Longitudinal Evaluation of Visual Function Impairments in Early and Intermediate Age-Related Macular Degeneration Patients.

Purpose: To evaluate visual function (VF) changes in early and intermediate age-related macular degeneration (eAMD and iAMD) over 24 months. Design: Prospective, observational natural history study. Participants: Participants were enrolled at the Duke Eye Center. Methods: A total of 101 subjects (33 with eAMD, 47 with iAMD, and 21 normal controls) were recruited. Visual function (VF) tests included best-corrected visual acuity (BCVA), low- luminance visual acuity (LLVA), microperimetry (MP), cone contrast tests (CCTs), and dark adaptation (DA). Mixed-effect model repeated measures based on absolute values and change from baseline identified VF tests differentiating AMD from controls and revealing longitudinal VF decline when controlling for covariates (baseline value, age, coronary artery disease, dry eye, and phakic status). Nine AMD genetic risk variants, combinations of these (genetic burden score), reticular pseudodrusen (RPD), and hyperreflective foci (HRF) were tested as predictors of diagnosis and VF performance. Main Outcome Measures: Longitudinal changes in VF metrics over 24 months. Results: A total of 70 subjects completed the 2-year visit (22 with eAMD, 31 with iAMD, and 17 controls). Percent reduced threshold (PRT) on MP and CCT red significantly distinguished iAMD versus controls after 12 and 24 months, respectively. Cone contrast test red, PRT, and absolute threshold (AT) on MP showed significant longitudinal deterioration of VF in iAMD versus baseline at 12 months and onward, however, with a reduced rate of worsening. The DA data confirmed a preexisting functional deficit in iAMD at baseline and revealed an increasing proportion of poorly performing iAMD subjects in DA over the study period. None of the other VF measures showed consistent significant changes among the normal, early, and intermediate groups or over time. The genetic burden score was significantly associated with AMD diagnosis (relative risk for iAMD = 1.64, P < 0.01) and DA (r = 0.42, P = 0.00005). Reticular pseudodrusen and HRF showed moderate associations with DA and weak to moderate associations with MP variables. Conclusions: In iAMD, MP variables, CCT red, and DA revealed slow and nonlinear functional decline over 24 months. A structure-function relationship in eAMD and iAMD stages was demonstrated among HRF, RPD, and DA, possibly modified by genetic risk factors. These structural and functional features represent potential end points for clinical trials in iAMD.

Genetic Variation in LPA, Calcific Aortic Valve Stenosis in Patients Undergoing Cardiac Surgery, and Familial Risk of Aortic Valve Microcalcification.

Importance: Genetic variants at the LPA locus are associated with both calcific aortic valve stenosis (CAVS) and coronary artery disease (CAD). Whether these variants are associated with CAVS in patients with CAD vs those without CAD is unknown. Objective: To study the associations of LPA variants with CAVS in a cohort of patients undergoing heart surgery and LPA with CAVS in patients with CAD vs those without CAD and to determine whether first-degree relatives of patients with CAVS and high lipoprotein(a) (Lp[a]) levels showed evidence of aortic valve microcalcification. Design, Setting, and Participants: This genetic association study included patients undergoing cardiac surgery from the Genome-Wide Association Study on Calcific Aortic Valve Stenosis in Quebec (QUEBEC-CAVS) study and patients with CAD, patients without CAD, and control participants from 6 genetic association studies: the UK Biobank, the European Prospective Investigation of Cancer (EPIC)-Norfolk, and Genetic Epidemiology Research on Aging (GERA) studies and 3 French cohorts. In addition, a family study included first-degree relatives of patients with CAVS. Data were collected from January 1993 to September 2018, and analysis was completed from September 2017 to September 2018. Exposures: Case-control studies. Main Outcomes and Measures: Presence of CAVS according to a weighted genetic risk score based on 3 common Lp(a)-raising variants and aortic valve microcalcification, defined as the mean tissue to background ratio of 1.25 or more, measured by fluorine 18-labeled sodium fluoride positron emission tomography/computed tomography. Results: This study included 1009 individuals undergoing cardiac surgery and 1017 control participants in the QUEBEC-CAVS cohort; 3258 individuals with CAVS and CAD, 41 100 controls with CAD, 2069 individuals with CAVS without CAD, and 380 075 control participants without CAD in the UK Biobank, EPIC-Norfolk, and GERA studies and 3 French cohorts combined; and 33 first-degree relatives of 17 patients with CAVS and high Lp(a) levels (≥60 mg/dL) and 23 control participants with normal Lp(a) levels (<60 mg/dL). In the QUEBEC-CAVS study, each SD increase of the genetic risk score was associated with a higher risk of CAVS (odds ratio [OR], 1.35 [95% CI, 1.10-1.66]; P = .003). Each SD increase of the genetic risk score was associated with a higher risk of CAVS in patients with CAD (OR, 1.30 [95% CI, 1.20-1.42]; P < .001) and without CAD (OR, 1.33 [95% CI, 1.14-1.55]; P < .001). The percentage of individuals with a tissue to background ratio of 1.25 or more or CAVS was higher in first-degree relatives of patients with CAVS and high Lp(a) (16 of 33 [49%]) than control participants (3 of 23 [13%]; P = .006). Conclusions and Relevance: In this study, a genetically elevated Lp(a) level was associated with CAVS independently of the presence of CAD. These findings support further research on the potential usefulness of Lp(a) cascade screening in CAVS.

