Filamin A heart valve disease as a genetic cause of inherited bicuspid and tricuspid aortic valve disease.

OBJECTIVE: Variants in the FLNA gene have been associated with mitral valve dystrophy (MVD), and even polyvalvular disease has been reported. This study aimed to analyse the aortic valve and root involvement in FLNA-MVD families and its impact on outcomes. METHODS: 262 subjects (37 (18-53) years, 140 male, 79 carriers: FLNA+) from 4 FLNA-MVD families were included. Echocardiography was performed in 185 patients and histological analysis in 3 explanted aortic valves. The outcomes were defined as aortic valve surgery or all-cause mortality. RESULTS: Aortic valve alterations were found in 58% of FLNA+ compared with 6% of FLNA- (p<0.001). 9 (13.4%) FLNA+ had bicuspid aortic valve compared with 4 (3.4%) FLNA- (p=0.03). Overall, the transvalvular mean gradient was slightly increased in FLNA+ (4.8 (4.1-6.1) vs 4.0 (2.9-4.9) mm Hg, p=0.02). The sinuses of Valsalva and sinotubular junction diameters were enlarged in FLNA+ subjects (all p<0.05). 8 FLNA+ patients underwent aortic valve surgery (0 in relatives; p<0.001). Myxomatous remodelling with an infiltration of immune cells was observed. Overall survival was similar between FLNA+ versus FLNA- subjects (86±5% vs 85±6%, p=0.36). There was no statistical evidence for an interaction between genetic status and sex (p=0.15), but the survival tended to be impaired in FLNA+ men (p=0.06) whereas not in women (p=0.71). CONCLUSION: The patients with FLNA variants present frequent aortic valve disease and worse outcomes. Bicuspid aortic valve is more frequent in patients carrying the FLNA-MVD variants. These unique features should be factored into the management of patients with dystrophic and/or bicuspid aortic valve.

Amylose cardiaque dite sénile : diagnostic et nouvelles perspectives thérapeutiques.

Résumé L'amylose cardiaque dite sénile, également dénommée « sauvage ¼, était considérée comme une maladie rare. Actuellement, grâce à des moyens diagnostiques non invasifs et à partir d'études autopsiques, nous estimons la prévalence à environ 10 à 20 % des sujets de plus de 80 ans. De même, l'amylose était un diagnostic sans conséquence thérapeutique, mis à part le traitement de l'insuffisance cardiaque et des troubles de conduction. De nouveaux traitements permettent de stabiliser le tétramère de transthyrétine et de diminuer la production d'oligomères, sources des dépôts d'amylose, en cas de formes héréditaires et sauvage d'amylose à transthyrétine. Deux médicaments bloquant la production de transthyrétine (anti-sens et oligonucléotides) sont également en phase d'essais cliniques dans les amyloses cardiaques. Ainsi, le diagnostic et la prise en charge de l'amylose cardiaque deviennent des démarches diagnostiques de pratique clinique et doivent être connus des cardiologues, mais également des gériatres qui permettront une prise en charge précoce et donc plus efficace. Abstract So-called senile cardiac amyloidosis was considered rare. Nowadays, thanks to non-invasive diagnostic means and autopsy studies, we estimate the prevalence to be about 20% of subjects over 75 years of age. Similarly, amyloidosis was a diagnosis with no therapeutic consequences, apart from the treatment of heart failure and conduction disorders. New treatments make it possible to stabilise the transthyretin tetramer and to reduce the production of oligomers that are the source of amyloid deposits, by acting in a non-genetic way and therefore adapted to the "wild" transthyretin forms of so-called senile cardiac amyloidosis. Thus, the diagnosis and management of cardiac amyloidosis are becoming diagnostic procedures in clinical practice and must be known by cardiologists, but also by geriatricians, who will allow early and therefore more effective management.

Heritability of aortic valve stenosis and bicuspid enrichment in families with aortic valve stenosis.

