Familial chylomicronemia syndrome. A sixty year follow-up in two siblings and their kindreds. Nosological and clinical considerations.

Familial chylomicronemia syndrome (FCS) is a rare and severe genetic disorder, characterized by marked elevation of plasma triglycerides, often diagnosed in infancy. We describe the long-term follow-up (almost 60 years), the diagnostic assessment and the management of two siblings with severe hypertriglyceridemia and a history of pancreatitis who also developed cardiovascular complications later in life. We recently disclosed that the surviving index case was homozygous for a pathogenic LPL gene variant (c.984 G>T, p.M328I). The same variant was also found in two apparently unrelated siblings with FCS living in the same geographical area as the index case.

A Modern Case Sheds Light on a Classical Enigma: Beethoven's Deafness.

Two hundred and fifty years have passed since the birth of Ludwig van Beethoven, and the enigma about his hearing loss and overall health status seems to be not completely solved. However, the admission to the hospital of a 64-year-old woman in 2018 with symptoms extremely similar to those experienced by the great composer may add further evidence to a theory previously underestimated. The health issues of the modern patient were found to be due to chronic lead intoxication. The lead was released during daily cooking using a ceramic-coated frying pan with worn surface that poisoned her breakfast most probably for years. Abdominal pain, asthenia, and hearing loss affecting the high frequencies with a many impact on speech intelligibility tormented the patient, as they had Beethoven. An extensive review of the music and medical literature was performed, as well as re-examination of manuscripts, correspondence, and autopsy reports of the famous composer; and great similarities have been found. The soundness of the most-cited classical theories about Beethoven's hearing loss will be discussed. After close scrutiny of the theories, our analysis points toward a progressive sensorineural hearing loss due to lead intoxication as the most probable cause of not only Beethoven's hypoacusis but his overall health status as well. Laryngoscope, 131:179-185, 2021.

Autosomal Recessive Hypercholesterolemia: Long-Term Cardiovascular Outcomes.

BACKGROUND: Autosomal recessive hypercholesterolemia (ARH) is a rare lipid disorder characterized by premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data for clinical management and cardiovascular outcomes in ARH. OBJECTIVES: Evaluation of changes in lipid management, achievement of low-density lipoprotein cholesterol (LDL-C) goals and cardiovascular outcomes in ARH. METHODS: Published ARH cases were identified by electronic search. All corresponding authors and physicians known to treat these patients were asked to provide follow-up information, using a standardized protocol. RESULTS: We collected data for 52 patients (28 females, 24 males; 31.1 ± 17.1 years of age; baseline LDL-C: 571.9 ± 171.7 mg/dl). During a mean follow-up of 14.1 ± 7.3 years, there was a significant increase in the use of high-intensity statin and ezetimibe in combination with lipoprotein apheresis; in 6 patients, lomitapide was also added. Mean LDL-C achieved at nadir was 164.0 ± 85.1 mg/dl (-69.6% from baseline), with a better response in patients taking lomitapide (-88.3%). Overall, 23.1% of ARH patients reached LDL-C of <100 mg/dl. During follow-up, 26.9% of patients had incident ASCVD, and 11.5% had a new diagnosis of aortic valve stenosis (absolute risk per year of 1.9% and 0.8%, respectively). No incident stroke was observed. Age (≥30 years) and the presence of coronary artery disease at diagnosis were the major predictors of incident ASCVD. CONCLUSIONS: Despite intensive treatment, LDL-C in ARH patients remains far from targets, and this translates into a poor long-term cardiovascular prognosis. Our data highlight the importance of an early diagnosis and treatment and confirm the fact that an effective treatment protocol for ARH is still lacking.

The history of Autosomal Recessive Hypercholesterolemia (ARH). From clinical observations to gene identification.

The most frequent form of monogenic hypercholesterolemia, also known as Familial Hypercholesterolemia (FH), is characterized by plasma accumulation of cholesterol transported in Low Density Lipoproteins (LDLs). FH has a co-dominant transmission with a gene-dosage effect. FH heterozygotes have levels of plasma LDL-cholesterol (LDL-C) twice normal and present xanthomas and coronary heart disease (CHD) in adulthood. In rare FH homozygotes plasma LDL-C level is four times normal, while xanthomas and CHD are present from infancy. Most FH patients are carriers of mutations of the LDL receptor (LDLR); a minority of them carry either mutations in the Apolipoprotein B (ApoB), the protein constituent of LDLs which is the ligand for LDLR, or gain of function mutations of PCSK9, the protein responsible for the intracellular degradation of the LDLR. From 1970 to the mid 90s some publications described children with the clinical features of homozygous FH, who were born from normocholesterolemic parents, strongly suggesting a recessive transmission of FH. In these patients the involvement of LDLR and APOB genes was excluded. Interestingly, several patients were identified in the island of Sardinia (Italy), whose population has a peculiar genetic background due to geographical isolation. In this review, starting from the early descriptions of patients with putative recessive hypercholesterolemia, we highlight the milestones that led to the identification of a novel gene involved in LDL metabolism and the characterization of its encoded protein. The latter turned out to be an adaptor protein required for the LDLR-mediated endocytosis of LDLs in hepatocytes. The loss of function of this protein is the cause of Autosomal Recessive Hypercholesterolemia (ARH).

