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Am J Cardiovasc Dis 2016;6(2):55-65 Original Article Arrhythmogenic Right Ventricular Cardiomyopathy - 4 Swedish families with an associated PKP2 c.2146-1G>C variant Anneli Svensson1, Meriam Åström-Aneq2, Kjerstin Ferm Widlund3, Christina Fluur1, Anna Green3, Malin Rehnberg3, Cecilia Gunnarsson3 1Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Swe- den; 2Department of Clinical Physiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; 3Department of Clinical Pathology and Clinical Genetics, and Department of Clinical Experi- mental Medicine, Linköping University, Linköping, SwedenReceived April 22, 2015; Accepted April 30, 2016; Epub May 18, 2016; Published May 30, 2016 Abstract: In this study, the genotype-phenotype correlations in four unrelated families with a PKP2 c.2146-1G>C gene variant were studied. Our primary aim was to determine the carriers that fulfilled the arrhythmogenic right ventricular cardiomyopathy (ARVC) diagnostic criteria of 2010. Our secondary aim was to investigate whether any specific clinical characteristics can be attributed to this particular gene variant. Index patients were assessed using next generation ARVC panel sequencing technique and their family members were assessed by Sanger sequencing targeted at the PKP2 c.2146-1G>C variant. The gene variant carriers were offered a clinical follow-up, with evalua- tion based on the patient's history and a standard set of non-invasive testing. The PKP2 c.2146-1G>C gene variant was found in 23 of 41 patients who underwent the examination. Twelve of the 19 family members showed "possible ARVC". One with "borderline ARVC" and the rest with "definite ARVC" demonstrated re-polarization disturbances, but arrhythmia was uncommon. A lethal event occurred in a 14-year-old boy. In the present study, no definitive genotype- phenotype correlations were found, where the majority of the family members carrying the PKP2 c.2146-1G>C gene variant were diagnosed with "possible ARVC". These individuals should be offered a long-term follow-up since they are frequently symptomless but still at risk for insidious sudden cardiac death due to ventricular arrhythmia.
Keywords: ARVC, heredity, PKP2, sudden cardiac death es of the disease. Therefore, the progression of the disease is still not completely understood. Arrhythmogenic right ventricular cardiomyopa- Although the manifestations of the disease are thy (ARVC) was first clinical y described in adults present mainly in the right ventricle (RV), there in 1982. It is characterized by progressive fibro- is also a left ventricular (LV) involvement, which fatty replacement of the right ventricular myo- has been shown earlier [4, 5].
cardium, creating a substrate for ventricular arrhythmia [1]. Ventricular fibril ation and sud- The heterogeneity of the clinical course in ARVC den cardiac death (SCD) may occur, and the may be related to the involvement of several increased risk is potentiated by physical activi- genes, mechanisms, and variable pathogenicity ty. The prevalence of ARVC is estimated to be of mutations [6]. The causative role of desmo- 1:5000, which probably is an underestimate somal gene mutations is speculative to a cer- [2]. Its diagnosis is based on the presence of tain extent. Impaired desmosomes function major and minor criteria as developed in the under the conditions of mechanical stress, modified Task Force Criteria of 2010 [3]. which is believed to induce detachment of myo- However, the application of these diagnostic cytes from one another, leading to cell death. criteria may be difficult due to the sparsely This injury may be accompanied by an inflam- observed symptoms and signs in the early stag- matory response leading to limited regenera- Unrelated ARVC families with an identical PKP2 variant Figure 1. Pedigree analysis of family B. Circles in the pedigree denote females, squares males. A crossed-over symbol indi- cates that this particular individual has died. The arrow points out the index patient for genetic screening. The ages given in the pedigree are from first contact and/or screening.
