Ruana Tiseo

Circadian rhythms and cardiovascular health

The functional organization of the cardiovascular system shows clear circadian rhythmicity. These and other circadian rhythms at all levels of organization are orchestrated by a central biological clock, the suprachiasmatic nuclei of the hypothalamus. Preservation of the normal circadian time structure from the level of the cardiomyocyte to the organ system appears to be essential for cardiovascular health and cardiovascular disease prevention. Myocardial ischemia, acute myocardial infarct, and sudden cardiac death are much greater in incidence than expected in the morning. Moreover, supraventricular and ventricular cardiac arrhythmias of various types show specific day-night patterns, with atrial arrhythmias--premature beats, tachycardias, atrial fibrillation, and flutter - generally being of higher frequency during the day than night--and ventricular fibrillation and ventricular premature beats more common, respectively, in the morning and during the daytime activity than sleep span. Furthermore, different circadian patterns of blood pressure are found in arterial hypertension, in relation to different cardiovascular morbidity and mortality risk. Such temporal patterns result from circadian periodicity in pathophysiological mechanisms that give rise to predictable-in-time differences in susceptibility-resistance to cyclic environmental stressors that trigger these clinical events. Circadian rhythms also may affect the pharmacokinetics and pharmacodynamics of cardiovascular and other medications. Knowledge of 24-h patterns in the risk of cardiac arrhythmias and cardiovascular disease morbidity and mortality plus circadian rhythm-dependencies of underlying pathophysiologic mechanisms suggests the requirement for preventive and therapeutic interventions is not the same throughout the day and night, and should be tailored accordingly to improve outcomes.

Administration-time-dependent effects of blood pressure-lowering medications: basis for the chronotherapy of hypertension.

There is growing interest on how to best tailor blood pressure (BP)-lowering medications according to the circadian (24 h) BP pattern of individual patients, that is, chronotherapy. Significant and clinically meaningful treatment–time differences in the beneficial and/or adverse effects of at least six different classes of hypertension medications are now known. Generally, calcium channel blockers are more effective with bedtime than morning dosing, and in the case of dihydropyridine derivatives bedtime dosing significantly reduces the risk of edema. Scheduling angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors at bedtime, as opposed to awakening, increases the proportion of patients with properly controlled BP, enhances the sleep-time relative BP decline towards a normal dipping pattern and best reduces urinary albumin excretion, a marker of functional renal status. The chronotherapy of conventional BP-lowering medications entails their correct scheduling with reference to the bodys circadian rhythms, not only to achieve control of daytime and night-time systolic and diastolic BP but to normalize the dipping status of the 24 h pattern. Chronotherapy constitutes a cost-effective strategy for enhancing BP control during both nocturnal sleep and daytime activity and for potentially reducing the risk of cardiovascular disease and end-organ injury of the blood vessels and tissue of the heart, brain, kidney, eye and other organs.

Chromosome 14q32 translocations involving the immunoglobulin heavy chain locus in chronic lymphocytic leukaemia identify a disease subset with poor prognosis

Immunophenotypic studies, fluorescence in situ hybridization (FISH) and conventional karyotyping were used to define the clinicobiological significance of 14q32 translocations involving the immunoglobulin gene locus (14q32/IGH) in 252 chronic lymphocytic leukaemia (CLL) patients. The following regions were studied: 13q14, centromere 12, 6q21; 11q22/ATM; 17p13/TP53, 14q32/IGH. Patients were classified as group 1 (favourable, i.e. 13q‐single or normal), group 2 (intermediate risk, i.e. +12, 6q‐, 1–2 anomalies), group 3 (unfavourable, i.e. 17p‐, 11q‐, complex karyotype), or group 4 (14q32/IGH translocation). Endpoints were treatment‐free survival (TFS) and overall survival (OS). One hundred and ten patients were included in group 1, 99 in group 2, 25 in group 3 and 18 in group 4. 14q32/IGH translocation partners were identified in eight cases (BCL2 in five cases, BCL11A, CCND3 and CDK6 in one case each). group 4 showed shorter TFS versus groups 2 and 1 (25% patients treated at 2 months vs. 12 (P = 0·02) and 20 months (P = 0·002), respectively) and shorter OS (25% patients dead at 18 months versus 50 (P = 0·0003) and >60 months (P < 0·0001) respectively. The 14q32/IGH translocation maintained prognostic significance at multivariate analysis on TFS (P = 0·025) and OS (P < 0·001), along with advanced stage and CD38+. These findings show that the 14q32/IGH translocation predicts for an unfavourable outcome in CLL and that this cytogenetic subset might be included as a separate entity in a hierarchical cytogenetic classification of CLL.