Brain-derived neurotrophic factor plasma levels: relationship with dementia and diabetes in the elderly population.

The mechanisms linking diabetes and cognitive impairment/dementia, two common conditions of elderly people, are not completely known. Brain-derived neurotrophic factor (BDNF) has antidiabetic properties, and reduced circulating BDNF was associated with dementia. We investigated the relationship between plasma BDNF levels, dementia, and diabetes in a sample of 164 community-dwelling elderly individuals, including 50 participants with vascular dementia, 44 with late onset Alzheimer's disease, 23 with cerebrovascular disease not dementia, and 47 controls (C). Presence/absence of diabetes was registered; new diagnoses of diabetes were made by the American Diabetes Association criteria. BDNF plasma levels were measured by ELISA. Both diagnosis of dementia and diabetes were associated with lower BDNF plasma values compared with the respective controls; moreover, dementia and diabetes correlated with BDNF plasma levels, independent of possible confounders. A progressive reductions of BDNF plasma levels from C (383.9 ± 204.6 pg/mL), to cerebrovascular disease not dementia (377.1 ± 130.2), to vascular dementia (313.3 ± 114.8), to late onset Alzheimer's disease (264.7 ± 147.7) was observed, (late onset Alzheimer's disease vs C, p: .03; late onset Alzheimer's disease vs cerebrovascular disease not dementia, p: .002). Demented patients affected by diabetes had the lowest BDNF mean levels (264.9 pg/mL) among individuals enrolled in this sample, suggesting the existence of a "synergistic" effect of dementia and diabetes on BDNF levels.

Nonalcoholic fatty liver and metabolic syndrome in Italy: results from a multicentric study of the Italian Arteriosclerosis society.

Nonalcoholic fatty liver disease (NAFLD) is associated with all the components of metabolic syndrome (MS) and might to be considered an additional component of MS itself. The Italian Society for the Study of Atherosclerosis (SISA) in 2005 started a research project aimed to study the NAFLD, using ultrasound (US), in nondiabetic MS subjects matching at least one of the ATP III criteria for HDL-C or triglycerides [TG]. Prevalence of US-NAFLD and its associated risk factors and prevalence of hypertransaminasemia and its possible determinants were evaluated. NAFLD prevalence was 0.78. Men with steatosis compared to men without steatosis were younger (P < 0.05) with higher TG (P < 0.03), homeostasis model assessment insulin resistance (HOMA-R) (P < 0.003), and visceral fat thickness (VFT) (P < 0.0001). Women with steatosis showed higher TG (P < 0.05), HOMA-R (P < 0.04), VFT (P < 0.0001), and lower age (P < 0.05). At multivariate analyses, VFT (P < 0.0001), HOMA-R (P < 0.02), and TG/HDL (P < 0.05) were associated with severity of NAFLD. Age (P < 0.05), LogTG (P < 0.005), and VFT (P < 0.01) were associated with higher ALT. The US prevalence of steatosis in this study (0.78) is the highest reported in patients with MS. Considering the exclusion of severe obese and diabetic patients and the recruitment criteria, this finding highlights the prominent role played by the alterations of lipid metabolism in the pathogenesis of NAFLD.

PPARγ Pro12Ala and ACE ID polymorphisms are associated with BMI and fat distribution, but not metabolic syndrome.

BACKGROUND: Metabolic Syndrome (MetS) results from the combined effect of environmental and genetic factors. We investigated the possible association of peroxisome proliferator-activated receptor-γ2 (PPARγ2) Pro12Ala and Angiotensin Converting Enzyme (ACE) I/D polymorphisms with MetS and interaction between these genetic variants. METHODS: Three hundred sixty four unrelated Caucasian subjects were enrolled. Waist circumference, blood pressure, and body mass index (BMI) were recorded. Body composition was estimated by impedance analysis; MetS was diagnosed by the NCEP-ATPIII criteria. A fasting blood sample was obtained for glucose, insulin, lipid profile determination, and DNA isolation for genotyping. RESULTS: The prevalence of MetS did not differ across PPARγ2 or ACE polymorphisms. Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but lower systolic blood pressure compared with Pro/Pro homozygotes. A significant PPARγ2 gene-gender interaction was observed in the modulation of BMI, fat mass, and blood pressure, with significant associations found in women only. A PPARγ2-ACE risk genotype combination for BMI and fat mass was found, with ACE DD/PPARγ2 Ala subjects having a higher BMI (p = 0.002) and Fat Mass (p = 0.002). Pro12Ala was independently associated with waist circumference independent of BMI and gender. CONCLUSIONS: Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but not a worse metabolic profile, possibly because of a more favorable adipose tissue distribution. A gene interaction exists between Pro12Ala and ACE I/D on BMI and fat mass. Further studies are needed to assess the contribution of Pro12Ala polymorphism in adiposity distribution.