Am J Cardiovasc Dis 2016;6(2):55-65 Unrelated ARVC families with an identical PKP2 variant tion of cardiac myocytes, fol owed by its repair was treated with a combination of sotalol and through fibro-fatty replacement mechanism, disopyramide, which could not provoke any resulting in ventricular remodeling. The most arrhythmia, and underwent an invasive electro- commonly mutated ARVC-related gene is PKP2 physiological examination in 1984. In 2000, (10-45%), followed by DSP (10-15%), DSG2 she was presented to the emergency room (ER) (7-10%), and DSC2 (2%). The use of genetic with dizzy spel s. The electrocardiograph (ECG) testing in individuals with clinical manifestation showed ventricular tachycardia originating from of ARVC helps in identifying the causative gene the RV. The ARVC diagnosis was based on the mutation in up to 50% of ARVC families [7-9].
classical criteria that included a positive endo- myocardial biopsy. Shortly after that, the Presymptomatic testing for the identification of patient was implanted with an implantable car- pathogenic mutations known to cause ARVC is dioverter defibril ator (ICD) sented with palpita- important when estimating the risk of the dis- tions due to ventricular premature beats.
ease in asymptomatic family members. How- ever, it may be difficult to manage such asymp- During repeated visits to the outpatient clinic, tomatic carrier individuals. Many mutation car- the ICD registered several episodes of non-sus- riers have a normal life span and continue to be tained ventricular arrhythmias, but no shock asymptomatic throughout their lifetime due to therapy was given by the internal defibril ator. the highly variable penetrance of the genetic There was no history of SCD or arrhythmia in abnormality. Therefore, the assessment of the risk for lethal arrhythmia, e.g., during exercise, has been prioritized [3]. Family B: Here, the index patient is a physical y active male from the South of Sweden. The Thus, the aim of this study was to investigate pedigree analysis is presented in Figure 1. In four Swedish ARVC families where a PKP2 2008, some months before his first medical c.2146-1G>C mutation was previously detect- contact, he noticed chest discomfort while ed so as to determine 1) the extent to which the exercising. The patient was presented to the ER mutation carriers fulfil ed the revised Task on the day after syncope when he had been Force Criteria of 2010, and 2) whether specific playing floorbal . After an extensive workup (see clinical characteristics can be attributed to car- Table 1), he received an ICD the same week. riers of this particular gene variant.
The syncope was believed to be due to ventricu- lar tachycardia. Later on, he was presented Materials and methods with recurrent ventricular tachycardia, which was related to physical activities. The ICD deliv- ered both ATP (Anti-Tachycardia Pacing) and shocks. He has now been forced to limit his ath- In the South-East region of Sweden, we have letic activities and is being treated with a com- performed a systematic clinical fol ow-up of bination of metoprolol and flecainide.
patients and their relatives with ARVC since the late 1980s. The present genetic investigation In this family, we found one case of SCD in a revealed that four unrelated families (Families physical y active 14-year old boy (I I:17 in Figure A, B, C, and D) carried the pathogenic PKP2 1). The death occurred in the same year of diag- c.2146-1G>C gene variant. The family mem- nosis of the index patient. The autopsy showed bers, defined by 1st to 4th-degree relatives of histological signs of ARVC. DNA testing could the index patients, were included in the study. not be performed on this boy, who was a cousin The details of each family are presented below: of the index patient. Family A: In the early 1980s, the physical y- The father (I :9) of the deceased boy showed a active index patient (a female from the South of right bundle branch block (RBBB) in the ECG Sweden presented with palpitations due to ven- report, and a dilated RV on the echocardio- tricular premature beats. In 1982, she had a gram. However, he did not show any clinical cri- cardiac arrest associated with physical exer- terion for ARVC. cise. The mechanism was believed to be ven- tricular tachycardia or primary ventricular fibril- A physical y active brother of the deceased boy lation. Resuscitation started immediately, and (I I:18) had an ICD implanted because of the she showed no physical sequelae. The patient family history. Only one month after the implan- Am J Cardiovasc Dis 2016;6(2):55-65 Unrelated ARVC families with an identical PKP2 variant Table 1. Task Force Criteria, revised of 2010 [3] includes the following parts: Group I: Global or regional dysfunction and structural alterations; Group II: Tissue characterization of wall (biopsies); Group III: Repolarization abnormalities; Group IV: Depolarization/conduction abnormalities; Group V: Arrhytmias; Group VI: Family history (including mutations). The diagnosis of ARVC relies on the demonstration of structural, functional, and electrophysiological abnormalities. Depending on the severity, the changes can fulfill minor or major criteria. Carriership of a known pathogenic mutation fulfills a major criterion in group IV. Definite diagnosis: 2 major or 1 major plus 2 minor or 4 minor cri- teria from different groups. Borderline: 1 major plus 1 minor or 3 minor criteria from different catego- ries. Possible: 1 major or 2 minor criterion from different groups Revised Task Force Criteria, 2010 Patient no/ Age at genetic symptom and Group Group Group Group Group Group Abbreviations: M = Male; F = Female; RV = right ventricular; - = normal results; X = major criteria; I = minor criteria; G = muta- tion positive; NA = not applicable/not performed; * = proband; ? = performed elsewhere and result not known.
