Adaptive servo-ventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF): a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial

BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely.

Adaptive servo-ventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF): a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial.

BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely. FUNDING: Canadian Institutes of Health Research and Philips RS North America.

Cardiovascular reflex contributions to sympathetic inhibition during low intensity dynamic leg exercise in healthy middle-age.

Aging augments resting muscle sympathetic nerve activity (MSNA) and sympatho-inhibition during mild dynamic 1-leg exercise. To elucidate which reflexes elicit exercise-induced inhibition, we recruited 19 (9 men) healthy volunteers (mean age 56 ± 9 SD years), assessed their peak oxygen uptake (VO2peak ), and, on another day, measured heart rate (HR), blood pressure (BP) and MSNA (microneurography) at rest and during 1-leg cycling (2 min each at 0 load and 30%-40% VO2peak ), 3 times: (1) seated +2 min of postexercise circulatory occlusion (PECO) (elicit muscle metaboreflex); (2) supine (stimulate cardiopulmonary baroreflexes);and (3) seated, breathing 32% oxygen (suppress peripheral chemoreceptor reflex). While seated, MSNA decreased similarly during mild and moderate exercise (p < 0.001) with no increase during PECO (p = 0.44). Supine posture lowered resting MSNA (main effect p = 0.01) BP and HR. MSNA fell further (p = 0.04) along with diastolic BP and HR during mild, not moderate, supine cycling. Hyperoxia attenuated resting (main effect p = 0.01), but not exercise MSNA. In healthy middle-age, the cardiopulmonary baroreflex and arterial chemoreflex modulate resting MSNA, but contrary to previous observations in young subjects, without counter-regulatory offset by the sympatho-excitatory metaboreflex, resulting in an augmented sympatho-inhibitory response to mild dynamic leg exercise.

Global Variations in Heart Failure Etiology, Management, and Outcomes.

Importance: Most epidemiological studies of heart failure (HF) have been conducted in high-income countries with limited comparable data from middle- or low-income countries. Objective: To examine differences in HF etiology, treatment, and outcomes between groups of countries at different levels of economic development. Design, Setting, and Participants: Multinational HF registry of 23 341 participants in 40 high-income, upper-middle-income, lower-middle-income, and low-income countries, followed up for a median period of 2.0 years. Main Outcomes and Measures: HF cause, HF medication use, hospitalization, and death. Results: Mean (SD) age of participants was 63.1 (14.9) years, and 9119 (39.1%) were female. The most common cause of HF was ischemic heart disease (38.1%) followed by hypertension (20.2%). The proportion of participants with HF with reduced ejection fraction taking the combination of a ß-blocker, renin-angiotensin system inhibitor, and mineralocorticoid receptor antagonist was highest in upper-middle-income (61.9%) and high-income countries (51.1%), and it was lowest in low-income (45.7%) and lower-middle-income countries (39.5%) (P < .001). The age- and sex- standardized mortality rate per 100 person-years was lowest in high-income countries (7.8 [95% CI, 7.5-8.2]), 9.3 (95% CI, 8.8-9.9) in upper-middle-income countries, 15.7 (95% CI, 15.0-16.4) in lower-middle-income countries, and it was highest in low-income countries (19.1 [95% CI, 17.6-20.7]). Hospitalization rates were more frequent than death rates in high-income countries (ratio = 3.8) and in upper-middle-income countries (ratio = 2.4), similar in lower-middle-income countries (ratio = 1.1), and less frequent in low-income countries (ratio = 0.6). The 30-day case-fatality rate after first hospital admission was lowest in high-income countries (6.7%), followed by upper-middle-income countries (9.7%), then lower-middle-income countries (21.1%), and highest in low-income countries (31.6%). The proportional risk of death within 30 days of a first hospital admission was 3- to 5-fold higher in lower-middle-income countries and low-income countries compared with high-income countries after adjusting for patient characteristics and use of long-term HF therapies. Conclusions and Relevance: This study of HF patients from 40 different countries and derived from 4 different economic levels demonstrated differences in HF etiologies, management, and outcomes. These data may be useful in planning approaches to improve HF prevention and treatment globally.