Dipper and Non-Dipper Blood Pressure 24-Hour Patterns: Circadian Rhythm–Dependent Physiologic and Pathophysiologic Mechanisms

Neuroendocrine mechanisms are major determinants of the normal 24-h blood pressure (BP) pattern. At the central level, integration of the major driving factors of this temporal variability is mediated by circadian rhythms of monoaminergic systems in conjunction with those of the hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, opioid, renin-angiotensin-aldosterone, plus endothelial systems and specific vasoactive peptides. Humoral secretions are typically episodic, coupled either to sleep and/or the circadian endogenous (suprachiasmatic nucleus) central pacemaker clock, but exhibiting also weekly, monthly, seasonal, and annual periodicities. Sleep induction and arousal are influenced also by many hormones and chemical substances that exhibit 24-h variation, e.g., arginine vasopressin, vasoactive intestinal peptide, melatonin, somatotropin, insulin, steroids, serotonin, corticotropin-releasing factor, adrenocorticotropic hormone, thyrotropin-releasing hormone, endogenous opioids, and prostaglandin E2, all with established effects on the cardiovascular system. As a consequence, physical, mental, and pathologic stimuli that activate or inhibit neuroendocrine effectors of biological rhythmicity may also interfere with, or modify, the temporal BP structure. Moreover, immediate adjustment to exogenous components/environment demands by BP rhythms is modulated by the circadian-time-dependent responsiveness of biological oscillators and their neuroendocrine effectors. This knowledge contributes to a better understanding of the pathophysiology of abnormalities of the 24-h BP pattern and level and their correction through circadian rhythm-based chronotherapeutic strategies. (Author correspondence: prf@unife.it)

Chronotype, gender and general health.

ABSTRACT Background: Light–dark alternation has always been the strongest external circadian “zeitgeber” for humans. Due to its growing technological preference, our society is quickly transforming toward a progressive “eveningness” (E), with consequences on personal circadian preference (chronotype), depending on gender as well. The aim of this study was to review the available evidence of possible relationships between chronotype and gender, with relevance on disturbances that could negatively impact general health, including daily life aspects. Methods: Electronic searches of the published literature were performed in the databases MEDLINE and Web of Science, by using the Medical Subject Heading (MeSH), when available, or other specific keywords. Results: Results were grouped into four general areas, i.e. (a) “General and Cardiovascular Issues”, (b) “Psychological and Psychopathological Issues”, (c) “Sleep and Sleep-Related Issues” and (d) “School and School-Related Issues”. (a) E is associated with unhealthy and dietary habits, smoking and alcohol drinking (in younger subjects) and, in adults, with diabetes and metabolic syndrome; (b) E is associated with impulsivity and anger, depression, anxiety disorders and nightmares (especially in women), risk taking behavior, use of alcohol, coffee and stimulants, psychopathology and personality traits; (c) E has been associated, especially in young subjects, with later bedtime and wake-up time, irregular sleep–wake schedule, subjective poor sleep, school performance and motivation, health-related quality of life; (d) E was associated with lowest mood and lower overall grade point average (especially for women). Conclusions: Eveningness may impact general health, either physical or mental, sleep, school results and achievements, especially in younger age and in women. The role of family support is crucial, and parents should be deeply informed that abuse of technological devices during night hours may lead to the immature adjustment function of children’s endogenous circadian pacemakers.

Twenty-Four-Hour Patterns in Occurrence and Pathophysiology of Acute Cardiovascular Events and Ischemic Heart Disease

The scientific literature clearly establishes the occurrence of cardiovascular (CV) accidents and myocardial ischemic episodes is unevenly distributed during the 24 h. Such temporal patterns result from corresponding temporal variation in pathophysiologic mechanisms and cyclic environmental triggers that elicit the onset of clinical events. Moreover, both the pharmacokinetics and pharmacodynamics of many, though not all, CV medications have been shown to be influenced by the circadian time of their administration, even though further studies are necessary to better clarify the mechanisms of such influence on different drug classes, drug molecules, and pharmaceutical preparations. Twenty-four-hour rhythmic organization of CV functions is such that defense mechanisms against acute events are incapable of providing the same degree of protection during the day and night. Instead, temporal gates of excessive susceptibility exist, particularly in the morning and to a lesser extent evening (in diurnally active persons), to aggressive mechanisms through which overt clinical manifestations may be triggered. When peak levels of critical physiologic variables, such as blood pressure (BP), heart rate (HR), rate pressure product (systolic BP × HR, surrogate measure of myocardial oxygen demand), sympathetic activation, and plasma levels of endogenous vasoconstricting substances, are aligned together at the same circadian time, the risk of acute events becomes significantly elevated such that even relatively minor and usually harmless physical and mental stress and environmental phenomena can precipitate dramatic life-threatening clinical manifestations. Hence, the delivery of CV medications needs to be synchronized in time, i.e., circadian time, in proportion to need as determined by established temporal patterns in risk of CV events, and in a manner that averts or minimizes undesired side effects. (Author correspondence: prf@unife.it)

Seasonal and Weekly Patterns of Occurrence of Acute Cardiovascular Diseases: Does a Gender Difference Exist?