tation, the ICD delivered an adequate shock the patient was abnormal with negative T-waves discharge due to fast ventricular tachycardia in V1-V3 present since at least 1981. An echo- associated with pre-syncope. It should also be cardiogram performed in 1998 showed normal noted that the pedigree of this family shows LV function. However, the RV showed minor three cases of leukemia (not marked here) that changes, and a fol ow-up with echo was sug- were of at least two different kinds. gested but was never performed. The present- ing syncopal episode was not considered to be Family C: The index patient, a woman of British caused by arrhythmia, but a comprehensive origin, was shifted to the cardiology ward from evaluation for ARVC was thought to be appropri- the ER in 2012 because of syncope. The ECG of ate, which resulted in the diagnosis of ARVC. Am J Cardiovasc Dis 2016;6(2):55-65 Unrelated ARVC families with an identical PKP2 variant Since the patient showed no further symptoms, exceeding 110 ms in V1-V3, and the presence she did not receive an ICD but was monitored of epsilon wave, defined as a distinct low-ampli- via the outpatient clinic.
tude deflection after the QRS complex.
Genetic testing has not been performed on her A signal-averaged ECG (SAECG) was recorded, children or her brother for various reasons. and band pass was filtered at 40-250 Hz. The There was no history of SCD or arrhythmia in SAECG was considered positive for late poten- this family.
tials when at least one of the three fol owing criteria was fulfil ed: (a) QRS-filtered duration Family D: The index patient was the daughter of >114 ms, (b) low amplitude signal duration >38 a man from Southern Sweden, who died in ms, and (c) the root mean square amplitude of 1992 due to ARVC that caused ventricular the last 40 ms of the QRS <20 uV. The frequen- arrhythmia. Her first clinical screening in 1994 cy and morphology of the ventricular premature showed subtle morphological abnormalities, complexes were assessed both from the rest- but she was not diagnosed with ARVC until ing 12-lead ECG and 24-hour LTER. Ventricular 1996. She had palpitations due to non-sus- tachycardia was defined by three or more con- tained ventricular tachycardia but did not expe- secutive premature ventricular complexes, and rience syncope or pre-syncope. When the echo- if it lasted longer than 30 s, it was defined as cardiography and magnetic resonance imaging sustained ventricular tachycardia.
(MRI) of the patient showed the progression of the abnormalities, an ICD was implanted in the Cardiac imaging index patient in 2010. Telemetry of stored The two-dimensional echocardiographic exami- rhythm strips revealed both non-sustained and nation was performed using a 3.5 MHz or 4 sustained ventricular tachycardia, of which the MHz transducer (Vivid 7 and E9, GE Healthcare, latter was treated with ATP but without shocks. Milwaukee, USA). Images from different stan- In 1994, her brother was also screened for the dard views were recorded. Dimensional and disease, and he has been regularly fol owed-up functional parameters of the RV and LV were since then. After discussions with the patient, analyzed. Cardiac magnetic resonance imaging (CMR) was requested at the discretion of the the subtle progress of echocardiographic attending physician and performed using the abnormalities led to the implantation of a pri- Philips 1.5-T Achieva Nova Dual scanner mary preventive ICD in 2009. Interrogations (Philips Healthcare, Best, the Netherlands). with the patient later revealed non-sustained Left and right ventricular volumes and ejection as well as sustained ventricular tachycardia on fraction were calculated. In most cases, the several occasions that were treated with ATP CMR was performed immediately after echo- but without shocks. He is presently completely cardiography. We have applied the modified free of symptoms.
ARVC criteria of 2010, presented by Marcus et al [3], to all studies.
