Association of bradykinin receptor 2 (BDKRB2) variants with physical performance and muscle mass: Findings from the LACE sarcopenia trial.

INTRODUCTION: Understanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722-9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia. METHODS: We performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants' blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures. RESULTS: Data from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9-1, p<0.001), suggesting an improvement. In men, the -9-9 genotype was associated with lower arm fat (-9-9 2.39kg vs -9+9 2.72kg vs +9+9 2.76kg, p = 0.019). CONCLUSION: In men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass.

Activin type I receptor polymorphisms and body composition in older individuals with sarcopenia-Analyses from the LACE randomised controlled trial.

BACKGROUND: Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia. METHODS: We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial. RESULTS: Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone. CONCLUSION: These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial.

BACKGROUND: Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study. METHODS: Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables. RESULTS: Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo. CONCLUSION: Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial.

BACKGROUND: This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. METHODS: Placebo-controlled, parallel group, double-blind, randomized two-by-two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4 m walk) and/or low handgrip strength (women < 20 kg, men < 30 kg) plus low muscle mass (using sex and body mass index category-specific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomized to perindopril 4 mg or placebo, and to oral leucine powder 2.5 g or placebo thrice daily. The primary outcome was the between-group difference in the short physical performance battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy. RESULTS: We screened 320 people and randomized 145 participants compared with an original target of 440 participants. For perindopril [n = 73, mean age 79 (SD 6), female sex 39 (53%), mean SPPB 7.1 (SD 2.3)] versus no perindopril [n = 72, mean age 79 (SD 6), female sex 39 (54%), mean SPPB 6.9 (SD 2.4)], median adherence to perindopril was lower (76% vs. 96%; P < 0.001). Perindopril did not improve the primary outcome [adjusted treatment effect -0.1 points (95%CI -1.2 to 1.0), P = 0.89]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.4 kg (95%CI -1.1 to 0.3), P = 0.27]. More adverse events occurred in the perindopril group (218 vs. 165), but falls rates were similar. For leucine [n = 72, mean age 78 (SD 6), female sex 38 (53%), mean SPPB 7.0 (SD 2.1)] versus no leucine [n = 72, mean age 79 (SD 6), female sex 40 (55%), mean SPPB 7.0 (SD 2.5)], median adherence was the same in both groups (76% vs. 76%; P = 0.99). Leucine did not improve the primary outcome [adjusted treatment effect 0.1 point (95%CI -1.0 to 1.1), P = 0.90]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.3 kg (95%CI -1.0 to 0.4), P = 0.47]. Meta-analysis of angiotensin converting enzyme inhibitor/angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB [between-group difference -0.1 points (95%CI -0.4 to 0.2)]. CONCLUSIONS: Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta-analysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.

Blood pressure variability and cognitive decline in older people: a 5-year longitudinal study.

BACKGROUND: Cognitive impairment is common in later life. Identifying potential modifiable risk factors for cognitive decline may ameliorate the burden of disease. Cross-sectional studies show an association between blood pressure (BP) variability and impaired cognitive function in patients with hypertension and/or dementia. However, research examining the association between BP variability and cognitive function in the general older population is scarce. OBJECTIVE: In this study, we examined the association between BP variability and cognitive function over 5-year follow-up in an unselected community-dwelling cohort. METHODS: Ambulatory BP monitoring was performed in 353 community-dwelling people aged at least 65 years. Cognitive assessment, using the Mini Mental State Examination (MMSE) and Cambridge Cognitive Examination (CAMCOG), was performed at baseline and at 5-year follow-up. BP variability was calculated using the coefficient of variation. Cognitive change over 5 years was defined as baseline score minus follow-up score. RESULTS: Increased daytime systolic variability was associated with poorer performance on the CAMCOG total score and subscores. Daytime diastolic variability was associated with poorer performance on total CAMCOG, CAMCOG executive score, and MMSE. These findings were independent of demographic and cardiovascular risk factors. Daytime systolic variability was also independently associated with greater decline in total CAMCOG and MMSE scores over 5-year follow-up. CONCLUSION: Increased BP variability is associated with poorer cognitive function in older people and may represent a novel modifiable risk factor for cognitive decline.

A prospective study of the association between orthostatic hypotension and falls: definition matters.