BACKGROUND Cardiovascular (CV) disease is the leading cause of death in women. It is known that acute CV events exhibit temporal patterns of onset, that is, seasonal and weekly. We aimed to verify whether such patterns show differences by gender. METHODS We analyzed cumulative data from our previous studies dealing with hospital admissions for CV events, such as acute myocardial infarction (AMI), stroke, transient ischemic attack (TIA), aortic diseases (AD), and pulmonary embolism (PE), in the region Emilia-Romagna (RER) of Italy (ICDM9-CM codes, years 1998?2006). Total population and subgroups by gender (percentage of monthly and daily events) were tested for uniformity with the chi-square test, and a chronobiologic method was applied to monthly percentage of data for seasonal rhythmic analysis. RESULTS Season: We considered 130,693 patients (45.1% women): 64,191 AMI, 43,642 TIA, 4,615 AD, 19,425 PE. The monthly and seasonal distribution showed respective peaks in January and in winter, with no differences by gender. Day-of-week: We considered 168,921 patients (45.6% women): 64,191 AMI, 56,453 stroke, 43,642 TIA, 4,615 AD. The weekly distribution showed a peak on Monday, with no differences by gender. A multivariate regression logistic analysis, including in the model either major CV risk factors (hypertension, dyslipidemia, diabetes mellitus) and subgroups by age, did not find any difference in the temporal distribution of events in women and men. CONCLUSIONS The seasonal and day-of-week distribution of occurrence of CV events seems to be independent of gender.

Evidence-based statin prescription for cardiovascular protection in renal impairment.

Dyslipidemia is a well-known risk factor for cardiovascular disease in the general population, and the cardioprotective role of statins is well established. However, although cardiovascular disease is the major cause of morbidity and mortality in chronic kidney disease (CKD), the role of statin therapy is still under investigation. In CKD the atherosclerotic burden is high and pathophysiology of dyslipidemia is complex; however, the majority of large-scale statin trials excluded patients with CKD. Statins could have different effects in the different stages of CKD. Two large trials involving haemodialysis patients showed unfavourable results, whereas in renal transplant subjects as well as in early CKD subjects, statins reduced cardiovascular risk. The studies involving early CKD patients are post-hoc analyses of large trials and they showed that statins are more effective in secondary than in primary prevention. The aim of this study was to evaluate the effectiveness of statins for prevention of cardiovascular events by calculating the number of patients needed to be treated in different interventional trials. We conclude that dyslipidemia is a modifiable cardiovascular risk and statins appear to be an effective treatment especially in the early stages of CKD. Patients on renal replacement therapy could obtain an advantage from this treatment; however, the patient’s clinical prognosis should be taken into account when evaluating treatment.

Elevated NT-proBNP levels should be interpreted in elderly patients presenting with dyspnea

BACKGROUND B-type natriuretic peptide (BNP) assay is a useful tool in order to diagnose dyspnea due to congestive heart failure (CHF). On the other hand many other diseases could affect BNP levels. The aim of this study was to investigate a group of elderly patients admitted to an Internal Medicine unit because of dyspnea. PATIENTS AND METHODS NT-proBNP was assessed in 132 consecutive patients aged 80±6 years because of dyspnea. History data, anthropometric, clinical and biochemical parameters were collected. Renal function was assessed by the CKD-EPI formula. Diagnosis of pulmonary disease such as infections and chronic obstructive disease was considered and was analyzed as a single parameter. Statistical analysis was carried out dividing patients with high NT-proBNP from those with normal NT-proBNP according to the Januzzi cut-off. RESULTS NT-proBNP was higher than the normal reference values in 68.7% of patients and its levels increased in the 5 different stages of chronic kidney disease. Subjects with high NT-proBNP had lower haemoglobin levels (11.6±2.1 vs 12.8±1.9 g/dl, p=0.003), higher prevalence of atrial fibrillation (54.3 vs 25%, p=0.001), and lower prevalence of pulmonary diseases (29.7 vs 57.5%, p=0.005). Logistic regression analysis showed that NT-proBNP levels were independently associated with haemoglobin (OR 1.307 95% CI 1.072-1.593, p=0.008) and pulmonary diseases (OR 3.069 95% CI 1.385-6.801, p=0.006). CONCLUSIONS A disease different from CHF appears to affect NT-proBNP plasma levels. Therefore, determination of its levels does not seem to help clinicians in the definition of dyspnea in elderly people with different comorbidities.

All-cause mortality and estimated renal function in type 2 diabetes mellitus outpatients: Is there a relationship with the equation used?

Background: We investigated the relationship between serum creatinine (SCr) and estimated glomerular filtration rate (eGFR), evaluated by different formulae, and all-cause mortality (ACM) in type 2 diabetes mellitus (T2DM) outpatients. Methods: This observational cohort study considered 1365 T2DM outpatients, who had been followed up for a period of up to 11 years. eGFR was estimated using several equations. Results: Seventy subjects (5.1%) died after a follow-up of 9.8 ± 3 years. Univariate analysis showed that diagnosis of nephropathy (odds ratio (OR): 2.554, 95% confidence interval (CI): 1.616–4.038, p < 0.001) and microvascular complications (OR: 2.281, 95% CI: 1.449–3.593, p < 0.001) were associated with ACM. Receiving operating characteristic (ROC) curves showed that the areas under the curve for ACM were similar using the different eGFR equations. eGFR values were predictors of ACM, and the hazard ratios (HRs) of the different equations for eGFR estimation were similar. Conclusion: In our cohort of T2DM outpatients, different eGFR equations perform similarly in predicting ACM, whereas SCr did not.