Autonomic and respiratory consequences of altered chemoreflex function: clinical and therapeutic implications in cardiovascular diseases.

The importance of chemoreflex function for cardiovascular health is increasingly recognized in clinical practice. The physiological function of the chemoreflex is to constantly adjust ventilation and circulatory control to match respiratory gases to metabolism. This is achieved in a highly integrated fashion with the baroreflex and the ergoreflex. The functionality of chemoreceptors is altered in cardiovascular diseases, causing unstable ventilation and apnoeas and promoting sympathovagal imbalance, and it is associated with arrhythmias and fatal cardiorespiratory events. In the last few years, opportunities to desensitize hyperactive chemoreceptors have emerged as potential options for treatment of hypertension and heart failure. This review summarizes up to date evidence of chemoreflex physiology/pathophysiology, highlighting the clinical significance of chemoreflex dysfunction, and lists the latest proof of concept studies based on modulation of the chemoreflex as a novel target in cardiovascular diseases.

Normal and excessive muscle sympathetic nerve activity in heart failure: implications for future trials of therapeutic autonomic modulation.

AIMS: Patients with sympathetic excess are those most likely to benefit from novel interventions targeting the autonomic nervous system. To inform such personalized therapy, we identified determinants of augmented muscle sympathetic nerve activity (MSNA) in heart failure, versus healthy controls. METHODS AND RESULTS: We compared data acquired in 177 conventionally-treated, stable non-diabetic patients in sinus rhythm, aged 18-79 years (149 males; 28 females; left ventricular ejection fraction [LVEF] 25 ± 11% [mean ± standard deviation]; range 5-60%), and, concurrently, under similar conditions, in 658 healthy, normotensive volunteers (398 males; aged 18-81 years). In heart failure, MSNA ranged between 7 and 90 bursts·min-1 , proportionate to heart rate (p < 0.0001) and body mass index (BMI) (p = 0.03), but was unrelated to age, blood pressure, or drug therapy. Mean MSNA, adjusted for age, sex, BMI, and heart rate, was greater in heart failure (+14.2 bursts·min-1 ; 95% confidence interval [CI] 12.1-16.3; p < 0.0001), but lower in women (-5.0 bursts·min-1 ; 95% CI 3.4-6.6; p < 0.0001). With spline modeling, LVEF accounted for 9.8% of MSNA variance; MSNA related inversely to LVEF below an inflection point of ∼21% (p < 0.006), but not above. Burst incidence was greater in ischaemic than dilated cardiomyopathy (p = 0.01), and patients with sleep apnoea (p = 0.03). Burst frequency correlated inversely with stroke volume (p < 0.001), cardiac output (p < 0.001), and peak oxygen consumption (p = 0.002), and directly with norepinephrine (p < 0.0001) and peripheral resistance (p < 0.001). CONCLUSION: Burst frequency and incidence exceeded normative values in only ∼53% and ∼33% of patients. Such diversity encourages selective deployment of sympatho-modulatory therapies. Clinical characteristics can highlight individuals who may benefit from future personalized interventions targeting pathological sympathetic activation.

Characterizing Hypertension Specialist Care in Canada: A National Survey.

Background: The hypertension specialist often receives referrals of patients with young-onset, severe, difficult-to-control hypertension, patients with hypertensive emergencies, and patients with secondary causes of hypertension. Specialist hypertension care compliments primary care for these complex patients and contributes to an overall hypertension control strategy. The objective of this study was to characterize hypertension centres and the practice patterns of Canadian hypertension specialists. Methods: Adult hypertension specialists across Canada were surveyed to describe hypertension centres and specialist practice in Canada, including the following: the patient population managed by hypertension specialists; details on how care is provided; practice pattern variations; and differences in access to specialized hypertension resources across the country. Results: The survey response rate was 73.5% from 25 hypertension centres. Most respondents were nephrologists and general internal medicine specialists. Hypertension centres saw between 50 and 2500 patients yearly. A mean of 17% (± 15%) of patients were referred from the emergency department and a mean of 52% (± 24%) were referred from primary care. Most centres had access to specialized testing (adrenal vein sampling, level 1 sleep studies, autonomic testing) and advanced therapies for resistant hypertension (renal denervation). Considerable heterogeneity was present in the target blood pressure in young people with low cardiovascular risk and in the diagnostic algorithms for investigating secondary causes of hypertension. Conclusions: These results summarize the current state of hypertension specialist care and highlight opportunities for further collaboration among hypertension specialists, including standardization of the approach to specialist care for patients with hypertension.

