Fabio Fabbian

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.

2013 Ambulatory Blood Pressure Monitoring Recommendations for the Diagnosis of Adult Hypertension, Assessment of Cardiovascular and other Hypertension-associated Risk, and Attainment of Therapeutic Goals

Correlation between systolic (SBP) and diastolic (DBP) blood pressure (BP) level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is much greater for ambulatory BP monitoring (ABPM) than daytime office measurements. The 2013 ABPM guidelines specified herein are based on ABPM patient outcomes studies and constitute a substantial revision of current knowledge. The asleep SBP mean and sleep-time relative SBP decline are the most significant predictors of CVD events, both individually as well as jointly when combined with other ABPM-derived prognostic markers. Thus, they should be preferably used to diagnose hypertension and assess CVD and other associated risks. Progressive decrease by therapeutic intervention of the asleep BP mean is the most significant predictor of CVD event-free interval. The 24-h BP mean is not recommended to diagnose hypertension because it disregards the more valuable clinical information pertaining to the features of the 24-h BP pattern. Persons with the same 24-h BP mean may display radically different 24-h BP patterns, ranging from extreme-dipper to riser types, representative of markedly different risk states. Classification of individuals by comparing office with either the 24-h or awake BP mean as “masked normotensives” (elevated clinic BP but normal ABPM), which should replace the terms of “isolated office” or “white-coat hypertension”, and “masked hypertensives” (normal clinic BP but elevated ABPM) is misleading and should be avoided because it disregards the clinical significance of the asleep BP mean. Outcome-based ABPM reference thresholds for men, which in the absence of compelling clinical conditions are 135/85 mmHg for the awake and 120/70 mmHg for the asleep SBP/DBP means, are lower by 10/5 mmHg for SBP/DBP in uncomplicated, low-CVD risk, women and lower by 15/10 mmHg for SBP/DBP in male and female high-risk patients, e.g., with diabetes, chronic kidney disease (CKD), and/or past CVD events. In the adult population, the combined prevalence of masked normotension and masked hypertension is >35%. Moreover, >20% of “normotensive” adults have a non-dipper BP profile and, thus, are at relatively high CVD risk. Clinic BP measurements, even if supplemented with home self-measurements, are unable to quantify 24-h BP patterning and asleep BP level, resulting in potential misclassification of up to 50% of all evaluated adults. ABPM should be viewed as the new gold standard to diagnose true hypertension, accurately assess consequent tissue/organ, maternal/fetal, and CVD risk, and individualize hypertension chronotherapy. ABPM should be a priority for persons likely to have a blunted nighttime BP decline and elevated CVD risk, i.e., those who are elderly and obese, those with secondary or resistant hypertension, and those diagnosed with diabetes, CKD, metabolic syndrome, and sleep disorders. (Author Correspondence: rhermida@uvigo.es or prf@unife.it).

Circadian Rhythms in Blood Pressure Regulation and Optimization of Hypertension Treatment With ACE Inhibitor and ARB Medications

Specific features of the 24 h-blood pressure (BP) pattern are linked to the progressive injury of target tissues and risk of cardiac and cerebrovascular events. Studies have consistently shown an association between blunted asleep BP decline and increased incidence of fatal and nonfatal cardiovascular events. Thus, there is growing interest in how to achieve better BP control during nighttime sleep in addition to during daytime activity, according to the particular requirements of each hypertension patient. One approach takes into consideration the endogenous circadian rhythm-determinants of the 24-h BP pattern, especially, the prominent day-night variation of the renin-angiotensin-aldosterone system, which activates during nighttime sleep. A series of clinical studies have demonstrated a different effect of the angiotensin-converting enzyme (ACE) inhibitors benazepril, captopril, enalapril, lisinopril, perindopril, quinapril, ramipril, spirapril, and trandolapril when routinely ingested in the morning vs. the evening. In most cases, the evening schedule exerts a more marked effect on the asleep than awake BP means. Similarly, a once-daily evening, in comparison to morning, ingestion schedule of the angiotensin receptor blockers (ARBs) irbesartan, olmesartan, telmisartan, and valsartan exerts greater therapeutic effect on asleep BP, plus significant increase in the sleep-time relative BP decline, with normalization of the circadian BP profile toward a more dipping pattern, independent of drug terminal half-life. Chronotherapy, the timing of treatment to body rhythms, is a cost-effective means of both individualizing and optimizing the treatment of hypertension through normalization of the 24-h BP level and profile, and it may constitute an effective option to reduce cardiovascular risk.