Atypical Presentation of Aspergillus Mediastinitis Infection in a Heart Transplant Patient: the Importance of Combined Medical and Surgical Treatment.

Aspergillus fumigatus is an opportunistic fungus that mainly affects immunocompromised patients. Due to significant immunosuppressive therapy, patients who undergo orthotopic heart transplant have an increased risk of infection. Aspergillosis is the most common fungal infection in orthotopic heart transplant recipients (70%) and usually presents as invasive aspergillosis, which has a rapidly progressive course and is highly fatal. In heart transplant patients with invasive aspergillosis, overall mortality may range from 53% to 78%. Aspergillus mediastinitis infection is somewhat rare in orthotopic heart transplant recipients, with only 6 reported cases. Treatment may require early surgical drainage and antifungal therapy. We present the case of a 50-year-old man who developed Aspergillus mediastinitis 1 year after heart transplant surgery. This case illustrates the diagnostic challenge of an atypical presentation of Aspergillus mediastinitis and the importance of multiple drainage procedures in refractory disease, combined with long-term antifungal therapy.

Lipoprotein(a), Oxidized Phospholipids, and Aortic Valve Microcalcification Assessed by 18F-Sodium Fluoride Positron Emission Tomography and Computed Tomography.

BACKGROUND: Lipoprotein(a) (Lp[a]) is the preferential lipoprotein carrier of oxidized phospholipids (OxPLs) and a well-established genetic risk factor for calcific aortic valve stenosis (CAVS). Whether Lp(a) predicts aortic valve microcalcification in individuals without CAVS is unknown. Our objective was to estimate the prevalence of elevated Lp(a) and OxPL levels in patients with CAVS and to determine if individuals with elevated Lp(a) but without CAVS have higher aortic valve microcalcification. METHODS: We recruited 214 patients with CAVS from Montreal and 174 patients with CAVS and 108 controls from Québec City, Canada. In a second group of individuals with high (≥75 nmol/L, n = 27) or low (<75 nmol/L, n = 28) Lp(a) levels, 18F-sodium fluoride positron emission tomography/computed tomography was performed to determine the difference in mean tissue-to-background ratio (TBR) of the aortic valve. RESULTS: Patients with CAVS had 62.0% higher Lp(a) (median = 28.7, interquartile range [8.2-116.6] vs 10.9 [3.6-28.8] nmol/L, P < 0.0001), 50% higher OxPL-apolipoprotein-B (2.2 [1.3-6.0] vs 1.1 [0.7-2.6] nmol/L, P < 0.0001), and 69.9% higher OxPL-apolipoprotein(a) (7.3 [1.8-28.4] vs 2.2 [0.8-8.4] nmol/L, P < 0.0001) levels compared with individuals without CAVS (all P < 0.0001). Individuals without CAVS but elevated Lp(a) had 40% higher mean TBR compared with individuals with low Lp(a) levels (mean TBR = 1.25 ± 0.23 vs 1.15 ± 0.11, P = 0.02). CONCLUSIONS: Elevated Lp(a) and OxPL levels are associated with prevalent CAVS in patients studied in an echocardiography laboratory setting. In individuals with elevated Lp(a), evidence of aortic valve microcalcification by 18F-sodium fluoride positron emission tomography/computed tomography is present before the development of clinically manifested CAVS.

