Hidden familial cardiomyopathies in children: Role of genetic testing.

Pediatric cardiomyopathies harbour significant phenotypic and genetic heterogeneity. Genetic testing is essential for the initial evaluation and the ongoing care of child and family, although challenges remain regarding its appropriate clinical implementation in minors. We here discuss the key role of genetic diagnosis in the clinical management of two patients.

Severity of aortic stenosis predicts early post-operative normalization of left atrial size and function detected by myocardial strain.

BACKGROUND: Aortic stenosis (AS) causes significant disturbances in left ventricular (LV) and left atrial (LA) function irrespective of the extent of myocardial hypertrophy which associates the increased afterload. We hypothesize that aortic valve replacement (AVR) and removal of LV outflow tract obstruction should result in LA size and function recovery, even partial, and were set to study this in a group of patients with AVR for AS. METHODS: Peak atrial longitudinal strain (PALS) was evaluated in 43 patients with severe isolated AS and normal EF (56.6 ± 3.8%) and no obstructive coronary artery disease candidates for AVR, pre-operatively and then 40 days and 3 months after surgery. Results were compared with those from 34 age- and gender-matched healthy controls. RESULTS: LVEF remained unchanged and LV mass regressed after AVR. Global PALS was reduced pre-operatively and increased 40 days after surgery (p=0.002) and showed only a slight further increase at 3 months follow-up (p<0.0001). Indexed LA volume was increased before surgery, but significantly fell 40 days after surgery (p<0.0001) and showed only a slight further reduction after 3 months (p<0.0001). Trans-aortic mean gradient change after surgery was the only independent predictor of the recovery of LA size and function. CONCLUSIONS: AVR reverses LA abnormalities and regains normal atrial function, a behavior which is directly related to the severity of pre-operative LV outflow tract obstruction. Early identification of LA size enlargement and functional disturbances might contribute to better patient's recruitment for AVR.

BELFAST centenarians: a case of optimised cardiovascular risk?

INTRODUCTION: Centenarians are reservoirs of genetic and environmental information to successful ageing and local centenarian groups may help us to understand some of these secrets. The current centenarian cohort in Belfast survived the 1970s epidemic of death from coronary heart disease in Northern Ireland, where cardiovascular mortality was almost highest in the world. These centenarians provided an opportunity to assess biological and genetic factors important in cardiovascular risk and ageing. METHODS: Thirty-five (27 female, 8 male) centenarians, participants of the Belfast Elderly Longitudinal Free-living Ageing STudy (BELFAST), were community-living and of good cognition at enrollment. RESULTS: Centenarians showed median Body Mass Index (BMI) at 25.7, systolic blood pressure 140 mmHg and diastolic blood pressure 90 mmHg respectively, and fasting glucose of 5.54 mmol/l with no sex-related difference. Lipoproteins showed median cholesterol 5.3, High Density Lipoprotein (HDL) 1.10 and Low Density Lipoprotein (LDL) 3.47 micromol/l respectively. Centenarian smokers showed no different blood pressure or lipid measurements compared with non-smokers. Malondialdehyde, a measure of lipid peroxidation, was low at 1.19, and measures of antioxidant status showed variable results. Male centenarians did not carry any of the vascular risk genotypes studied-Apolipoprotein E (ApoE), Angiotensin-Converting Enzyme (ACE) and Methylenetetrafolatedehydrogenase reductase (MTFHR), though this was not true for female centenarians. CONCLUSIONS: This small local study shows, apart from age, that Belfast centenarians carry a reasonably optimized risk profile with respect to cardiovascular disease. There is also some evidence suggesting that vascular risk factors and genotypes may be tolerated differently between the male and female centenarians. Maintaining an optimized cardiovascular risk profile seems likely to improve the chance of becoming a centenarian, especially for males.

The value of glycosylated hemoglobin (HbA1c) as a predictive risk factor in the diagnosis of diabetes mellitus (DM) in the elderly.