Administration-Time Differences in Effects of Hypertension Medications on Ambulatory Blood Pressure Regulation

Specific features of the 24-h blood pressure (BP) pattern are linked to progressive injury of target tissues and risk of cardiovascular disease (CVD) events. Several studies have consistently shown an association between blunted asleep BP decline and risk of fatal and nonfatal CVD events. Thus, there is growing focus on ways to properly control BP during nighttime sleep as well as during daytime activity. One strategy, termed chronotherapy, entails the timing of hypertension medications to endogenous circadian rhythm determinants of the 24-h BP pattern. Significant and clinically meaningful treatment-time differences in the beneficial and/or adverse effects of at least six different classes of hypertension medications, and their combinations, are now known. Generally, calcium channel blockers (CCBs) are more effective with bedtime than morning dosing, and for dihydropyridine derivatives bedtime dosing significantly reduces risk of peripheral edema. The renin-angiotensin-aldosterone system is highly circadian rhythmic and activates during nighttime sleep. Accordingly, evening/bedtime ingestion of the angiotensin-converting enzyme inhibitors (ACEIs) benazepril, captopril, enalapril, lisinopril, perindopril, quinapril, ramipril, spirapril, trandolapril, and zofenopril exerts more marked effect on the asleep than awake systolic (SBP) and diastolic (DBP) BP means. Likewise, the bedtime, in comparison with morning, ingestion schedule of the angiotensin-II receptor blockers (ARBs irbesartan, olmesartan, telmisartan, and valsartan exerts greater therapeutic effect on asleep BP, plus significant increase in the sleep-time relative BP decline, with the additional benefit, independent of drug terminal half-life, of converting the 24-h BP profile into a more normal dipping pattern. This is the case also for the bedtime versus upon-awakening regimen of combination ARB-CCB, ACEI-CCB, and ARB-diuretic medications. The chronotherapy of conventional hypertension medications constitutes a new and cost-effective strategy for enhancing the control of daytime and nighttime SBP and DBP levels, normalizing the dipping status of their 24-h patterning, and potentially reducing the risk of CVD events and end-organ injury, for example, of the blood vessels and tissues of the heart, brain, kidney, and retina. (Author correspondence: rhermida@uvigo.es)

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)

Interventional treatment of venous thromboembolism: A review

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cardiovascular disease after coronary artery disease and cerebrovascular disease and is responsible for significant morbidity and mortality in the general population. Full dose anticoagulation is the standard therapy for VTE, both for the acute and the long-term phase. The latest guidelines of the American College of Chest Physicians recommend treatment with a full-dose of unfractioned heparin (UFH), low-molecular-weight-heparin (LMWH), fondaparinux, vitamin K antagonist (VKA) or thrombolysis for most patients with objectively confirmed VTE. Catheter-guided thrombolysis and trombosuction are interventional approaches that should be used only in selected populations; interruption of the inferior vena cava (IVC) with a filter can be performed to prevent life-threatening PE in patients with VTE and contraindications to anticoagulant treatment, bleeding complications during antithrombotic treatment, or VTE recurrences despite optimal anticoagulation. In this review we summarize the currently available literature regarding interventional approaches for VTE treatment (vena cava filters, catheter-guided thrombolysis, thrombosuction) and we discuss current evidences on their efficacy and safety. Moreover, the appropriate indications for their use in daily clinical practice are reviewed.