Background: falls are a common cause of morbidity and mortality in older people. Orthostatic hypotension (OH) is considered an important risk factor for falls, but longitudinal studies have failed to show a clear association. This disparity may be because conventional methods of measuring blood pressure (BP) changes are too imprecise and/or the diagnostic criteria for OH are inappropriate. Over recent years, beat-to-beat BP monitoring techniques, which enabled accurate measurement of vasodepression, have become widely used and in 2011 the American Academy of Neurology produced revised diagnostic criteria for OH. Objective: to use beat-to-beat monitoring to compare the prevalence of OH using the standard and revised diagnostic criteria and to establish which criteria are most valuable in predicting future falls. Design: two hundred and ninety-seven community-dwelling older people aged ≥65 years underwent assessment. Active stand using digital photoplethysmography was used to record postural change in BP. One hundred participants were asked to complete prospective weekly falls diaries for 12 months. Results: OH, defined according to the revised American Academy of Neurology diagnostic criteria, affected 25% of participants and was an independent predictor of falls (odds ratio 10.299, 95% confidence interval [95% CI]: 1.703-61.43, P = 0.011) and time to first fall (hazard ratio 3.017, 95% CI: 1.291-7.050, P = 0.011). OH, defined according to standard criteria, affected 80% of the population and was not associated with falls. Conclusion: OH, defined according to 2011 criteria, is associated with falls and time to first fall. These findings indicate that beat-to-beat monitoring and the 2011 criteria for OH are valuable in the clinical assessment of older fallers.

Modified criteria for carotid sinus hypersensitivity are associated with increased mortality in a population-based study.

AIMS: Carotid sinus hypersensitivity (CSH) is arbitrarily defined as ≥3 s asystole or vasodepression of ≥50 mmHg in response to carotid sinus massage (CSM). Using this definition, 39% of older people meet the criteria for CSH. It has been suggested that current criteria are too sensitive. Krediet et al. [The history of diagnosing carotid sinus hypersensitivity: why are the current criteria too sensitive? Europace 2011;13:14-22] and Kerr et al. [Carotid sinus hypersensitivity in asymptomatic older persons: implications for diagnosis of syncope and falls. Arch Intern Med 2006;166:515-20] have proposed modified criteria. This population-based study aimed to compare the prevalence of CSH defined according to standard, Krediet and Kerr criteria, and to establish if CSH defined according these criteria is associated with all-cause mortality. METHODS AND RESULTS: A total of 272 community-dwelling people aged ≥65 were recruited at random. Carotid sinus massage was performed for 5 s in supine and head-up positions. Heart rate and blood pressure response were recorded using an electrocardiogram and photoplethysmography. Cox regression analysis was used to examine the association between each definition of CSH and all-cause mortality. The prevalence of CSH defined according to standard, Krediet, and Kerr criteria was 39, 52, and 10%, respectively. Seventy-one participants died over a mean follow-up of 8.6 years (SD 2.1). Carotid sinus hypersensitivity defined according to standard and Krediet criteria was not associated with survival. Carotid sinus hypersensitivity defined according to Kerr criteria was associated with all-cause mortality independent of age and sex [hazard ratio (HR) 2.023 (95% confidence interval (95% CI) 1.131-3.618) P = 0.018)]. This remained significant after adjusting for cardiovascular risk factors [HR 2.174 (1.075-3.900) P = 0.009]. CONCLUSION: Carotid sinus hypersensitivity defined according to Kerr criteria is associated with increased mortality. This raises an interesting question as to the suitability of the current criteria used to define CSH.

Ambulatory Blood Pressure Variability Increases Over a 10-Year Follow-Up in Community-Dwelling Older People.

BACKGROUND: Greater ambulatory blood pressure variability (ABPV) is associated with end-organ damage and increased mortality. Age-related changes in the cardiovascular and autonomic nervous systems make age-associated increases in ABPV likely. Cross-sectional studies support this hypothesis, showing greater ABPV among older compared to younger adults. The only longitudinal study to examine changes in ABPV, however, found ABPV decreased over 5 years follow-up. This unexpected observation probably reflected the highly selected nature of the study participants. METHODS: In this longitudinal study, we assessed changes in ABPV over 10 years in a community-cohort of older people. In addition, we examined the extent to which ABPV was predicted by demographics, cardiovascular risk factors, and medication. Clinical examination and 24-hour ambulatory blood pressure monitoring were carried out at baseline and at 10 years follow-up in 83 people, median age 70 years. ABPV was calculated using SD and coefficient of variation (Cv). Three time periods were examined: daytime, nighttime, and 24 hours. RESULTS: Daytime and 24-hour, systolic and diastolic, SD, and Cv were significantly greater at follow-up than at baseline (P < 0.001 in all cases). Mean BP did not change. CONCLUSIONS: Multilevel modeling showed follow-up interval had a significant, positive effect on SD and Cv (P < 0.004), independent of age, sex, and medication.ABPV increased over a 10-year follow-up despite stable mean BP. ABPV may therefore be an additional target for treatment in older people. Future studies should examine what degree of ABPV is harmful and if control of ABPV reduces adverse outcome.