Genetic analyses The evaluation of patients and relatives involved their detailed medical history and their Genetic sequencing analyses were performed thorough physical examination. A local algo- regarding PKP2, DSP, DSG2, DSC2, JUP, DES, rithm was used for the clinical fol ow-up of TGFB3, and TMEM43.
patients suspected of ARVC. The study was approved by the regional ethical review board DNA extraction, quantification, and quality in Linköping (Decision number M68-09), and informed consent was obtained from each DNA extraction from whole blood samples was performed using either EZ1 (Qiagen) or Prepito (Techtum). DNA concentration and quality were determined using NanoDrop spectrophotome- A standard 12-lead ECG was recorded and ana- ter. Samples with A260/A280 ratios between lyzed with regard to T-wave inversion beyond 1.8 and 2.0, and A260/A230 ratios above 1.5 V1, in the absence of RBBB, QRS-duration were accepted for further sequencing. Am J Cardiovasc Dis 2016;6(2):55-65 Unrelated ARVC families with an identical PKP2 variant Next generation sequencing In family D, 12 relatives were examined; of which 7 showed positive results.
Next Generation Sequencing (NGS) was per- formed using HaloPlex PCR target enrichment Thus, in total, 41 family members were exam- system (Agilent) and MiSeq (Il umina) as ined, and 19 ( 46%) were detected to be muta- described by Greén et al [10]. The ARVC panel probes were generated to cover the exons of the genes DES (CCDS33383.1), DSC2 (CCDS- The 23 subjects with a PKP2 c.2146-1G>C 11892.1, CCDS11893.1), DSG2 (CCDS424- mutation in the heterozygous form underwent 23.1), DSP (CCDS47368.1, CCDS4501.1), JUP clinical examinations as outlined in Table 1. (CCDS11407.1), PKP2 (CCDS31771.1, CCDS8- Two children were excluded from the fol ow-up 731.1), TGFB3 (CCDS9846.1), and TMEM43 program due to their young age, as presented (CCDS2618.1). Library preparation, sequenc- ing, and bioinformatic analyses were carried out as described by Greén et al [10].
Seven of 23 mutation carriers established a definite ARVC diagnosis. This included the index Sanger sequencing patients from the four families. However, since the father of the index patient in family D had Sanger sequencing was performed for all exons died, his genetic analysis could not be per- of PKP2 in the probands according to earlier formed. Four of the mutation carriers are cate- studies performed in our lab [10]. Testing for gorized as "borderline ARVC", and the remain- the c.2146-1G>C gene variant in family mem- ing 12 as "possible ARVC" - in several cases bers was performed using the Sanger sequenc- due to detected genetic abnormality. None of the probands had additional mutations in the remaining ARVC-related genes.
One of the family members with borderline The families A, B, C, and D were selected for ARVC, and others with definite ARVC exhibited this study because the probands had pre- repolarization disturbances on 12-lead ECG, viously been diagnosed with a heterozygous but clinical arrhythmia was uncommon. PKP2 c.2146-1 C>T mutation. No other patho- genic mutation in other ARVC-related genes, Involvement of the LV in ARVC is well document- i.e., DES (CCDS33383.1), DSC2 (CCDS11892.1, ed but is not a part of the diagnostic criteria. In CCDS11893.1), DSG2 (CCDS42423.1), DSP our study, three index patients and one family (CCDS47368.1, CCDS4501.1), JUP (CCDS11- member in family D had LV-dysfunction. 407.1), PKP2 (CCDS31771.1, CCDS8731.1), TGFB3 (CCDS9846.1), TMEM43 (CCDS2618.1), TTN (NM_133432, NM_133437, NM_003319, NM_133378, NM_133379), was found in any The PKP2 c.2146-1G>C mutation detected in of the index patients. The PKP2 c.2146-1G>C the four Swedish families selected for this study result was confirmed by Sanger sequencing. has been described earlier in individuals with a This variant was predicted to be pathogenic by clinical diagnosis of ARVC [8, 11, 12]. However, several bioinformatic tools (Polyphen, Mutation to the best of our knowledge, the present study taster), and the mutation has been reported is the first to report extensive clinical fol ow-up earlier as pathogenic (ARVC/D database).
and genetic testing of 1st to 4th degree relatives with an identical PKP2 c.2146-1G>C mutation In family A, two first-degree relatives were (ascertained through cascade screening of examined, but none of them tested positive for the PKP2 c.2146-1G>C mutation. The diagnostic criteria for ARVC include genetic In family B, 27 relatives were examined; of diagnosis. The progress in molecular genetics which, only 12 relatives showed positive results has facilitated the genetic diagnosis of this potential y lethal disease in asymptomatic fam- ily members. New categories of patients or In family C, no relatives were examined.
