Vincenzo Canonico

Cognitive impairment and cardiovascular diseases in the elderly. A heart–brain continuum hypothesis

The aging population is increasing and, therefore, a higher prevalence of cardiac disease is emerging; including hypertension, coronary artery disease, atrial fibrillation and chronic heart failure. Large cohort studies have revealed a relationship among increased risk for cognitive impairment and dementia in cardiovascular diseases probably due to embolic stroke or chronic cerebral hypoperfusion. Thus, the aim of the present review is to overview the studies that investigate the presence and/or the development of cognitive impairments and dementia in patients with varied types of cardiovascular disease. Finally, a continuum among hypertension, coronary artery disease, atrial fibrillation and chronic heart failure with to the development of cognitive impairment and progression to dementia has been hypothesized.

Role of Ventricular Rate Response on Dementia in Cognitively Impaired Elderly Subjects with Atrial Fibrillation: A 10-Year Study

Background: The role of ventricular rate response (VRr) on the incidence of dementia in elderly subjects with cognitive impairment and atrial fibrillation (AF) is not known. Thus, we examined the ability of VRr to predict dementia in cognitively impaired elderly subjects with and without AF. Methods: A total of 358 cognitively impaired elderly subjects (MMSE <24) with and without AF were stratified in low/high (<50/>90) and moderate (>50/<90 bpm) VRr. A 10-year follow-up was performed. Results: Cognitively impaired subjects with dementia at the end of the follow-up were 135 (37.7%): 33 in the presence (75.0%) and 102 (32.5%) in the absence of AF (p < 0.001). Multivariate analysis shows that AF is a strong predictor of dementia (hazard ratio, HR = 4.10; 95% confidence interval, CI = 1.80–9.30, p < 0.001). More importantly, low/high VRr (<50/>90 bpm) is predictive of dementia in the presence (HR = 7.70, 95% CI = 1.10–14.20, p = 0.03) but not in the absence (HR = 1.85; 95% CI = 0.78–4.47; p = 0.152) of AF. Conclusions: This study demonstrates that AF predicts dementia in elderly subjects with cognitive impairment. Moreover, VRr seems to play a key role in the incidence of dementia in cognitively impaired elderly subjects with AF.

Autonomic dysfunction in Alzheimer's disease: tools for assessment and review of the literature.

Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimers disease are also implicated in autonomic nervous system regulation, and it has been hypothesized that the deficit in central cholinergic function observed in Alzheimers disease could likely lead to autonomic dysfunction. Several feasible tests can be used in clinical practice for the assessment of parasympathetic and sympathetic functions, especially in terms of cardiovascular autonomic modulation. In this review, we describe the different tests available and the evidence from the literature which indicate a definite presence of autonomic dysfunction in dementia at various degrees. Importantly, the recognition of dysautonomia, besides possibly being an early marker of dementia, would help prevent the disabling complications which increase the risk of morbidity, institutionalization, and mortality in these individuals.

Lymphocyte G-protein-coupled receptor kinase-2 is upregulated in patients with Alzheimer's disease.

Alterations in signal transduction pathway of G-protein-coupled receptors (GPCRs) have been found in the cerebrocortex and in the peripheral cultured tissues of patients with Alzheimers disease (AD). The G-protein-coupled receptor kinase-2 (GRK2) plays an important role in regulating the GPCRs signaling: its increased expression is associated with receptor desensitization. The aim of this study was to explore GRK2 levels in peripheral lymphocytes of AD patients and to establish a correlation between lymphocyte protein concentrations and the degree of cognitive impairment. GRK2 mRNA and protein expression were evaluated in the lymphocytes of AD patients with mild or moderate/severe cognitive impairment and in age-matched healthy subjects. Both GRK2 mRNA and protein expression were higher in AD patients lymphocytes compared to controls. Furthermore, lymphocyte GRK2 levels were significantly correlated to the degree of cognitive decline. Our preliminary data suggest that GRK2 is involved in GPCRs coupling dysfunction observed in AD patients. Further studies are needed in order to verify whether the lymphocyte GRK2 might be utilized as a novel biomarker in AD diagnosis and clinical monitoring.

