Circadian rhythms, cardiac arrhythmias and sudden death.

The heart, like most mammalian organs, is influenced by circadian patterns. The suprachiasmatic nucleus in the hypothalamus has a key role in this influence, via various neurohumoral factors, particularly the autonomic nervous system. In addition, a local cardiac peripheral clock might drive a circadian rhythm related to the expression of ion channels. Several myocardial functions are influenced by these circadian cycles including activity/rest, regeneration, nutrient storage, growth, and myocardial repair. Numerous circadian genes have been identified in basic studies, and both biological factors and environmental features (including epigenetic) influence the human circadian rhythm. A normal circadian rhythm is important to maintain a normal heart rhythm and circadian rhythm disturbances can predispose to the development of cardiac arrhythmias. The normal heart rate presents a daily variability with a morning peak and nocturnal bradycardization. Ventricular arrhythmias and sudden death are more likely to occur in the morning after waking, while atrial fibrillation and heart blocks most commonly occur at night. Drugs such as beta-blockers might modify the chronobiology of some of these arrhythmias. On the other hand, drugs that influence circadian rhythm, like the circadian hormone melatonin, have demonstrated pleiotropic properties and show promising results as antiarrhythmics. This review is focused on the current understanding of the basic mechanism and clinical implications of the association circadian rhythms-cardiac arrhythmias/sudden death. The close relationship between circadian patterns and arrhythmias may provide us with the possibility of novel interventions to decrease the arrhythmic risk in some patients.

Toward a geriatric approach to patients with advanced age and cardiovascular diseases: position statement of the EuGMS Special Interest Group on Cardiovascular Medicine.

Cardiovascular diseases (CVD) are highly prevalent in older adults and represent a major geriatric health-care concern. Management of CVD in older patients may be challenging due to specific geriatric issues, such as frailty and multi-morbidity, which may influence patients' outcomes. In this clinical context, diagnostic and therapeutic strategies should target those outcomes that have higher priority in geriatric health care, including disability prevention and quality of life. Older adults with CVD should be offered a reasonably optimized treatment, customized to the individual's frailty level and functional status. Yet, most clinical trials excluded comorbid and frail patients and evidence to support CVD management in this vulnerable population is lacking. Therefore, a geriatric approach is needed in cardiovascular medicine, characterized by a holistic, patient-centered perspective focusing on functional status and quality of life. With a view to promote the geriatric approach in the management of older patients with CVD, the EuGMS Special Interest Group (SIG) on Cardiovascular Medicine was founded in 2018, consisting of a network of geriatricians with an extensive expertise in geriatric cardiovascular medicine. The present position paper aims to present the Cardiovascular SIG and illustrate its main purposes and action programs.

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.

AIMS: To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). METHODS AND RESULTS: A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. CONCLUSIONS: Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group.

Pharmacological treatment in patients with heart failure: patients knowledge and occurrence of polypharmacy, alternative medicine and immunizations.

AIMS: To evaluate in patients with heart failure (HF) due to systolic dysfunction the occurrence of polypharmacy, alternative medicine, immunization against influenza, and patients' knowledge about their medication. METHODS AND RESULTS: Sixty-five patients, 49 men, mean age 60.5+/-12.0 years answered a confidential questionnaire during 2002. Polypharmacy was frequent, 48 (74%) were taking six or more pills per day and 18 (28%) 11 or more. Fifteen patients (23%) used over-the-counter analgesics. Eight patients (12%) used alternative medicine [five women (31%) vs. three men (6%), P=0.02]. Forty-four patients (68%) received immunization against influenza (18 patients <65 years (54%) vs. 25 patients > or =65 years (79%), P=0.03). Half the patients knew that beta-blockers and vasodilators decreased blood pressure, 31 patients receiving diuretics (88%) knew that this drugs help to eliminate liquids, 12 patients (38%) recognized this effect with low dose spironolactone and 23% or less with other drugs. Only 12 patients (42%) treated with acenocoumarol and 13 of those treated with aspirin (32%) recognized the action of these drugs. CONCLUSION: Patients with HF and systolic dysfunction have a poor knowledge about the medication they receive. Polypharmacy, over-the-counter, homeopathic and alternative medicine use is frequent whereas the rate of immunization against influenza is low.