CONTEXTE: La lipoprotéine(a) (Lp[a]), la principale lipoprotéine assurant le transport des phospholipides oxydés (PLOx), est un facteur de risque génétique bien établi de la sténose aortique calcifiante (SAC). On ignore si la présence de Lp(a) est un facteur prédictif de la microcalcification de la valve aortique chez les individus non atteints de SAC. Notre objectif était d'estimer la prévalence de taux élevés de Lp(a) et de PLOx chez des patients atteints de SAC et de déterminer si la microcalcification de la valve aortique est plus marquée chez les individus affichant des taux élevés de Lp(a) en l'absence de SAC. MÉTHODOLOGIE: Nous avons recruté 214 patients atteints de SAC à Montréal et 174 patients atteints de SAC et 108 patients témoins à Québec (Canada). Dans un second groupe de patients présentant des taux de Lp(a) élevés (≥ 75 nmol/l, n = 27) ou faibles (< 75 nmol/l, n = 28), une tomographie par émission de positons au fluorure de sodium marqué au 18F a été réalisée en vue de comparer la valeur moyenne du rapport signal/bruit (RSB) de la valve aortique. RÉSULTATS: Les patients atteints de SAC présentaient des taux de Lp(a) plus élevés de 62,0 % (médiane = 28,7, intervalle interquartile [de 8,2 à 116,6] vs 10,9 [de 3,6 à 28,8] nmol/l, p < 0,0001), des taux de OxPL-apolipoprotéine-B plus élevés de 50 % (2,2 [de 1,3 à 6,0] vs 1,1 [de 0,7 à 2,6] nmol/l, p < 0,0001) et des taux de PLOx-apolipoprotéine(a) plus élevés de 69,9 % (7,3 [de 1,8 à 28,4] vs 2,2 [de 0,8 à 8,4] nmol/l, p < 0,0001) comparativement aux patients non atteints de SAC (toutes les valeurs p < 0,0001). Les patients non atteints de SAC mais présentant des taux élevés de Lp(a) avaient un RSB moyen supérieur de 40 % à celui des individus affichant un faible taux de Lp(a) (RSB moyen = 1,25 ± 0,23 vs 1,15 ± 0,11, p = 0,02). CONCLUSIONS: Des taux élevés de Lp(a) et de PLOx sont associés à la prévalence de la SAC chez des patients étudiés par échocardiographie. Chez les individus présentant un taux élevé de Lp(a), les signes d'une microcalcification de la valve aortique, décelés par tomographie par émission de positons au fluorure de sodium marqué au 18F /tomodensitométrie sont présents avant l'apparition des manifestations cliniques de la SAC.

Role of radionuclide imaging for diagnosis of device and prosthetic valve infections.

Cardiovascular implantable electronic device (CIED) infection and prosthetic valve endocarditis (PVE) remain a diagnostic challenge. Cardiac imaging plays an important role in the diagnosis and management of patients with CIED infection or PVE. Over the past few years, cardiac radionuclide imaging has gained a key role in the diagnosis of these patients, and in assessing the need for surgery, mainly in the most difficult cases. Both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and radiolabelled white blood cell single-photon emission computed tomography/computed tomography (WBC SPECT/CT) have been studied in these situations. In their 2015 guidelines for the management of infective endocarditis, the European Society of Cardiology incorporated cardiac nuclear imaging as part of their diagnostic algorithm for PVE, but not CIED infection since the data were judged insufficient at the moment. This article reviews the actual knowledge and recent studies on the use of 18F-FDG PET/CT and WBC SPECT/CT in the context of CIED infection and PVE, and describes the technical aspects of cardiac radionuclide imaging. It also discusses their accepted and potential indications for the diagnosis and management of CIED infection and PVE, the limitations of these tests, and potential areas of future research.

Usefulness of fluorine-18 positron emission tomography/computed tomography for identification of cardiovascular implantable electronic device infections.