BACKGROUND: Although a familial component of calcific aortic valve stenosis (CAVS) has been described, its heritability remains unknown. Hence, we aim to assess the heritability of CAVS and the prevalence of bicuspid aortic valve among CAVS families. METHODS: Probands were recruited following aortic valve replacement (AVR) for severe CAVS on either tricuspid (TAV) or bicuspid aortic valve (BAV). After screening, relatives underwent a Doppler-echocardiography to assess the aortic valve morphology as well as the presence and severity of CAVS. Families were classified in two types according to proband's aortic valve phenotype: TAV or BAV families. Control families were recruited and screened for the presence of BAV. RESULTS: Among the 2371 relatives from 138 CAVS families (pedigree cohort), heritability of CAVS was significant (h2 = 0.47, p < 0.0001), in TAV (h2 = 0.49, p < 0.0001) and BAV families (h2 = 0.50, p < 0.0001). The prevalence of BAV in 790 relatives (phenotype cohort) was significantly increased in both TAV and BAV families compared to control families with a prevalence ratio of 2.6 ([95%CI:1.4-5.9]; p = 0.005) and 4.6 ([95%CI:2.4-13.4]; p < 0.0001), respectively. At least one relative had a BAV in 22.2% of tricuspid CAVS families. CONCLUSIONS: Our study confirms the heritability of CAVS in both TAV and BAV families, suggesting a genetic background of this frequent valvular disease. In addition, BAV enrichment in TAV families suggests an interplay between tricuspid CAVS and BAV. Overall results support the need to improve phenotyping (i.e. BAV, TAV, risk factors) in CAVS families in order to enhance the identification of rare and causal genetic variants of CAVS. CLINICAL TRIALS IDENTIFIER: NCT02890407.

Atrial fibrillation: a geriatric perspective on the 2020 ESC guidelines.

BACKGROUND: The Task Force for the diagnosis and management of atrial fibrillation (AF) of the European Society of Cardiology (ESC) published in 2020 the updated Guidelines for the Diagnosis and Management of Atrial Fibrillation with the contribution of the European Heart Rhythm Association (EHRA) of the ESC and the European Association for Cardiothoracic Surgery (EACTS). METHODS AND RESULTS: In this narrative viewpoint, we approach AF from the perspective of aging medicine and try to provide the readers with information usually neglected in clinical routine, mainly due to the fact that while the large majority of AF patients in real life are older, frail and cognitively impaired, these are mostly excluded from clinical trials, and physicians' attitudes often prevail over standardized algorithms. CONCLUSIONS: On the basis of existing evidence, (1) opportunistic AF screening by pulse palpation or ECG rhythm strip is cost-effective, and (2) whereas advanced chronological age by itself is not a contraindication to AF treatment, a Comprehensive Geriatric Assessment (CGA) including frailty, cognitive impairment, falls and bleeding risk may assist in clinical decision making to provide the best individualized treatment.

[Looking for frailty in elderly using the Gérontopôle Frailty Screening Tool: an observational cross-sectional study]. / Repérage de la fragilité du sujet âgé en médecine générale à l'aide du Gérontopôle Frailty Screening Tool : une étude observationnelle transversale.

Frailty in elderly people is frequent and places a person at increased risk of adverse outcomes, but it is potentially reversible. Easy and quick to complete, the Gérontopôle Frailty Screening Tool (GFST) has been designed for early diagnosis of frail elderly. The answer comes from the GP's impression in front of the patient, guided by six frailty characteristic parameters. The aim of this study was to determine the proportion of frail patients among the 75-and-older population, using the GFST. Quantitative cross-sectional observational study. A Chi2 square test and a multivariate analysis have been performed. Twenty-six GPs have taken part in this study, enabling the collection of 191 tests: 42% [95% CI, 0,35-0.49] of surveyed patients are considered frail. Frailty is significantly associated with each of the GFST parameters, except "living alone". After adjusting on age, gender and other parameters, the factors most strongly associated with frailty are: difficulty with walking, memory complaint (P < 0.001) and age (P < 0.05). The prevalence observed is consistent with the literature data. Our results confirm the relationship between frailty and physical domain, and reaffirm the close interaction between frailty and cognitive domain.

Association of Preoperative Geriatric Assessment With Length of Stay After Combined Cardiac Surgery.

BACKGROUND: For older patients undergoing cardiac surgery, geriatric factors are known to increase postoperative complications and prolong length of stay (LOS). Comprehensive geriatric assessment (CGA) is an evidence-based method for geriatric evaluation to develop an individualized-care plan to optimize physical, functional, and social issues. This study analyzed the association between preoperative CGA and hospital LOS after combined cardiac surgery. METHODS: This retrospective monocentric study included all patients aged 75 years and greater who underwent combined cardiac surgery between 2014 and 2017. Hospital LOS, intensive care unit LOS, and postoperative complications were compared between patients with or without preoperative CGA before and after propensity-score matching. RESULTS: Mean age of the 407 patients was 79.6 years; 114 underwent a preoperative CGA (28%). For 305 patients (74.9%), coronary artery bypass was associated with aortic valve replacement. After propensity-score matching, a significant difference was found between the 2 groups (preoperative CGA versus none) for in-hospital LOS (12 versus 13 days; P = .04) and intensive care unit LOS (3 versus 4 days; P = .01). In multivariable analysis, a significant association remained between hospital LOS and CGA (P = .02), renal function (P = .02), mitral replacement (P = .001), and complications (P = .001). CONCLUSIONS: Our results favor the use of systematic preoperative CGA. These encouraging results need to be validated by prospective studies that assess the impact of individualized-care plan established after CGA on postoperative outcomes. With an aging population, efforts are required to determine how to implement preoperative individualized-care plans to improve postoperative outcomes for vulnerable patients undergoing cardiac surgery.

