in humans, spleen in mice). To elucidate adducin's role in vivo, we created beta-adducin null mice by gene targeting, deleting exons 9-13. A 55-kDa chimeric polypeptide is produced from the first eight exons of beta-adducin and part of the neo cassette in spleen but is not detected in peripheral RBCs or brain. beta-adducin null RBCs are osmotically fragile, spherocytic, and dehydrated compared with the wild type, resembling RBCs from patients with hereditary spherocytosis. The lack of beta-adducin in RBCs leads to decreased membrane incorporation of alpha-adducin (30% of normal) and unexpectedly promotes a 5-fold increase in gamma-adducin incorporation into the RBC membrane skeleton. This study demonstrates adducin's importance to RBC membrane stability in vivo.
Anemia↗
Exclusion of the stomatin, alpha-adducin and beta-adducin loci in a large kindred with dehydrated hereditary stomatocytosis.
Defects in stomatin, alpha-adducin, and beta-adducin have been implicated in erythrocyte disorders of cation permeability. We performed linkage analysis of the genetic loci for these proteins in a large kindred with xerocytosis (dehydrated hereditary stomatocytosis). Using polymerase chain reaction-based genotyping techniques, all three loci are excluded as disease gene candidates.
Alleles↗
Induction of ventricular fibrillation by T wave shocks: observations from monophasic action potential recordings.
INTRODUCTION: Shocks given during the vulnerable period of cardiac repolarization may induce ventricular fibrillation (VF). However, the relationship of the vulnerable period and the monophasic action potential (MAP) has not yet been reported in humans. The purpose of this study was, therefore, to determine how the monophasic action potential recorded from the right ventricle correlates with inducibility of VF using T wave shocks during ventricular pacing. METHODS: Eleven patients undergoing implantable cardioverter defibrillator (ICD) implantation had a MAP catheter positioned in the right ventricle (RV). The local monophasic action potential duration at 90% repolarization (MAP90) duration was measured during pacing at 400 ms. VF induction was attempted by pacing at 400 ms for 10 cycles and then giving a 1.0 joule monophasic T wave shock at varying coupling intervals (CI) to the last paced stimulus. The maximum and minimum CI that induced VF were determined and mapped in relation to the MAP90 recording. RESULTS: The average paced MAP duration was 275 +/- 20 ms. The minimum and maximum CI to induce VF were 255 +/- 24 ms and 325 +/- 36 ms respectively. This ranged from 93% to 118% of the MAP90 duration but because of delay in conduction time to the MAP catheter, shocks that induced ventricular fibrillation occurred between 74% and 99% of local repolarization time. CONCLUSION: VF is inducible with low energy T wave shocks falling during the last 25% of the right ventricular MAP90 recording. This corresponds with VF initiation during phase III repolarization.
Action Potentials↗
Steroid eluting high impedance pacing leads decrease short and long-term current drain: results from a multicenter clinical trial. CapSure Z investigators.
Pacemaker lead technology has changed considerably over the past decades. The widespread use of low polarization highly porous electrodes and steroid elution electrodes has resulted in low chronic pacing thresholds, as well as a decrease in the incidence of exit block. Efforts to develop pacing leads with high impedance might theoretically lead to lower lead current drain, which is a component of battery capacity. Pulse generator longevity can be increased without sacrificing pacemaker capabilities if pacing current drain can be decreased. Decreasing the size of the stimulation electrode results in increased pacing impedance, and if pacing thresholds are unchanged, a decreased current drain is predicted by Ohm's law (I = V/R). There is limited data available on the pacing characteristics of large numbers of patients with high impedance leads, despite their recent general availability and increasing widespread use. This multicenter, controlled trial examined the differences in performance between standard steroid-eluting pacing leads in the atrium (Medtronic model 5524) and ventricle (Medtronic model 5024), and new high impedance steroid-eluting pacing leads in the atrium (Medtronic model 5534) and ventricle (Medtronic model 5034). Measurements of bipolar pacing thresholds at 2.5 V, pacing impedance, and sensing thresholds were determined within 24 hours of pacemaker implantation, and at 0.5, 1, 3, 6 and 12 months after pacemaker implantation in 609 patients. Pacing and sensing thresholds were similar for the control and high impedance leads at all times except for a slightly larger R wave with the high impedance leads at implantation and 12 months. The mean impedance of the high impedance pacing leads in the atrium and ventricle at 12 months was 992 +/- 175 and 1,080 +/- 220 omega, compared to 522 +/- 69 and 600 +/- 89 omega for the standard pacing leads in the atrium and ventricle (P < or = 0.001 for the high impedance leads compared to standard leads in each chamber). The mean atrial lead current (measured at 2.5 V) at 12 months was 2.6 +/- 0.5 mA with the high impedance lead, and 4.9 +/- 0.7 mA with the standard lead in the atrium (P < or = 0.001). In the ventricle, the mean lead current at 12 months was 2.4 +/- 0.4 mA with the high impedance pacing lead and 4.3 +/- 0.6 mA with the standard lead (P < or = 0.001). High impedance leads are associated with lower lead current drain than standard pacing leads in the atrium and ventricle for up to 1 year. No clinically important differences in sensing characteristics was noted with the high impedance leads in the atrium or ventricle compared to standard pacing leads. High impedance leads may result in increased pulse generator longevity.