Brain oxygenation responses to an autonomic challenge: a quantitative fMRI investigation of the Valsalva manoeuvre.

In late age, the autonomic nervous system (ANS) has diminished ability to maintain physiological homeostasis in the brain in response to challenges such as to systemic blood pressure changes caused by standing. We devised an fMRI experiment aiming to map the cerebral effects of an ANS challenge (Valsalva manoeuvre (VM)). We used dual-echo fMRI to measure the effective transverse relaxation rate (R2*, which is inversely proportional to brain tissue oxygenation levels) in 45 elderly subjects (median age 80 years old, total range 75-89) during performance of the VM. In addition, we collected fluid-attenuated inversion recovery (FLAIR) data from which we quantified white matter hyperintensity (WMH) volumes. We conducted voxelwise analysis of the dynamic changes in R2* during the VM to determine the distribution of oxygenation changes due to the autonomic stressor. In white matter, we observed significant decreases in oxygenation levels. These effects were predominantly located in posterior white matter and to a lesser degree in the right anterior brain, both concentrated around the border zones (watersheds) between cerebral perfusion territories. These areas are known to be particularly vulnerable to hypoxia and are prone to formation of white matter hyperintensities. Although we observed overlap between localisation of WMH and triggered deoxygenation on the group level, we did not find significant association between these independent variables using subjectwise statistics. This could suggest other than recurrent transient hypoxia mechanisms causing/contributing to the formation of WMH.

Cardiac Iodine-123-Meta-Iodo-Benzylguanidine Uptake in Carotid Sinus Hypersensitivity.

BACKGROUND: Carotid sinus syndrome is the association of carotid sinus hypersensitivity with syncope, unexplained falls and drop attacks in generally older people. We evaluated cardiac sympathetic innervation in this disorder in individuals with carotid sinus syndrome, asymptomatic carotid sinus hypersensitivity and controls without carotid sinus hypersensitivity. METHODS: Consecutive patients diagnosed with carotid sinus syndrome at a specialist falls and syncope unit were recruited. Asymptomatic carotid sinus hypersensitivity and non-carotid sinus hypersensitivity control participants recruited from a community-dwelling cohort. Cardiac sympathetic innervation was determined using Iodine-123-metaiodobenzylguanidine (123-I-MIBG) scanning. Heart to mediastinal uptake ratio (H:M) were determined for early and late uptake on planar scintigraphy at 20 minutes and 3 hours following intravenous injection of 123-I-MIBG. RESULTS: Forty-two subjects: carotid sinus syndrome (n = 21), asymptomatic carotid sinus hypersensitivity (n = 12) and no carotid sinus hypersensitivity (n = 9) were included. Compared to the non- carotid sinus hypersensitivity control group, the carotid sinus syndrome group had significantly higher early H:M (estimated mean difference, B = 0.40; 95% confidence interval, CI = 0.13 to 0.67, p = 0.005) and late H:M (B = 0.32; 95%CI = 0.03 to 0.62, p = 0.032). There was, however, no significant difference in early H:M (p = 0.326) or late H:M (p = 0.351) between the asymptomatic carotid sinus hypersensitivity group and non- carotid sinus hypersensitivity controls. CONCLUSIONS: Cardiac sympathetic neuronal activity is increased relative to age-matched controls in individuals with carotid sinus syndrome but not those with asymptomatic carotid sinus hypersensitivity. Blood pressure and heart rate measurements alone may therefore represent an over simplification in the assessment for carotid sinus syndrome and the relative increase in cardiac sympathetic innervation provides additional clues to understanding the mechanisms behind the symptomatic presentation of carotid sinus hypersensitivity.

Symptomatic presentation of carotid sinus hypersensitivity is associated with impaired cerebral autoregulation.

