COVID-19 as a Paradigmatic Model of the Heterogeneous Disease Presentation in Older People: Data from the GeroCovid Observational Study.

COVID-19 may have a heterogeneous onset, especially in older age. However, whether and how COVID-19 signs and symptoms may present and aggregate together according to sociodemographic and health factors is unclear, as well as their prognostic value. This study included 981 COVID-19 inpatients who participated in the GeroCovid Observational study. Signs/symptoms at disease onset, sociodemographic, health, cognitive status, and mobility were systematically recorded. Clusters of signs/symptoms were identified through agglomerative hierarchical clustering. The associations of single signs/symptoms and symptom clusters with longer hospitalization (≥16 days) and in-hospital mortality were explored through logistic and Cox regressions. The signs/symptoms most reported in our sample (age 78.3 ± 9.39 years; 49.4% women) were fever (62.5%), cough (45.5%), and dyspnea (62.7%). Atypical symptoms were reported by up to one-third of patients, and delirium by 9.1%. Atypical symptoms were more frequent with advancing age and with lower pre-COVID-19 cognitive and mobility levels. Older men more likely reported respiratory symptoms than women. Dyspnea (hazard ratio [HR] = 1.47, 95% confidence interval [CI]: 1.02-2.12), tachypnea (HR = 1.53, 95% CI: 1.14-2.07), low oxygen saturation (HR = 1.95, 95% CI: 1.32-2.88) and delirium (HR = 1.60, 95% CI: 1.13-2.28) were associated with higher in-hospital mortality. Four symptom clusters were identified. Compared with the mild respiratory symptoms cluster, the severe clinical impairment cluster was associated with higher mortality (HR = 2.57, 95% CI: 1.58-4.18). The severe clinical impairment and aspecific symptoms clusters were associated with longer hospitalization (odds ratio [OR] = 2.38, 95% CI: 1.56-3.63, and OR = 1.75, 95% CI: 1.08-2.83, respectively). Multiple health aspects influence COVID-19 clinical presentation. A symptom clusters approach may help predict adverse health outcomes in older patients. In addition to respiratory symptoms, delirium is independently associated with mortality risk. ClinicalTrials.gov (NCT04379440).

Defective endoplasmic reticulum-mitochondria contacts and bioenergetics in SEPN1-related myopathy.

SEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired.

Toward a geriatric approach to patients with advanced age and cardiovascular diseases: position statement of the EuGMS Special Interest Group on Cardiovascular Medicine.

Cardiovascular diseases (CVD) are highly prevalent in older adults and represent a major geriatric health-care concern. Management of CVD in older patients may be challenging due to specific geriatric issues, such as frailty and multi-morbidity, which may influence patients' outcomes. In this clinical context, diagnostic and therapeutic strategies should target those outcomes that have higher priority in geriatric health care, including disability prevention and quality of life. Older adults with CVD should be offered a reasonably optimized treatment, customized to the individual's frailty level and functional status. Yet, most clinical trials excluded comorbid and frail patients and evidence to support CVD management in this vulnerable population is lacking. Therefore, a geriatric approach is needed in cardiovascular medicine, characterized by a holistic, patient-centered perspective focusing on functional status and quality of life. With a view to promote the geriatric approach in the management of older patients with CVD, the EuGMS Special Interest Group (SIG) on Cardiovascular Medicine was founded in 2018, consisting of a network of geriatricians with an extensive expertise in geriatric cardiovascular medicine. The present position paper aims to present the Cardiovascular SIG and illustrate its main purposes and action programs.

The role of the Arrhythmia Team, an integrated, multidisciplinary approach to treatment of patients with cardiac arrhythmias: results of the European Heart Rhythm Association survey.

Management of patients with cardiac arrhythmias is increasingly complex because of continuous technological advance and multifaceted clinical conditions associated with ageing of the population, the presence of co-morbidities and the need for polypharmacy. The aim of this European Heart Rhythm Association Scientific Initiatives Committee survey was to provide an insight into the role of the Arrhythmia Team, an integrated, multidisciplinary approach to management of patients with cardiac arrhythmias. Forty-eight centres from 18 European countries replied to the Web-based questionnaire. The presence of an Arrhythmia Team was reported by 44% of the respondents, whereas 17% were not familiar with this term. Apart from the electrophysiologist, health professionals who should belong to such teams, according to the majority of the respondents, include a clinical cardiologist, a nurse, a cardiac surgeon, a heart failure specialist, a geneticist, and a geriatrician. Its main activity should be dedicated to the management of patients with complex clinical conditions or refractory or inherited forms of arrhythmias. When present, the Arrhythmia Team was considered helpful by 95% of respondents; the majority of centres (79%) agreed that it should be implemented. The Arrhythmia Team seems to be connected to important expectations in the management of cardiac arrhythmias. The efficacy of such an integrated and multidisciplinary approach should be encouraged and tested in clinical practice.

Coenzyme Q10 terclatrate and creatine in chronic heart failure: a randomized, placebo-controlled, double-blind study.

BACKGROUND: Studies have suggested that micronutrient deficiency has some role in the progression of chronic heart failure (CHF). HYPOTHESIS: Oral supplementation with coenzyme Q(10) (CoQ(10)) and creatine may reduce mitochondrial dysfunction that contributes to impaired physical performance in CHF. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to determine the effect of a mixture of water-soluble CoQ(10) (CoQ(10) terclatrate; Q-ter) and creatine on exercise tolerance and health-related quality of life. Exercise tolerance was measured as total work capacity (kg·m) and peak oxygen consumption (VO(2), mL/min/kg), both from a cardiopulmonary exercise test. Health-related quality of life was measured by the Sickness Impact Profile (SIP) in CHF secondary to left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 35%). After baseline assessment, 67 patients with stable CHF were randomized to receive Q-ter 320 mg + creatine 340 mg (n = 35) or placebo (n = 32) once daily for 8 weeks. RESULTS: At multivariate analysis, 8-week peak VO(2) was significantly higher in the active treatment group than in the placebo group (+1.8 ± 0.9 mL/min/kg, 95% CI: 0.1-3.6, P < 0.05). No untoward effects occurred in either group. CONCLUSIONS: This study suggests that oral Q-ter and creatine, added to conventional drug therapy, exert some beneficial effect on physical performance in stable systolic CHF. Results may support the design of larger studies aimed at assessing the long-term effects of this treatment on functional status and harder outcomes.

Polyunsaturated fatty acids and cardiovascular disease.

Several observational and experimental studies show the beneficial effects of omega-3 poly-unsaturated fatty acids (PUFA) in cardiovascular disease. The results from such studies justify supplementation of omega-3 PUFA in primary and secondary prevention of several clinical conditions, including coronary heart disease, sudden cardiac death and heart failure. Supplementation of omega-3 PUFA is also indicated as monotherapy in the treatment of hypertriglyceridemia. Analysis of their biological actions suggests a variety of anti-arrhythmic, anti-thrombotic, anti-atherosclerotic and anti-inflammatory mechanisms underlying their clinical benefits.