Aged↗
Optimal cardiac pacing after heart transplantation.
The transplanted heart is characterized physiologically by autonomic denervation, chronotropic incompetence, intermittent episodes of allograft rejection, and frequently by diastolic dysfunction. Sinus node dysfunction resulting in bradycardia is common in the early postoperative period following standard orthotopic cardiac transplantation. Bradycardia tends to remit spontaneously but there are no factors that accurately identify patients who will need long-term pacing. Patients in whom bradycardia persists beyond the second postoperative week despite treatment with theophylline require permanent pacemaker implantation. It has been observed that chronotropic incompetence and diastolic dysfunction are important determinants of exercise capacity following heart transplantation. Pacing that restores chronotropic competence improves exercise capacity, confirming the importance of impaired heart rate response. As in other settings, pacing that preserves atrioventricular (AV) synchrony results in increased cardiac output. For these reasons when pacing is necessary we recommend the DDDR mode (AAIR if intact AV nodal conduction is present) so that the 30%-50% of patients who remain pacemaker-dependent long-term obtain maximal benefit from their transplant.
Animals↗
Symptomatic hypertrophic obstructive cardiomyopathy: the role of dual-chamber pacing.
BACKGROUND AND PURPOSE: The management of symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM) has traditionally consisted of beta blockers and calcium channel blockers. Surgical treatment has been employed for operable patients who became refractory to medical therapy. However, associated complications, mortality rate, and recurrence of functional limitations have shifted the focus toward alternative therapy modalities. Recently, permanent dual-chamber (DDD) pacemaker has been introduced as an alternative treatment option. PATIENTS AND METHODS: This study comprises clinical, angiographic, echocardiographic, and electrophysiologic data obtained at a single center on 10 symptomatic patients with HOCM who received a DDD pacemaker after medical therapy failed to relieve symptoms. Presenting symptoms were exertional dyspnea and chest pain (60%), syncope (20%), and presyncope (20%). These symptoms were documented for 8.9+/-7.1 years before pacemaker implantation. All patients were in New York Heart Association functional class III or IV before pacemaker therapy. RESULTS: Placement of a permanent DDD pacemaker decreased the left ventricular outflow tract gradient from 83+/-44 mm Hg (range: 35-180 mm Hg) to 47.1+/-25.3 mm Hg (range: 10-75 mm Hg) in these patients. Within 1 to 30 months, follow-up found that the functional status of eight out of the 10 patients had improved to New York Heart Association class 0 or I. CONCLUSION: In selected patients with symptomatic HOCM who fail to respond to medical therapy, DDD pacemaker may offer a nonsurgical alternative treatment option. Large-scale multicenter, prospective, randomized trials are needed to establish the role of this modality in the treatment of hypertrophic obstructive cardiomyopathy.
Activities of Daily Living↗
Effect of atherosclerosis on endothelium-dependent inhibition of platelet activation in humans.