Predictive value of the Short Physical Performance Battery following hospitalization in older patients.

BACKGROUND: Hospitalization represents a stressful and potentially hazardous event for older persons. We evaluated the value of the Short Physical Performance Battery (SPPB) in predicting rates of functional decline, rehospitalization, and death in older acutely ill patients in the year after discharge from the hospital. METHODS: Prospective cohort study of 87 patients aged 65 years and older who were able to walk and with a Mini-Mental State Examination score ≥ 18 and admitted to the hospital with a clinical diagnosis of congestive heart failure, pneumonia, chronic obstructive pulmonary disease, or minor stroke. Patients were evaluated with the SPPB at hospital admission, were reevaluated the day of hospital discharge, and 1 month later. Subsequently, they were followed every 3 months by telephone interviews to ascertain functional decline, new hospitalizations, and vital status. RESULTS: After adjustment for potential confounders, including self-report activity of daily living and comorbidity, the SPPB score at discharge was inversely correlated with the rate of decline in activity of daily living performance over the follow-up (p < .05). In a multivariable discrete-time survival analysis, patients with poor SPPB scores at hospital discharge (0-4) had a greater risk of rehospitalization or death (odds ratio: 5.38, 95% confidence interval: 1.82-15.9) compared with those with better SPPB scores (8-12). Patients with early decline in SPPB score after discharge also had steeper increase in activity of daily living difficulty and higher risk of rehospitalization or death over the next year. CONCLUSIONS: In older acutely ill patients who have been hospitalized, the SPPB provides important prognostic information. Lower extremity performance-based functional assessment might identify older patients at high risk of poor outcomes after hospital discharge.

Association of tumor necrosis factor-related apoptosis-inducing ligand with total and cardiovascular mortality in older adults.

OBJECTIVE: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits biological activity on vascular cells in vitro. Rapid variation of circulating TRAIL levels occurs during acute coronary ischemia, suggesting that biological pathways involving TRAIL may be activated during ischemic heart disease. However, whether differential levels of soluble TRAIL in normal individuals are associated with adverse health outcomes has not been investigated. We tested the hypothesis that TRAIL levels predict mortality in a population based sample of community dwelling men and women. METHODS: Plasma TRAIL level was measured by ELISA at baseline in 1282 adults (mean age 68 years) enrolled in the InCHIANTI study. Vital status was ascertained over the six-year follow-up. RESULTS: In multivariable Cox regression analysis adjusted for potential confounders including prevalent cardiovascular diseases (CVD), ankle-brachial index, electrocardiogram abnormalities, and inflammatory markers, baseline TRAIL levels were inversely related to all-cause mortality (p=0.008). In stratified analyses, the prognostic effect of TRAIL level was strong and highly significant in participants with prevalent CVD (N=321), (lowest versus highest quartile: HR 3.1; 95% CI 1.5-6.5) while it was negligible in those free of CVD (p value for the interaction term between CVD status and TRAIL levels=0.038). Similar findings were obtained when CVD mortality was considered as the outcome of interest. CONCLUSIONS: In older patients with CVD, low levels of TRAIL were associated with increased risk of death over a period of 6 years. Lower concentration of circulating TRAIL may be related to the clinical evolution of older adults with CVD.

Pharmacotherapy of dyslipidemias in the adult population.

IMPORTANCE OF THE FIELD: Lipid-modifying drugs are therapeutic options that have been shown to reduce the biological and clinical burden related to atherosclerosis; they can be used to correct minor lipid abnormalities, as well as the more severe dyslipidemias that can be met in clinical practice. AREAS COVERED IN THIS REVIEW: HMG-CoA reductase inhibitors (statins) surely represent the choice agents, and must be utilized in relation to the global cardiovascular risk of a hypercholesterolemic subject. When treatment is only partly effective, association therapy is a reasonable solution or, alternatively, a shift towards other less effective 'rescue' drugs or nutraceutical 'ancillary remedies'. In every case, drug tolerability warrants consideration. WHAT THE READER WILL GAIN: Pharmacotherapy of lipid disorders cannot be separated from the knowledge of the main clinical trial results and the pharmacological characteristics of hypocholesterolemic drugs. An appropriate treatment protocol is proposed and examined. TAKE HOME MESSAGE: Hypolipidemic drugs must be added to therapeutic lifestyle changes, and not substituted for them; they may be prosecuted indefinitely, without any interruption; drug adherence is a prerequisite of efficacy and clinical monitoring is necessary for both compliance and safety issues.