BACKGROUND: Carotid sinus hypersensitivity (CSH) is associated with syncope, unexplained falls, and drop attacks in older people but occurs asymptomatically in 35% of community-dwelling elders. We hypothesized that impaired cerebral autoregulation is associated with the conversion of asymptomatic CSH to symptomatic CSH. We therefore conducted a case-control study evaluating individuals with CSH with and without the symptoms of syncope or unexplained falls, as well as non-CSH controls, to determine whether the blood pressure and heart rate changes associated with CSH are associated with symptoms only when cerebral autoregulation is altered. METHODS AND RESULTS: Bilateral middle cerebral artery blood flow velocities (BFV) were measured in consecutive patients with symptomatic CSH (n=22) and asymptomatic controls with (n=18) and without CSH (n=14) using transcranial Doppler ultrasonography during lower body negative pressure-induced systemic hypotension. Within-group comparisons revealed significantly lower cerebrovascular resistance index (CVRi) at nadir for the asymptomatic CSH group (right, mean [95% CI]: 2.2 [1.8, 2.8] versus 2.6 [2.2, 3.0]; P=0.005; left: 2.8 [2.4, 3.3] versus 3.1 [2.7, 3.8]; P=0.016). Between-group comparisons showed higher mean BFV (right: estimated mean difference, B=5.49 [1.98, 8.80], P=0.003; left: 4.82 [1.52, 8.11], P=0.005) and lower CVRi (right: B=0.08 [0.03, 0.12], P=0.003, left: B=0.07 [0.02, 0.12], P=0.006) in asymptomatic CSH versus symptomatic CSH groups. There were no significant differences in bilateral mean BFV or right CVRi between the non-CSH and symptomatic CSH groups but differences were present for left CVRi (B=0.07 [0.02, 0.013], P=0.015). CONCLUSION: Cerebral autoregulation is altered in symptomatic CSH and therefore appears to be associated with the development of hypotension-related symptoms in individuals with CSH.

Falls and fall-related injury are common in older people with chronic liver disease.

BACKGROUND: Improved survival with chronic liver disease (CLD) and increased incidence in the older has led to a rapidly expanding population which faces similar "geriatric syndromes" as the general population. With risk factors such as autonomic dysfunction, cognitive impairment, and muscle abnormalities in CLD it is expected that falls and injury will be common. AIM: To determine prevalence of falls and injury in chronic liver disease and to identify potential modifiable fall associations. METHODS: Falls prevalence was estimated by providing patients aged ≥ 65 years with CLD a falls data collection tool, via the post or in the clinic. A younger CLD cohort and age-matched and sex-matched community controls was used for comparison. A sub-group underwent multidisciplinary falls assessment to identify modifiable fall associations. RESULTS: Falls were significantly more common in older people with CLD (47 % in previous year) than in controls; incidence of injury did not differ. Regression identified orthostatic symptoms, lower-limb strength, and fear of falling as being independently associated with falls in CLD. Those who had fallen had significantly greater difficulty with daily activities. CONCLUSION: Falls are prevalent in older people with CLD, and are potentially preventable with multifactorial intervention. Services must prepare for expansion in the older CLD population; here we demonstrate how this expansion may affect falls services and provide a potential therapeutic target.

Carotid sinus hypersensitivity: disease state or clinical sign of ageing? Insights from a controlled study of autonomic function in symptomatic and asymptomatic subjects.

AIMS: This study sought to improve the currently limited understanding of the pathophysiology of carotid sinus hypersensitivity (CSH) by comparing autonomic function measured by heart rate variability (HRV) and baroreflex sensitivity inpatients with symptomatic CSH and asymptomatic individuals with and without CSH. METHODS AND RESULTS: Twenty-two patients with symptomatic CSH, 18 individuals with asymptomatic CSH, and 14 asymptomatic older individuals without CSH were recruited to our study. Non-invasive measurements of heart rate and blood pressure were obtained during 10 min of supine rest. Low frequency (LF), high frequency (HF), and total power spectral density (PSD) for HRV were determined using the autoregressive method. The baroreflex slope (BRS) and baroreflex effectiveness index (BEI) were determined using the sequence method for baroreflex sensitivity. There were significant increases in the LF-HRV (P = 0.014), total PSD (P = 0.031), LF:HF (P = 0.047), normalized (nu) LF-HRV (0.049), down ramp BEI (P = 0.017), and total BEI (P = 0.038) in the symptomatic CSH group compared with non-CSH controls. The asymptomatic CSH group had significantly higher LF-HRV (P = 0.001), total PSD (P = 0.002), nuLF-HRV (P = 0.026), and LF:HF (P = 0.030), as well as up, down, and total BRS (P = 0.012, P = 0.015, and P = 0.011, respectively) and BEI (P = 0.049, P = 0.001, and P = 0.006, respectively) than non-CSH control participants. CONCLUSION: This study has demonstrated an association between CSH with increased resting sympathetic activity and baroreflex sensitivity regardless of the presence of symptoms, indicating the presence of autonomic dysregulation in individuals with CSH. Our findings therefore suggest that CSH is part of a generalized autonomic disorder but do not differentiate between asymptomatic and symptomatic individuals.