BACKGROUND: We investigated whether luminal release of nitric oxide (NO) contributes to inhibition of platelet activation and whether these effects are reduced in patients with atherosclerosis. METHODS AND RESULTS: Femoral blood flow velocity and ex vivo whole blood platelet aggregation by impedance aggregometry were measured in femoral venous blood during femoral arterial infusion of acetylcholine (ACh; 30 microg/min) in 30 patients, 19 of whom had angiographic atherosclerosis. Measurements were repeated with sodium nitroprusside (40 microg/min), L-arginine (160 micromol/min), and N(G)-monomethyl-L-arginine (L-NMMA; 16 micromol/min). There was significant inhibition of collagen-induced platelet aggregation with ACh (45+/-9.5% lower, P<0.001), and this inhibition was greater in patients without atherosclerosis (68.7+/-10.4% reduction) than in those with atherosclerosis (32.5+/-8.1%, P=0.04). The magnitude of inhibition correlated with vasodilation with ACh, indicating an association between the smooth muscle and antiplatelet effects of endothelium-dependent stimulation. Neither L-NMMA nor sodium nitroprusside altered platelet aggregation. L-Arginine inhibited platelet aggregation equally in vitro (34+/-8% reduction, P<0.01) and in vivo (37+/-13% reduction, P<0.01). CONCLUSIONS: Stimulation of NO release into the vascular lumen with ACh inhibits platelet aggregation, an effect that is attenuated in patients with atherosclerosis and endothelial dysfunction. Basal NO release does not appear to contribute to platelet passivation in vivo. L-Arginine inhibited platelet aggregation by its direct action on platelets. These findings provide a pathophysiological basis for the observed increase in thrombotic events in atherosclerosis. Use of L-arginine and other strategies to improve endothelial NO activity may impact favorably on thrombotic events in atherosclerosis.
Acetylcholine↗
Utilization of an 86 bp exon generates a novel adducin isoform (beta 4) lacking the MARCKS homology domain.
A novel isoform of beta-adducin has been amplified and characterized from a human bone marrow cDNA library (GenBank #U43959). This isoform arises from the insertion of an 86 bp alternatively spliced and previously unrecognized exon (now termed exon 15) within codon 581 of the human red blood cell beta-adducin sequence. This results in an insertion of 28 novel amino acids. The remainder of the red cell beta-adducin mRNA is then translated in a different reading frame, adding an additional 35 novel amino acids prior to the stop codon. This new isoform, thus, replaces beta 1-adducin sequence after residue 580 with a total of 63 new amino acids. Sequences from genomic clones of the human beta-adducin gene show that this alternate exon is flanked by splice consensus sequences and is appropriately located in the genomic map between exons encoding up-stream and down-stream sequences, thus defining a new exon. The COOH-terminus of this new isoform, which we designate beta 4, lacks a 22 amino acid lysine-rich sequence common to both the human red cell alpha- and beta-adducin subunits and homologous to a highly conserved region in MARCKS, a filamentous actin-cross linking protein regulated by protein kinase C and calcium/calmodulin. beta 4-adducin preserves a previously identified calmodulin binding domain. PCR analysis indicates that this new beta-adducin isoform is expressed in fetal brain and liver, bone marrow, and NT-2 (neuroepithelial) cells, but is not detected in several other tissues. We anticipate that this new beta 4 isoform of beta-adducin will display unique and tissue-specific functional properties.
Alternative Splicing↗
Intravenous amiodarone for acute heart rate control in the critically ill patient with atrial tachyarrhythmias.