more accurately, potential patients, are defined Am J Cardiovasc Dis 2016;6(2):55-65 Unrelated ARVC families with an identical PKP2 variant in accordance with the subtle findings in ECG In the present study, the patients have been and ventricular premature beats rather than screened for mutations in eight genes that full blown arrhythmia or sudden death that have relevance in the prediction of such dis- characterizes those who qualify for a definitive ease, but undoubtedly future studies may ARVC diagnosis. An even larger group consists determine new genes pertaining to ARVC that of those diagnosed with "possible" or "proba- will add to our understanding of the disease. ble" disease through cascade screening, where Marcus et al [18] reported that as many as 48% the mere presence of a mutation means "pos- of people with ARVC showed at least two differ- sible ARVC". This presents a chal enge to the ent mutations. In contrary to these reports, the dissemination of information. The fol ow-up patient population from the South-east region unveils low predictive value since we do not of Sweden exhibited 43 probands that fulfil ed possess the tools that are required for the the ARVC-related Task Force Criteria, and none accurate prediction of the disease develop- of the probands had a known pathogenic muta- ment and arrhythmia predisposition in the indi- tion in more than one of the eight genes investi- vidual mutation carrier. As per the study, the gated (data not shown). It has been described clinical phenotype varied due to the variable earlier that gender is of importance for the penetrance and expressivity. This means that a development of ARVC and arrhythmic symp- clearly pathogenic mutation can have a high toms as well as SCD [19]. The only death due to diagnostic value but may have a low prognostic arrhythmia was observed in the 14-year-old utility. An advanced chal enge lies in distin- boy belonging to family B, who was also the guishing the pathogenicity of a mutation from cousin of the athletic proband. The non-inva- normal genetic variation. sive evaluation did not reveal additional severe The PKP2 c.2146-1G>C variant found in our pathological findings in male mutation carriers study patients is a splice site mutation predict- than in female mutation carriers and thus did ed to activate a cryptic splice acceptor site in not lead to more positive diagnoses in any of intron 12 or, alternatively, another cryptic splice the two sexes.
acceptor site in PKP2 exon 13. Gerull et al [8] could not detect this variant among 500 healthy Earlier studies have indicated that the patients controls, and it was earlier described as patho- with one or more family members with a history genic [11, 12]. Both the bioinformatic tools, of SCD were at an elevated risk [11]. However, Polyphen and Mutation taster, suggested this markers predicting SCD in patients with ARVC variant to be non-tolerable [13, 14].
have not been ful y defined in large prospective studies [20, 21] as such studies are hard to Three families in this study come from different perform in case of rare diseases. Several sub- regions of Sweden, and one family is of British groups of patients with ARVC have an increased origin. This suggests that the mutation is not of risk for SCD or, in those with an ICD, appropri- pure Swedish origin, even though our material ate device intervention. Such patients are of a is too small to be certain. Recent publications lower age and with previous syncope [21]. have claimed that mutations in ARVC-related Patients with two or more disease-causing genes are rather common among healthy popu- mutations as well as patients with LV involve- lations [15]. Kapplinger et al [15] showed that a ment [20, 22-25] are also considered to be at a supposedly pathogenic variant can be found in higher risk. In this study, three index cases and 16% of a normal population. However, they one family member with definite diagnosis had described missense mutations that are less serious than splice site mutations. This empha- sizes the importance of cautiousness when giv- In our study, all the mutation carriers were con- ing missense mutations clinical value, espe- sidered as "possible ARVC" based on the carri- cial y during the screening of first-degree ership alone. In most cases, "borderline ARVC" relatives. It has also been suggested that com- was based on ECG changes with repolarization pound and digenic heterozygosity may be of or depolarization disturbances. Three of the great importance with regard to the severity of first-degree relatives were diagnosed with "defi- the disease in individuals from the same family nite ARVC" with significant arrhythmias, which was confirmed from their ICD report.