In order to evaluate the significance of HbA1c in the diagnosis of Diabetes Mellitus (DM) and the risk of future DM in the elderly, the HbA1c and the fasting glycemia of 2167 elderly subjects of 65-84 years were determined, taking part in the epidemiological Italian Longitudinal Study on Aging (ILSA). The subjects were divided in 3 groups according to their glycemic values, namely those with normal fasting glucose (NFG), with impaired fasting glucose (IFG), and diabetics. It has been revealed that the values of HbA1c in these 3 groups overlapped in more than 80%. The evaluation of the HbA1c levels represents a clearly lower diagnostic validity for the DM, than the fasting plasma glucose (FPG). The identification of new cases of DM in a follow-up of 3 years was modest: in the NFG group (2.35% among those who had an HbA1c<7.02 and of 2.99% of those who had HbA1c>7.02%), while in the IFG group the same analysis gave 14.14% of those with normal HbA1c, increasing progressively in parallel with the increase of the HbA1c values above 7.02%, reaching 19.59%. It is evident from these results, in agreement with the multifactorial characteristics of type 2 DM that one has to look for other predictive factors, such as the dysmetabolic lipid components, and first of all the genetic ones in the predictive diagnosis of DM.

Autopsy reports in extreme longevity.

This study aimed at establishing the prevalence, the type, the severity of various diseases, as well as the main causes of death in the elderly and ultralongevous subjects. The autopsy findings of 140 centenarians (21 males and 119 females) of the age range of 100-109 years were compared to those of 96 elderly subjects (14 males and 82 females) of the age range of 75-95 years. In all cases the clinical diagnosis, the clinical record, the macro- and microscopic findings and the autopsy protocols were evaluated. A lower prevalence (16.3% vs. 39.0%), as well as a slower and less aggressive evolution of neoplastic pathologies (frequency of metastases: 26.0% vs. 55.0%) in the centenarians, as compared to the general aging population, have been found. The chronic-degenerative pathologies, especially the cerebro-degenerative ones were observed more frequently and were of major gravity in the centenarians, compared to the elderly population. The cerebrovascular damage and the consequent cognitive deficit do not influence the survival of the longevous subjects. Intercurrent events or external accidents may interrupt the weak equilibrium of these "frail" subjects.

Pharmacotherapy in the extreme longevity.

The increased longevity brings to the appearance of more polypathologies, being frequently of chronic-degenerative type, and also an increased use of pharmaca. The present study evaluated the usual drug consumption in the ultralongevous people in comparison with their clinical conditions. A total of 602 centenarians were involved: clinical anamnesis, objective examinations and clinico-functional evaluations were performed. In 555 of them an acceptable pharmacological anamnesis was obtained. The results showed that 28 centenarians (5%) did not take any drug, 527 (95%) of them used regularly some pharmacological therapy. Their distribution was: 1 drug/day 68 (13%), 2 drugs/day 86 (16.3%), 3 drugs/day 344 (65.2%), more than 3 drugs/day 29 (5.5%). The mean daily drug consumption was 2.7+/-1.4. Good clinical conditions could be established in 115 (20.7%) of the centenarians, of them 28 subjects (24.3%) had used no drugs, 87 (75.7%) of them used 1-3 drugs/day. It was an important observation that adverse drug events (ADE) occurred in 15.2%. The ADE occurs frequently also in polypharmacological treatments, with various pharmacodynamic and pharmaco-kinetic modifications of the drugs. The mean daily drug consumption of the ultralongevous subjects was lower than that of the common elderly. This may be due to the past life of our centenarians, characterized by satisfactory health conditions, and also to a higher attention of the general practitioners in the drug prescriptions, as well as of the family members who administer the pharmaca.

Laboratory parameters in centenarians of Italian ancestry.

Studies aimed at collecting reference parameters for haematochemical analysis in the elderly are scarce and for the oldest old subjects even more rare. In order to establish the reference values for the most common laboratory text in long living individuals, we measured haematochemical parameters in >100 years old subjects and in aged subjects as control. Six hundred and two centenarians accepted to be enrolled in the study. A case history containing the complete anamnesis, clinical examinations, evaluation of the clinical cognitive and functional tests, was prepared for each centenarian. Blood samples from 120>100 years old subjects free of chronic or acute Illness (i.e. Alzheimer's disease, metabolic diseases, cardiovascular disease, stroke, neoplastic and infectious diseases) were analysed. A population of 381 healthy old subjects (age range 65-85 years old), recruited in the same geographic areas and with the same clinical characteristic of the health centenarians, was utilized as control. Significant differences were observed for blood glucose, ALT, cholesterol and platelet levels, reduced in centenarians respect to the old subjects, whereas blood urea nitrogen levels were found significantly increased in centenarians. In conclusion, reference values of the healthy adults can generally been utilized also for the healthy oldest old group, with the notable exception of the above mentioned laboratory parameters that appear to be modified in long living subjects.

Diabetes mellitus in the extreme longevity.