Control of heart rate in critically ill patients who develop atrial fibrillation or atrial flutter can be difficult. Amiodarone may be an alternative agent for heart rate control if conventional measures are ineffective. We retrospectively studied intensive care unit patients (n = 38) who received intravenous amiodarone for heart rate control in the setting of hemodynamically destabilizing atrial tachyarrhythmias resistant to conventional heart rate control measures. Atrial fibrillation was present in 33 patients and atrial flutter in 5 patients. Onset of rapid heart rate (mean 149 +/- 13 beats/min) was associated with a decrease in systolic blood pressure of 20 +/- 5 mm Hg (p <0.05). Intravenous diltiazem (n = 34), esmolol (n = 4), or digoxin (n = 24) had no effect on heart rate, while reducing systolic blood pressure by 6 +/- 4 mm Hg (p <0.05). The infusion of amiodarone (242 +/- 137 mg over 1 hour) was associated with a decrease in heart rate by 37 +/- 8 beats/min and an increase in systolic blood pressure of 24 +/- 6 mm Hg. Both of these changes were significantly improved (p <0.05) from onset of rapid heart rate or during conventional therapy. Beneficial changes were also noted in pulmonary artery occlusive pressure and cardiac output. There were no adverse effects secondary to amiodarone therapy. Intravenous amiodarone is efficacious and hemodynamically well tolerated in the acute control of heart rote in critically ill patients who develop atrial tachyarrhythmias with rapid ventricular response refractory to conventional treatment. Cardiac electrophysiologic consultation should be obtained before using intravenous amiodarone for this purpose.
Aged↗
Genetic fine mapping of the Miyoshi myopathy locus and exclusion of eight candidate genes.
Miyoshi myopathy (MM) is an early adult-onset, autosomal recessive disorder characterized by weakness and muscular atrophy starting in the distal muscles. The disease locus has been previously mapped by linkage analysis to chromosome 2p using the microsatellite marker D2S291. Initial haplotype analysis of markers in families from three different origins (North American, Japanese, and Tunisian) suggested that the MM gene is located in a 4-cM region flanked by markers D2S292 on the telomeric side and D2S286 on the centromeric side. To delineate critical recombination events revealing a more refined localization of the MM gene, we have determined the pattern of segregation of 12 marker loci in two consanguineous families of Tunisian origin. In this study we have: (1) detected recombination events with the disease locus in one family, placing the MM gene most likely between markers D2S443 (CHLC.GGAA4D07.1876) and D2S2109; (2) generated a yeast artificial chromosome contig that spans approximately 3.8 megabases and extends from marker D2S358 to marker D2S286; (3) physically mapped 21 polymorphic markers, 5 genes, 3 STSs, and 1 EST within this contig; (4) detected and mapped a new polymorphism within this interval, allowing us to further reduce the MM locus to a 360-kilobase segment; (5) mapped the gene for the cytoskeletal protein beta-adducin within the MM candidate region, failing to find a consistent pattern of mutation of this gene in our MM patients; (6) excluded seven other candidate myopathy genes from the Miyoshi locus.
Calmodulin-Binding Proteins↗
Suppression of inducible ventricular tachycardia by ibutilide in patients with coronary artery disease. Ibutilide Investigators.
BACKGROUND: Recent studies suggest that class III antiarrhythmic agents may have enhanced efficacy in the treatment of ventricular tachycardia. This study describes the first clinical assessment of the new class III agent ibutilide to suppress inducible monomorphic ventricular tachycardia (VT) in human beings. METHODS AND RESULTS: Fifty-five patients with coronary artery disease and inducible sustained monomorphic VT at baseline received either low (0.005 mg/kg + 0.001 mg/kg, load and maintenance infusion, respectively), middle (0.01 mg/kg + 0.002 mg/kg), or high dose (0.02 mg/kg + 0.004 mg/kg) infusions of ibutilide followed by repeat programmed ventricular stimulation. The mean age of the study group was 65.5 +/- 9.5 years and mean left ventricular ejection fraction was 36% +/- 11%. Of 48 evaluable patients, 21 (44%) were rendered noninducible after ibutilide, with no difference in efficacy among the three dosing groups (p = 0.83). Ventricular effective refractory periods, QTc interval, and ventricular monophasic action potential duration were prolonged over baseline at all tested cycle lengths. The QTc and action potential prolongation were dose related. Serious drug-related adverse reactions included sustained polymorphic VT in two patients (3.6%), spontaneous monomorphic VT in one patient (1.8%), heart block in one patient (1.8%), and hypotension in one patient (1.8%). CONCLUSIONS: Ibutilide prolongs ventricular repolarization in human beings and demonstrates efficacy in suppressing inducible monomorphic VT. Significant cardiovascular side effects occurred in 12.7% of patients.
Aged↗