Pulmonary Hypertension in Dialysis Patients: A Cross-Sectional Italian Study

Introduction. Pulmonary hypertension (PHT) is an independent predictor of mortality. The aim of this study was to relate pulmonary arterial pressure (PAP) to the cardiovascular status of dialysis patients. Methods. 27 peritoneal dialysis (PD) and 29 haemodialysis (HD) patients (60 ± 13 years, 37 males, dialysis vintage was 40 ± 48 months) had PAP measured by echocardiography. Clinical and laboratory data of the patients were recorded. Results. PHT (PAP > 35 mmHg) was detected in 22 patients (39%; PAP 42 ± 6 mmHg) and was diagnosed in 18.5% of PD patients and 58.6% of HD patients (P = .0021). The group of subjects with PH had higher dialysis vintage (63 ± 60 versus 27 ± 32 months, P = .016), interdialytic weight gain (2.1 ± 1 versus 1.3 ± 0.9 Kg, P = .016), lower diastolic blood pressure (73 ± 12 versus 80 ± 8 mmHg, P = .01) and ejection fraction (54 ± 13 versus 60 ± 7%, P = .021) than the patients with normal PAP. PAP was correlated positively with diastolic left ventricular volume (r = 0.32, P = .013) and negatively with ejection fraction (r = −0.54, P < .0001). PHT was independently associated with dialysis vintage (OR 1.022, 95% CI 1.002–1.041, P = .029) and diastolic blood pressure (OR 0.861, 95% CI 0.766–0.967, P = .011). Conclusions. PHT is frequent in dialysis patients, it appears to be a late complication of HD treatment, mainly related to cardiac performance and cardiovascular disease history.

Do restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) play a role in nocturnal hypertension and increased cardiovascular risk of renally impaired patients

Hypertension can cause or promote renal failure and is related to cardiovascular mortality, the major cause of death in patients with renal impairment. Changes in the circadian BP pattern, particularly the blunting or reversal of the nocturnal decline in BP, are common in chronic renal failure. These changes in turn are among the major determinants of left ventricular hypertrophy. Using a chronobiological approach, it is possible to obtain better insight into the reciprocal relationship between hypertension, renal disease, and increased cardiovascular risk of renal patients. Disruption of the normal circadian rhythm of rest/activity may be hypothesized to underlie the high cardiovascular morbidity and mortality of such patients. Epidemiological studies reveal that hemodialysis patients experience poor subjective sleep quality and insomnia and, in comparison to healthy persons, are more likely to show shorter sleep duration and lower sleep efficiency. Sleep apnea may be present and is usually investigated in these patients; however, the prevalence of restless legs syndrome (RLS), which is high in dialysis patients and which has been associated with increased risk for cardiovascular disease in the general population, could also play a role in the pathogenesis of sleep-time hypertension in renal patients. Careful assessment of sleep quality, in particular, diagnostic screening for RLS and periodic limb movements (PLM) in renal patients, is highly recommended. In renal failure, attention to sleep quality and related perturbations of the sleep/wake cycle may help prevent the occurrence and progression of cardiovascular disease. (Author correspondence: prf@unife.it)

Clinical approach to lupus nephritis: Recent advances

Kidney involvement is common in systemic lupus erythematosus (SLE). Its clinical presentations are highly variable, ranging from mild asymptomatic proteinuria and/or hematuria to rapidly progressive uremia. Histological evidence of lupus nephritis is present in most patients with SLE, even when they do not yet have clinical manifestations. Current classification ISN/RPS 2003 (International Society of Nephrology/Renal Pathology Society) of lupus nephritis was promoted by a widely perceived need to re-examine existing classification, provide clearer distinctions between the histological classes, and improve diagnostic reproducibility and interobserver agreement. Lupus nephritis is a serious disease whose prognosis can usually be improved dramatically by treatment, but treatment is potentially toxic, prolonged, and complex. Current treatment regimens combine corticosteroids with cyclophosphamide, azathioprine or ciclosporin; mycophenolate mofetil has received much recent attention as a potentially immune suppressive agent and less aggressive immunosuppressive regimens can be prescribed. SLE patients should be regular followed to detect early kidney involvement.

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.