Plasma soluble gp130 levels are increased in older subjects with metabolic syndrome. The role of insulin resistance.

OBJECTIVE: Increased interleukin-6 plasma levels have been reported in metabolic syndrome (MS); nevertheless, it is unclear whether interleukin-6 activity is exerted through direct signalling only or also through the "trans-signalling". This issue is important to clarify since signalling and "trans-signalling" affect different tissues. We investigated the relationship between MS and the interleukin-6 system in an older population. METHODS: Data from 997 older community dwelling individuals (age ≥ 65 years; females: 56.2%) enrolled the InChianti study were analysed. Interleukin-6, soluble interleukin-6 receptor (sIL-6r), and soluble glycoprotein 130 (sgp130) were measured on plasma by ELISA. MS was defined by the NCEP ATP III criteria; 309 individuals (31%) resulted affected by MS. RESULTS: Subjects with MS had higher interleukin-6 and sgp130 levels compared to controls; a trend toward higher levels of sIL-6R was also observed. The risk of having MS was increased in individuals with high sIL-6r or/and sgp130 levels, independent of age, gender, and interleukin-6 levels. Elevated sgp130 levels were associated with higher plasma glucose, HOMA, triglycerides, and with diabetes both in subjects with and without MS. Although the risk of high sgp130 levels was generally associated with MS (O.R.: 1.77, 95%C.I.: 1.39-2.25), this excess of risk was not present in MS phenotypes excluding the criteria "elevated glucose" or "elevated triglycerides". Furthermore, the association between sgp130 and MS disappeared after adjustment for HOMA. CONCLUSIONS: We found that older individuals with MS have increased sgp130 plasma levels compared with controls; nevertheless, our data suggest that this association might be mediated by insulin resistance.

The benefit and risk of testosterone replacement therapy in older men: effects on lipid metabolism.

Over the last decades, testosterone replacement therapy for middle-aged and older men has been gaining increasing and widespread attention and popularity. Although several benefits of testosterone replacement therapy are well established, including but not limited to improvement in libido, body composition, and bone density, concerns for multiple potential adverse effects remain. In particular, concerns are frequently raised regarding the possibility that testosterone replacement therapy may increase the risks of prostate cancer and cardiovascular disease as consequence of a potential detrimental effect of testosterone on cardiovascular risk factors. This mini-review will present and discuss the current knowledge on the relationship between testosterone replacement therapy and change in lipid fractions in older men.

Lipoprotein(a), inflammation, and peripheral arterial disease in a community-based sample of older men and women (the InCHIANTI study).

Lipoprotein(a) (Lp[a]) may represent an independent risk factor for peripheral arterial disease of the lower limbs (LL-PAD), but prospective data are scant. We estimated the association between baseline Lp(a) with prevalent and incident LL-PAD in older subjects from the InCHIANTI Study. LL-PAD, defined as an ankle-brachial index <0.90, was assessed at baseline and over a 6-year follow-up in a sample of 1,002 Italian subjects 60 to 96 years of age. Plasma Lp(a) and potential traditional and novel cardiovascular risk factors (including a score based on relevant inflammatory markers) were entered in multivariable models to assess their association with prevalent and incident LL-PAD. At baseline, Lp(a) concentration was directly related to the number of increased inflammatory markers (p <0.05). There were 125 (12.5%) prevalent cases of LL-PAD and 57 (8.3%) incident cases. After adjustment for potential confounders, participants in the highest quartile of the Lp(a) distribution (>/=32.9 mg/dl) were more likely to have LL-PAD compared to those in the lowest quartile (odds ratio [OR] 1.83, 95% confidence interval [CI] 1.01 to 3.33). The association was stronger (OR 3.80, 95% CI 1.50 to 9.61) if LL-PAD was defined by harder criteria, namely an ankle-brachial index <0.70. Compared to subjects in the lowest Lp(a) quartile, those in the highest quartile showed a somewhat increased risk of incident LL-PAD (lowest quartile 7.7%, highest quartile 10.8%), but the association was not statistically significant (OR 1.52, 95% CI 0.71 to 3.22). In conclusion, Lp(a) is an independent LL-PAD correlate in the cross-sectional evaluation, but further prospective studies in larger populations, with longer follow-up and more definite LL-PAD ranking, might be needed to establish a longitudinal association.