Am J Cardiovasc Dis 2016;6(2):55-65 Unrelated ARVC families with an identical PKP2 variant The amount and intensity of physical activity in In conclusion, this is the first study based on each individual in our group are unfortunately genetic cascade screening that demonstrates not known. This is a difficult area to investigate, the variability in the clinical presentation among and we could not determine the exact number individuals with the PKP2 c.2146-1G>C genetic of hours per week or the intensity of activities. variant. We have shown that the vast majority In patient interviews, we found that two of our of healthy family members carrying the muta- probands were regularly engaged in athletic tion were classified as "possible ARVC" using activities before the diagnosis of ARVC. It has the present revised Task Force Criteria of 2010, been shown earlier that athletes have a more and it was based mainly on the mutation carri- structural y severe form of the disease, and this ership alone. No definite genotype-phenotype was also seen in an animal study where athletic correlations were found. However, age and heterozygous plakoglobin-deficient mice devel- physical activity may be of importance for those oped RV dysfunction and arrhythmia [25, 26]. carrying this particular gene variant. Family Human data also revealed that exercise is members with borderline or definite diagnoses associated with a higher degree of disease frequently had ECG disturbances but rarely expression and risk of arrhythmia [27-29]. It is showed any significant signs of arrhythmia. The possible that other genetic factors could also clinical presentation was variable and included be relevant for ARVC. Future studies should one case of potential y lethal arrhythmia, il us- quantify the amount of exercise in every poten- trating the unpredictable course of the disease. tial ARVC patient and also consider providing Our investigation supports the idea that family strong advice against intense exercises in members carrying the PKP2 c.2146-1G>C patients belonging to families with ARVC mutation should be offered long-term fol ow-up since the clinical presentation is variable and frequently symptomless with an apparent risk Of the 41 tested family members, 19 (46%) for insidious SCD from arrhythmia.
were found to be mutation carriers. In a review of 37 families, 9.6% of initial clinical y unaffect- ed subjects developed echocardiographic abnormalities, and almost 50% had symptom- We are thankful to the patients as the study atic ventricular arrhythmias during a mean fol- would not have been possible without their low-up of 8.5 years [30]. The prognosis of ARVC invaluable assistance. We also thank Annelie patients who experience ventricular tachycar- Raschperger for genetic counseling and mak- dia is uncertain. Patients with mild disease and ing contact with the families and Lennart non-sustained ventricular tachycardia appe- Malmqvist and PärHedberg for their help with ared to have a relatively low risk of arrhythmic data col ection. We are also grateful to Jan death. The long-term outcome was worse in Engvall and Eva Nylander for their valuable dis- patients with LV involvement due to arrhythmia cussions and Jon Jonasson for the excel ent and clinical heart failure. In patients with reviewing of the manuscript's content as well advanced disease, ARVC may be difficult to dis- as its language. This work was supported by the tinguish from dilated cardiomyopathy [28]. Medical Research Council of Southeast Sweden Nava et al [30] classified 151 of 365 family and Åke Wiberg Foundation. The funders had members as being affected with ARVC.
no role in the study design, data col ection, analysis, and decision to publish or in the prep- In our study, three family members fulfil ed the aration of the manuscript.
diagnostic criteria for ARVC during the clinical screening. One of them was a middle-aged Disclosure of conflict of interest woman with no clinical symptoms, il ustrating the fact that signs of disease may develop slow- ly, if at al . Another was a physical y-active boy, who based on ECG changes and family history Address correspondence to: Dr. Cecilia Gunnarsson, (brother with SCD) received an ICD. One month Department of Clinical Pathology and Clinical later, he had an appropriate shock therapy for Genetics, Linköping University Hospital, S-581 85 fast ventricular tachycardia. This could suggest Linköping, Sweden. Tel: +46 10 103 6551; Fax: that age and physical activity may be of impor- +46 10 1032145; E-mail: tance in this particular genetic mutation study.
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DIFLUCAN® (Fluconazole Tablets) (Fluconazole Injection - for intravenous infusion only) (Fluconazole for Oral Suspension) DESCRIPTION DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration, as a powder for oral suspension and as a sterile solution for intravenous use in glass and in Viaflex® Plus plastic containers. Fluconazole is designated chemically as 2,4-difluoro-α,α1-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with an empirical formula of C13H12F2N6O and molecular weight 306.3. The

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Relationship Between Selective Cyclooxygenase-2 Inhibitors and Acute Myocardial Infarction in Older Adults Daniel H. Solomon, MD, MPH; Sebastian Schneeweiss, MD, ScD; Robert J. Glynn, PhD, ScD; Yuka Kiyota, MD, MPH; Raisa Levin, MSc; Helen Mogun, MSc; Jerry Avorn, MD Background—Although cyclooxygenase-2 inhibitors (coxibs) were developed to cause less gastrointestinal hemorrhage