A study of orthostatic hypotension in late-life depression.

OBJECTIVE: Studies examining vascular risk factors in depression report conflicting evidence but have not assessed orthostatic hypotension, a recently recognized risk factor for white matter hyperintensities. METHOD: The authors used noninvasive phasic orthostatic blood pressure monitoring to assess orthostatic hypotension in 17 subjects with late-life major depression and 17 comparison subjects. All received a neuropsychiatric assessment and standardized cardiovascular assessment. RESULTS: The authors found a higher proportion of subjects met standard criteria for orthostatic hypotension in the depressed group (94% versus 65%, X = 4.5, df = 1, p = 0.034), and the degree of systolic blood pressure drop on standing was highly significantly greater in this group (t = 4.02, df = 32, p <0.001; mean drop of 46 mm Hg). Depressed subjects also experienced more clinical symptoms consistent with orthostatic hypotension. CONCLUSIONS: Our findings suggest orthostatic hypotension may be an important factor in explaining the absence of an excess of clinically determined vascular risk factors in late-life depression.

Autonomic dysfunction in primary biliary cirrhosis correlates with fatigue severity.

BACKGROUND AND AIMS: Autonomic dysfunction has previously been described in primary biliary cirrhosis patients. In nonhepatic diseases, fatigue is associated with autonomic dysfunction and impaired baroreflex sensitivity. Here, we investigate the prevalence of autonomic dysfunction using highly sensitive detection modalities and its relationship with fatigue in both noncirrhotic and cirrhotic primary biliary cirrhosis patients. METHODS: Autonomic reflex tests were performed, using continuous blood pressure and electrocardiograph measurement in 47 primary biliary cirrhosis patients and age and sex-matched controls. Fatigue was measured using the primary biliary cirrhosis-40. RESULTS: In all, 100% of precirrhotic and 81% of cirrhotic primary biliary cirrhosis patients exhibited autonomic dysfunction. Valsalva ratio and 30 : 15 ratio (measures of parasympathetic autonomic dysfunction) were significantly lower in primary biliary cirrhosis patients than in controls (valsalva ratio: 1.42 vs. 1.57; P=0.01, 30 : 15: 1.1 vs. 1.2; P=0.01). Blood pressure drop on standing (sympathetic autonomic dysfunction) was greater in the primary biliary cirrhosis group (31+/-22 vs. 23+/-15 mmHg; P=0.03). Valsalva phase IV size was similar between primary biliary cirrhosis patients and controls, however, time to phase IV was significantly longer (P=0.01), suggesting adrenergic failure. Increasing fatigue was associated with impaired baroreflex sensitivity and an earlier, bigger phase IV (sympathetic overactivity). No significant differences were seen, between cirrhotic and noncirrhotic patients. CONCLUSION: The prevalence of autonomic dysfunction in primary biliary cirrhosis patients is significantly higher than has previously been thought to be the case. Indeed, when sensitive detection modalities are used, it is found to be almost universal at all stages of the disease process. Fatigue in primary biliary cirrhosis is associated with abnormalities of autonomic function.

Carotid sinus hypersensitivity in asymptomatic older persons: implications for diagnosis of syncope and falls.