Tele-ophthalmology for screening for eye diseases in older patients with cognitive complaints.

INTRODUCTION: Population-based studies show a significant increase in the prevalence of visual impairment in older patients. However, older patients and patients with lower Mini-Mental State Examination (MMSE) scores have few ophthalmological assessments. The main objective of our study was to evaluate the feasibility of tele-ophthalmological screening for ophthalmological diseases in older patients referred for cognitive assessment. METHODS: This monocentric prospective study included patients referred to a memory clinic for cognitive assessment. All patients underwent a geriatric assessment comprising a cognitive assessment associated with tele-ophthalmological screening undertaken by an orthoptist, including undilated retinal photography. The retinal photographs were subsequently sent to an ophthalmologist. We identified patients who were not eligible for ophthalmological assessment, for patients that had to come back due to poor-quality retinal photographs and finally for detected eye diseases. The association between the geriatric variable and newly detected eye diseases was analysed in univariable and multivariable analyses. RESULTS: The mean age of the 298 patients included was 83.5 years ± 5.65; 29.5% were male. The mean MMSE score was 20.8 ± 5.2; 66.3% of patients had a diagnosis of dementia. Eighteen patients (6.0%) were not eligible for ophthalmological examination and 13 patients (4.6%) were asked to come back owing to poor-quality retinal photographs. Forty-one patients (13.7%) had a newly detected eye disease. In multivariable analysis, patients with a lower MMSE had significantly more newly identified eye diseases. DISCUSSION: The tele-ophthalmological screening method identified unknown ophthalmological diseases requiring specialised management in this older population with cognitive complaints.

[Cancer and microbiota in elderly patients: challenges and management]. / Apport de l'analyse du microbiote intestinal pour améliorer la prise en charge oncologique chez le sujet âgé.

Aging is a major risk factor of cancers. In recent years, several studies highlighted a change in the diversity and the abundance of the intestinal microbiota associated with aging. Moreover, epidemiological studies, experimental and clinical studies have suggested that the microbiota is implicated in cancer physiopathology and could modulate the efficacy and the tolerance of oncological treatments, for example the incidence of gastrointestinal toxicity and infectious disease. In this review, our objective was first to described the main studies that have focused on the composition of the microbiota associated with aging, cancer and during cancer therapies. Second, we discussed challenges and perspectives on cancer management and research, in elderly patients. Finally, we assume that further studies will confirm that the composition of the intestinal microbiota could be considered as a biomarker of frailty that could be used to optimize cancer management in elderly patients.

Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis.

BACKGROUND: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD, have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. METHODS: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. RESULTS: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. CONCLUSIONS: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.

Geriatric factors associated with 1-year mortality after aortic valve replacement.

BACKGROUND: Surgical aortic valve replacement has been shown to improve survival and quality of life in patients with severe aortic stenosis. However, clinical variables are known to be associated with an increased mortality rate. As geriatric conditions are highly prevalent in this older population, the aim of this study was to identify geriatric factors associated with 1-year mortality after a surgical aortic valve replacement among older patients with severe symptomatic aortic stenosis. METHODS: Between January 2012 and September 2014, all patients ≥ 75 years referred for a surgical aortic valve replacement after a complete pre-operative evaluation in a university-affiliated center were included in this observational study. Association between 1-year mortality surgical aortic valve replacement and baseline characteristics including cardiac and geriatric factors was analysed by Cox models. RESULTS: Mean age of the 197 patients studied was 81.3 ± 3.5 years and 48.2% were men. At 1 year of the intervention, 19 patients (9.6%) were dead. On multivariate analysis, previous cardiac surgery (Hazard ratio [HR] = 10.47, p = 0.03), undergoing concomitant cardiac surgery (HR = 6.22, p = 0.03), pulmonary hypertension (HR = 3.73, 0.04) were still associated with 1-year mortality. Moreover, cognitive impairment was also associated with 1-year mortality (HR = 4.67, p = 0.04). CONCLUSIONS: This study is the first study to show that among geriatric factors, cognitive impairment was a strong predictor of 1-year mortality after a surgical aortic valve replacement in patients aged 75 years old and older, independently of other geriatric and cardiac factors. This study highlights the importance of pre-operative cognitive assessment.