Evaluation of the efficacy of slow-release nifedipine in systemic hypertension by ambulatory intraarterial blood pressure monitoring

We assessed the effect on blood pressure of administration of slow-release nifedipine tablets (20 mg) by continuous intraarterial blood pressure monitoring (Oxford system) in 10 patients with untreated essential hypertension. Blood pressure was recorded under control conditions and during nifedipine therapy. During each monitoring period patients were instructed to perform various types of exercise. The initial dose of nifedipine was 20 mg twice a day (8:00 a.m. and 8:00 p.m.). For patients in whom arterial pressure control was not achieved, the dose of the drug was increased at weekly intervals, first to 40 mg in the morning and 20 mg at night and then to 40 mg twice a day. The average daily dose was 52 mg. Nifedipine twice a day significantly reduced systolic and diastolic blood pressures both during the day and during the night. The rise in blood pressure due to dynamic or isometric exercise or to mental testing was blunted. Heart rate did not change. Orthostatic hypotension was not observed, and there were only minor side effects, which did not require withdrawal of the patient from the trial. Unavailability of nifedipine from this preparation svas satisfactory, as shown by plasma concentrations which remained constantly in the therapeutic range. Thus, slow-release nifedipine given twice a day represents an effective treatment in patients with essential arterial hypertension. The reduced frequency of administration required may improve patient compliance with this treatment.

Comparison of verapamil versus felodipine on heart rate variability in hypertensive patients.

OBJECTIVE We evaluated the effect of two calcium channel blockers, verapamil and felodipine, on heart rate variability in hypertensive patients. DESIGN Time and frequency domain measures of heart rate variability were obtained from 24 h Holter recording in 25 previously untreated hypertensive patients without left ventricular hypertrophy, before and after 3 months of verapamil slow-release treatment (240 mg once daily) or felodipine extended-release treatment (10 mg once daily). RESULTS Blood pressure values decreased with both drugs. Measures of heart rate variability, comparable at baseline in the two groups, were unchanged after felodipine. After verapamil, the average RR interval, the square root of the mean of the squared differences between all adjacent normal RR intervals (r-MSSD) and the percentage of differences between all adjacent normal RR intervals > 50 ms (pNN50), measures of vagal modulation of heart rate, increased (from 735 +/- 67 to 827 +/- 84 ms, P < 0.001; from 30 +/- 10 to 44 +/- 15 ms, P < 0.001; and from 3 +/- 2 to 7 +/- 6%, P < 0.01, respectively) and were higher than after felodipine. The coefficient of variation, a measure that compensates for heart rate effects, increased only after verapamil (from 5.8 +/- 1.3% to 6.6 +/- 1.0%; P < 0.05). High frequency power and its coefficient of component variance, both representing the vagal modulation of heart rate, increased after verapamil (from 5.33 +/- 0.29 to 5.80 +/- 0.27 In units, P < 0.001 and from 1.9 +/- 0.3 to 2.2 +/- 0.25%; P < 0.05). Finally, the low to high frequency power ratio, an indicator of sympathovagal balance, with a high value suggesting a sympathetic predominance, decreased after verapamil (from 2.16 +/- 0.41 to 1.36 +/- 0.35; P < 0.001), confirming the improvement in vagal modulation of heart rate. CONCLUSION In hypertensive patients, despite a comparable anti-hypertensive effect, verapamil, but not felodipine, has favourable effect on cardiac autonomic control.

Regional coronary hemodynamic effects of diltiazem in man

We evaluated the changes in regional coronary hemodynamics induced by diltiazem, 0.25 mg/kg intravenously, in nine patients with 75% to 90% diameter stenosis of the left anterior descending coronary artery (LAD) (group 1) and in 10 patients with 100% occlusion of the LAD and collaterals to the distal LAD (group 2). Although diltiazem induced similar changes in systemic hemodynamics in the two groups, a decrease in anterior coronary vascular resistance (ACVR) and an increase in great cardiac vein flow (GCVF) were observed after administration of diltiazem in all patients in group 1 but in only 6 of 10 patients in group 2 (subgroup 2B). ACVR increased and GCVF decreased after administration of diltiazem in 4 of 10 patients in group 2 (subgroup 2A). Clinico-angiographic characteristics, origin of collaterals, and diltiazem-induced changes in systemic hemodynamics were similar in subgroups 2A and 2B. Thus diltiazem increases coronary flow distal to a stenotic coronary artery but can decrease regional coronary flow and increase regional coronary resistance in a minority of patients with an occluded coronary artery supplied by collaterals, probably through a steal mechanism.