OBJECTIVES: This study evaluated the usefulness of fluorodesoxyglucose marked by fluorine-18 ((18)F-FDG) positron emission tomography (PET) and computed tomography (CT) in patients with suspected cardiovascular implantable electronic device (CIED) infection. BACKGROUND: CIED infection is sometimes challenging to diagnose. Because extraction is associated with significant morbidity/mortality, new imaging modalities to confirm the infection and its dissemination would be of clinical value. METHODS: Three groups were compared. In Group A, 42 patients with suspected CIED infection underwent (18)F-FDG PET/CT. Positive PET/CT was defined as abnormal uptake along cardiac devices. Group B included 12 patients without infection who underwent PET/CT 4 to 8 weeks post-implant. Group C included 12 patients implanted for >6 months without infection who underwent PET/CT for another indication. Semi-quantitative ratio (SQR) was obtained from the ratio between maximal uptake and lung parenchyma uptake. RESULTS: In Group A, 32 of 42 patients with suspected CIED infection had positive PET/CT. Twenty-four patients with positive PET/CT underwent extraction with excellent correlation. In 7 patients with positive PET/CT, 6 were treated as superficial infection with clinical resolution. One patient with positive PET/CT but negative leukocyte scan was considered false positive due to Dacron pouch. Ten patients with negative-PET/CT were treated with antibiotics and none has relapsed at 12.9 ± 1.9 months. In Group B, patients had mild uptake seen at the level of the connector. There was no abnormal uptake in Group C patients. Median SQR was significantly higher in Group A (A = 2.02 vs. B = 1.08 vs. C = 0.57; p < 0.001). CONCLUSIONS: PET/CT is useful in differentiating between CIED infection and recent post-implant changes. It may guide appropriate therapy.

Usefulness of an accelerated transoesophageal stress echocardiography in the preoperative evaluation of high risk severely obese subjects awaiting bariatric surgery.

BACKGROUND: Severe obesity is associated with an increased risk of coronary artery disease (CAD). Bariatric surgery is an effective procedure for long term weight management as well as reduction of comorbidities. Preoperative evaluation of cardiac operative risk may often be necessary but unfortunately standard imaging techniques are often suboptimal in these subjects. The purpose of this study was to demonstrate the feasibility, safety and utility of transesophageal dobutamine stress echocardiography (TE-DSE) using an adapted accelerated dobutamine infusion protocol in severely obese subjects with comorbidities being evaluated for bariatric surgery for assessing the presence of myocardial ischemia. METHODS: Subjects with severe obesity [body mass index (BMI) >40 kg/m2] with known or suspected CAD and being evaluated for bariatric surgery were recruited. RESULTS: Twenty subjects (9M/11F), aged 50 +/- 8 years (mean +/- SD), weighing 141 +/- 21 kg and with a BMI of 50 +/- 5 kg/m2 were enrolled in the study and underwent a TE-DSE. The accelerated dobutamine infusion protocol used was well tolerated. Eighteen (90%) subjects reached their target heart rate with a mean intubation time of 13 +/- 4 minutes. Mean dobutamine dose was 31.5 +/- 9.9 ug/kg/min while mean atropine dose was 0.5 +/- 0.3 mg. TE-DSE was well tolerated by all subjects without complications including no significant arrhythmia, hypotension or reduction in blood arterial saturation. Two subjects had abnormal TE-DSE suggestive of myocardial ischemia. All patients underwent bariatric surgery with no documented cardiovascular complications. CONCLUSIONS: TE-DSE using an accelerated infusion protocol is a safe and well tolerated imaging technique for the evaluation of suspected myocardial ischemia and cardiac operative risk in severely obese patients awaiting bariatric surgery. Moreover, the absence of myocardial ischemia on TE-DSE correlates well with a low operative risk of cardiac event.

A longitudinal study of gene expression in healthy individuals.