BACKGROUND: Carotid sinus hypersensitivity is the most commonly reported cause of falls and syncope in older persons. Recent guidelines recommend 5 to 10 seconds of carotid sinus massage in supine and upright positions with beat-to-beat monitoring. The aim of this study was to determine the prevalence of carotid sinus hypersensitivity in (1) an unselected community sample of older people and (2) a subsample with no history of syncope, dizziness, or falls using recently standardized diagnostic criteria. METHODS: One thousand individuals older than 65 years were randomly sampled from a single general practice register; 272 participants underwent supine and upright carotid sinus massage with continuous heart rate and phasic blood pressure monitoring. Carotid sinus hypersensitivity was defined as asystole of 3 seconds or greater and/or a drop in systolic blood pressure of 50 mm Hg or greater. RESULTS: Carotid sinus hypersensitivity was present in 107 individuals (39%); 24% had asystole of 3 seconds or greater during carotid sinus massage; and 16% had symptoms (including syncope) with carotid sinus hypersensitivity. Age (odds ratio, 1.05; 95% confidence interval, 1.00-1.09) and male sex (odds ratio, 1.71; 95% confidence intervals, 1.04-2.82) were the only predictors of carotid sinus hypersensitivity. In 80 previously asymptomatic individuals, carotid sinus hypersensitivity was present in 28 (35%) and accompanied by symptoms in 10. The 95th percentile for carotid sinus massage response was 7.3 seconds' asystole and a 77-mm Hg drop in systolic blood pressure. CONCLUSIONS: Carotid sinus hypersensitivity is common in older persons, even those with no history of syncope, dizziness, or falls. The finding of a hypersensitive response should not necessarily preclude further investigation for other causes of syncope.

Reduced heart rate variability and baroreflex sensitivity in primary biliary cirrhosis.

BACKGROUND: Standardized mortality ratio for primary biliary cirrhosis (PBC) is 2.87. Even after accounting for liver and cancer-related deaths there is an unexplained excess mortality associated with PBC. We have assessed heart rate variability (HRV) and baroreflex sensitivity (BRS) risk factors associated with cardiovascular mortality, in 57 PBC patients and age- and sex-matched normal controls. METHODS: HRV and BRS were measured non-invasively in subjects and controls. Beat to beat RR interval and 'Portapres' blood pressure data were processed using power spectral analysis. Power was calculated in very low frequency (VLF), low-frequency (LF) and high-frequency (HF) bands according to international guidelines. BRS (alpha) was computed using cross-spectrum analysis. Patients also underwent fatigue severity assessment using a measure validated for use in PBC. RESULTS: PBC patients had significantly lower total HRV compared with controls (P=0.02), with the reduction occurring predominantly in the LF domain (P=0.03). BRS was also significantly reduced compared with controls (P=0.02). There were no significant differences in HRV or BRS between cirrhotic and non-cirrhotic patients. Within the PBC patient group HRV was significantly lower in fatigued than in non-fatigued patients (P<0.05). CONCLUSION: Abnormalities of HRV and BRS in PBC are not specific to advanced disease but are associated with fatigue severity. Abnormalities could be associated with increased risk of sudden cardiac death, potentially contributing to the excess mortality seen in PBC.

Autonomic function is impaired in elderly stroke survivors.

BACKGROUND AND PURPOSE: Impaired autonomic function is common in the acute poststroke phase but little is known about the longer term effects, particularly in older people. We sought to determine if autonomic function is impaired after stroke recovery in older patients. METHODS: A cross-sectional case-control study comparing autonomic function in 76 nondemented stroke patients with 70 community-living controls aged older than 75 years. RESULTS: Cases were assessed on average 9 months after stroke. From power spectral analysis of heart rate variability, stroke patients had lower total (P=0.032) and low-frequency (P=0.014) spectral densities and impaired baroreflex sensitivity (alpha low-frequency baroreflex sensitivity, P=0.006). From a series of cardiovascular autonomic reflex tests, heart rate variation during forced respiration, Valsalva ratio, and blood pressure overshoot during Valsalva maneuver were significantly lower in stroke patients (P=0.003, <0.001, and 0.027, respectively). Blood pressure response to isometric exercise was significantly exaggerated in stroke patients (P=0.007). CONCLUSIONS: Cardiovascular autonomic function is impaired long after the index event in stroke survivors. Impaired autonomic function may increase the risk of all-cause mortality and cardiovascular mortality in older stroke survivors.

Familial neurocardiogenic (vasovagal) syncope.

Vasovagal syncope (VSS) is an exaggerated tendency towards the common faint caused by a sudden and profound hypotension with or without bradycardia. The etiology of VVS is unknown though several lines of evidence indicate central and peripheral abnormalities of sympathetic function. Studies however indicate a strong heritable component to the etiology of VVS in over 20% of cases. Here, we report the findings from a family that shows apparently autosomal dominant VVS in at least three generations. Clinical findings included an absence of any discernible cardiac or autonomic abnormalities and reproducible hypotension on tilt table testing in affected family members.