Epidemiological studies have revealed a progressive increase in the prevalence of diabetes mellitus in the elderly. Numerous factors are responsible for this trend, among them there are (a) the long-lasting disease due the improved therapeutic remedial (pharmacological, dietary treatments and physical activity), (b) the increased life span expectancy. The prevalence of diabetes mellitus in long living subjects is lower than in elderly people (subjects aged from 65 to 84). Senile diabetes is prevalent in long living people, and usually begins after 90 years. The incidence of neodiagnosed diabetes is higher in the oldest old than in the elderly people. Based on the results, diabetes mellitus is a negative factor for survival, and does not usually allow to achieve very old age, i.e. centenarian.

Cognitive and functional status in the extreme longevity.

Usually, the effects of cognitive decline are not noted before the age of 70 years, which involve the intellectual capacities, the attention, the processes of elaboration and the memory. The studies on the cognitive disturbances of the elderly are numerous, and document the progressive increase of cerebral deterioration with advancing age. However, only a few studies refer to the significance of the cognitive disturbances in the clinical conditions and autonomy of the long living subjects. For this reason, we studied the cerebral deterioration of an adequate number of centenarians in correlation with their clinical conditions and autonomy. Our centenarian sample derived from the Italian multi-center study on centenarians (IMUSCE), which was an epidemiological study which identified 1173 centenarians (202 males, 971 females) in the age range of 100-109 years. From this sample, we analyzed 346 subjects as far as the cognitive functions and the degree of autonomy by using the psychometric tests of the mini-mental state examination (MMSE) and the instrumental activities of daily living (IADL) for the functional evaluations. In addition, we evaluated the clinical conditions of the subjects dividing them in three groups: Group A (those in good clinical conditions), Group B (those in discrete clinical conditions), and Group C (those in deteriorated clinical conditions). These analyses revealed that 187 (54.1%) of the 346 examined centenarians have shown an MMSE score in the normal range (score ratio from 1.0 to 0.63). The cognitive disorders are present in the centenarians in a clearly higher frequency (13.1%), than found in the common elderly (5.1%). The severe cognitive disorders do not allow a total autonomy or even a slight dependency. Only six subjects (1.7%) of the total sample were totally independent. These subjects had no cognitive disorders, and were in good clinical conditions. The results show that having an MMSE score in the normal range, and being in good clinical conditions are necessary but not sufficient prerequisites for a total autonomy in the IADL scores.

Genealogy of centenarians and their relatives: a study of 12 families.

The longevity is a complex phenomenon in which specific genetic properties seem to play a role. The present study intended to reconstruct the genealogical tree of 12 subjects, being residents of one Northern and one Southern province of Italy, in order to establish the longevity of the ancestors. Detailed studies have been performed in the registry offices and the historic archives. The research method started from the identification of the centenarians on the basis of the documentation of the relevant birth document, it was continued by identifying the documents of birth, marriages and death of the parents of the centenarians. This way we proceeded systematically backwards in time. In addition, we verified the medium life span of the Italian population in the given periods of time, when the centenarians and their ascending lines had lived. These results offer clear historic-statistical evidences for the genetic basis of longevity.

Diabetes mellitus in the elderly: diagnostic features.

The new diagnostic criteria of the diabetes do not consider the age of the subjects. It has been demonstrated that the fasting glucose values as well as the glycemia levels after oral glucose load increase with age. Therefore, it is necessary to evaluate whether the new diagnostic criteria are valid for the elderly subjects also. In spite of the findings that among the subjects with fasting glycemia of 126-140 mg/ml subsequent controls after long times often revealed the presence of impaired fasting glucose (IFG) and numerous cases with IFG displayed values <110 mg/dl after longer times, the present authors accept the new diagnostic criteria even for the elderly subjects. However, they emphasize the importance of distinguishing diabetes in the elderly in subclasses, such as clinically manifest diabetes, mild diabetes and diabetic glucose tolerance (DGT) type, in order to establish the early diagnosis of diabetes, and therefore, to prevent the chronic vascular complications.

Successful aging in centenarians: myths and reality.