BACKGROUND: The use of gene expression in venous blood either as a pharmacodynamic marker in clinical trials of drugs or as a diagnostic test requires knowledge of the variability in expression over time in healthy volunteers. Here we defined a normal range of gene expression over 6 months in the blood of four cohorts of healthy men and women who were stratified by age (22-55 years and > 55 years) and gender. METHODS: Eleven immunomodulatory genes likely to play important roles in inflammatory conditions such as rheumatoid arthritis and infection in addition to four genes typically used as reference genes were examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), as well as the full genome as represented by Affymetrix HG U133 Plus 2.0 microarrays. RESULTS: Gene expression levels as assessed by qRT-PCR and microarray were relatively stable over time with approximately 2% of genes as measured by microarray showing intra-subject differences over time periods longer than one month. Fifteen genes varied by gender. The eleven genes examined by qRT-PCR remained within a limited dynamic range for all individuals. Specifically, for the seven most stably expressed genes (CXCL1, HMOX1, IL1RN, IL1B, IL6R, PTGS2, and TNF), 95% of all samples profiled fell within 1.5-2.5 Ct, the equivalent of a 4- to 6-fold dynamic range. Two subjects who experienced severe adverse events of cancer and anemia, had microarray gene expression profiles that were distinct from normal while subjects who experienced an infection had only slightly elevated levels of inflammatory markers. CONCLUSION: This study defines the range and variability of gene expression in healthy men and women over a six-month period. These parameters can be used to estimate the number of subjects needed to observe significant differences from normal gene expression in clinical studies. A set of genes that varied by gender was also identified as were a set of genes with elevated expression in a subject with iron deficiency anemia and another subject being treated for lung cancer.

Ongoing genome reduction in Mycobacterium ulcerans.

Elucidation of the transmission, epidemiology, and evolution of Mycobacterium ulcerans, the causative agent of Buruli ulcer, is hampered by the striking lack of genetic diversity of this emerging pathogen. However, by using a prototype plasmid-based microarray that covered 10% of the genome, we found multiple genomic DNA deletions among 30 M. ulcerans clinical isolates of diverse geographic origins. Many of the changes appear to have been mediated by insertion sequence (IS) elements IS2404 and IS2606, which have high copy numbers. Classification of the deleted genes according to their biological functions supports the hypothesis that M. ulcerans has recently evolved from the generalist environmental M. marinum to become a niche-adapted specialist. The substantial genomic diversity, along with a prototype microarray that covered a small portion of the genome, suggests that a genome-wide microarray will make available a genetic fingerprinting method with the high resolution required for microepidemiologic studies.

Complex transradial three vessel brachytherapy in a single session.

BACKGROUND: We report the case of a patient who underwent transradial brachytherapy in 3 different coronary vessels during a single session. She initially presented with unstable angina 4 months after the index procedure; control angiography showed severe and diffuse in-stent restenosis in the LAD, Cx and Mg arteries. METHODS: After successful dilatation of the three vessels, we performed vascular brachytherapy using the Novoste Beta-Rail system and a 60 mm length source train of 90Sr/Y radioactive seeds. No further stent was implanted. The patient left the hospital the next day. Follow-up angiography revealed widely patent vessels with no restenosis. CONCLUSION: Transradial multivessel brachytherapy can be done during the same session.

Transradial coronary brachytherapy with the Novoste Beta-Rail system.

We report our initial experience in 10 consecutive patients who underwent transradial coronary brachytherapy for in-stent restenosis using a 90Sr/Y source and the Novoste Beta-Rail system. In all patients, procedures were successfully completed using a right transradial approach. We performed the procedures with the Beta-Rail catheter using 7 Fr (Zuma II, Medtronic, MN; n = 5) or 8 Fr (Cordis, Miami, FL; n = 5) guiding catheters. All lesions were successfully dilated and no additional stent was inserted. We used a 40 mm source (n = 3) or a 60 mm source (n = 7) with manual stepping in four cases. In three cases, we did one stepping, and in one case, we did three steppings. The mean dwell time was 195 plus minus 44 sec. The mean delivered dose was 23 +/- 3 Gy at 2 mm distance from the source. No radiation treatment was interrupted. Mean fluoroscopy time was 26 +/- 13 min. Procedural success was achieved in all patients. Three patients had mild CK elevations (< 3 times upper normal limit). All patients were pretreated with clopidogrel (300 mg) and combined treatment with aspirin + clopidogrel is to be continued for at least 1 year. Clinical follow-up up to 3 months has not yielded any complication and all patients have remained free from angina.