The term "successful aging" appeared in the first issue of "The Gerontologist" in 1961. During the successive years, this expression has changed its meaning. Nowadays, successful aging means "absence of diseases and disabilities, maintenance of high levels of physical and cognitive abilities, preservation of the social and productive activities". It has become a common opinion that the centenarians may represent the prototypes of the successful aging. This motivated our work to study the clinical, psychical, and functional aspects in a centenarian group, verifying the real autonomy, instrumental capacities, and working abilities. Our study pool consisted of 602 centenarians, who were also subjects of then epidemiological studies of the Italian Multicenter Studies on Centenarians (IMUSCE). All subjects underwent a clinical-anamnestic evaluation, cognitive-functional tests by means of the mini mental state examination (MMSE), the independence index in activities of daily living (ADL), the instrumental activities of daily living (IADL) scale. The centenarians were classified in three groups, according to the criteria elaborated previously by us, based on their psychophysical status and autonomy, as follows. Group A: centenarians in good health status; Group B: centenarians in an intermediate health status. Group C: centenarians in bad health status. Group A represented 20.0% of the total pool, Group B amounted to 33.4%, and the Group C was 46.6%. The centenarians of Group A presented normal ADL values, and 47.9% of them were autosufficient in all functions; 5.7% of them were independent in all IADL items. These data confirm that the centenarians of Group A are free of invalidating chronic diseases, are autonomous, maintain good physical and cognitive capacities, however, have not maintained any social or productive activities. Therefore, they cannot be considered as prototypes of successful aging.

Interleukin-18 (IL-18) and matrix metalloproteinase-9 (MMP-9) in post-menopausal osteoporosis.

This survey covered 60 post-menopausal women with osteoporosis. The patients were divided into three equal groups, and each group was treated with one of the three so-called anti-resorptive drugs, namely alendronate (10 mg/day) risedronate (5 mg/day) and raloxifene (60 mg/day) for 12 months. The Elisa technique was used to measure circulating IL-18 and MMP-9. Lumbar bone mineral density (BMD) levels were determined by using dexa mineralometry (Lunar DPX) at baseline and after 12 months of treatment. The results showed comparable responses of the patients treated with alendronate or risedronate, being a significant increase in BMD, an increase in circulating IL-18, and only slight modifications in circulating MMP-9 levels. After 12 months of treatment with raloxifene, there were minimal, non-significant increases in BMD, slight modifications in IL-18 levels, and a significant reduction in circulating MMP-9 levels. The conclusions can be drawn that all three drugs, albeit through different mechanisms, can be considered valid treatments for post-menopausal osteoporosis. Although measurements of circulating IL-8 and MMP-9 levels allowed us to differentiate the effects of the three drugs used, as of today, they have no real role in the diagnosis and/or follow-up of osteoporosis.

Cardiovascular aging and psychometric performances: correlations in a group of ultraseptagenarian elderly.

Aging of the Italian population resulted in a net increase of the cardiovascular pathologies, and the correlated disabilities. In addition, the cardiovascular diseases represent actually in Italy the most frequent cause of death. With advancing age, both the heart and the blood vessels undergo numerous morphological and functional modifications, which are reducing the functional reserves of these organs. The present study looked for correlation between the cardiac functionality and the cognitive, as well as affective functions. Furthermore, we evaluated the functional variations of the autonomy and autosufficiency of the same patients. We had 171 enrolled subjects (108 women and 63 men), all above the age of 70 years. Based on the classification of the New York Heart Association (NYHA), 85 of these patients (35 men and 50 women) had a II class (Group A), and 86 of them (28 men and 58 women) a III NYHA class of heart function (Group B). We included only patients who did not have any cerebrovascular event yet, and were not bed-ridden. The psychometric performance has been evaluated by using the mini-mental state examination (MMSE), the geriatric depression scale (GDS), the activities of daily living (ADL) and the instrumental activities of daily living (IADL) scales. Cardiac functions have been measured by Doppler echocardiography, in M-mode. The Group A (of mean age 71 +/- 3 years) displayed ventricular ejection fraction (VEF) values in average of 43 +/- 4%, MMSE scores 27 +/- 2; GDS scores 14 +/- 3; IADL 6 +/- 1, and ADL = 6, i.e., maintained a complete autosufficiency. The Group B (mean age 74 +/- 4 years) displayed VEF values in average of 26 +/- 3%, MMSE scores 23 +/- 4; GDS scores 22 +/- 3; IADL 4 +/- 2, and ADL = 4 +/- 1, i.e., had a reduced autosufficiency. These results confirm that also the heart pays a toll for aging: the myocardial contractility becomes significantly altered, meaning the loss of cardiac functions itself. These morpho-functional heart alterations are accompanied by decreased psychometric performances during aging, with consequent reductions of cognitivity, affectivity, autosufficiency and autonomy, involving a complex decrease of the quality of life.