Contexte: Le spécialiste de l'hypertension reçoit souvent des patients orientés pour une hypertension sévère, d'apparition précoce et difficile à maîtriser, pour une urgence hypertensive ou pour des causes secondaires de l'hypertension. Les soins spécialisés de l'hypertension complètent les soins primaires pour ces cas complexes et font partie d'une stratégie globale de maîtrise de l'hypertension. Cette étude avait pour objectif de caractériser les centres de traitement de l'hypertension et les habitudes de pratique des spécialistes canadiens qui traitent l'hypertension. Méthodologie: Un sondage a été mené auprès de spécialistes de l'hypertension adulte de l'ensemble du Canada afin de décrire les centres de traitement de l'hypertension et la pratique des spécialistes au Canada, notamment les éléments suivants : la population de patients prise en charge par des spécialistes de l'hypertension, les renseignements sur la façon dont les soins sont prodigués, les variations dans les habitudes de pratique ainsi que les différences relatives à l'accès aux ressources spécialisées en hypertension à l'échelle du pays. Résultats: Le taux de réponse au sondage a été de 73,5 % dans 25 centres de l'hypertension. La plupart des répondants étaient des néphrologues et des spécialistes en médecine interne générale. Les centres de l'hypertension recevaient entre 50 et 2500 patients par année. En moyenne, 17 % (± 15 %) des patients provenaient du service des urgences et 52 % (± 24 %) provenaient d'une unité de soins primaires. La plupart des centres avaient accès à des tests spécialisés (prélèvements veineux surrénaliens, études du sommeil de niveau 1, tests autonomes) et à des traitements avancés pour l'hypertension résistante (dénervation rénale). Une hétérogénéité considérable a été constatée en ce qui concerne la pression artérielle cible chez les jeunes présentant un faible risque cardiovasculaire et les algorithmes diagnostiques pour étudier les causes secondaires de l'hypertension. Conclusions: Ces résultats résument la situation actuelle des soins spécialisés de l'hypertension et font ressortir des occasions d'accroître la collaboration entre les spécialistes de l'hypertension, notamment en ce qui concerne une normalisation de l'approche des soins spécialisés pour les patients hypertendus.

Muscle Sympathetic Excitatory Response to Dynamic 1-Leg Cycling in Heart Failure With Preserved Ejection Fraction.

We provide the first description in a patient with heart failure with preserved ejection fraction of the "paradoxical," exaggerated reflex increase in muscle sympathetic nerve activity in the opposite, stationary limb during dynamic 1-leg cycling exercise that was documented previously in patients with reduced ejection fraction. (Level of Difficulty: Advanced.).

Influence of sex and age on the relationship between aerobic fitness and muscle sympathetic nerve activity in healthy adults.

We examined the influence of sex and age on the relationship between aerobic fitness and muscle sympathetic nerve activity (MSNA) in healthy adults. Data were assessed from 224 volunteers (88 females), aged 18-76 yr, in whom resting MSNA (microneurography) and peak oxygen uptake (V̇o2peak; incremental exercise test) were evaluated. When separated into younger (<50 yr) and older (≥50 yr) subgroups, there were inverse relationships between relative V̇o2peak (mL·kg-1·min-1) and MSNA burst frequency in younger males (R2 = 0.21, P < 0.0001) and older females (R2 = 0.36, P < 0.01), but not older males (R2 = 0.05, P = 0.08) or younger females (R2 = 0.03, P = 0.14). Similar patterns were observed with absolute V̇o2peak (L·min-1) and percent-predicted (based on age, sex, weight, height, and modality), and with burst incidence. Sex and age influence the relationship between aerobic fitness and resting MSNA, and, thus, must be considered as key variables when studying these potential associations; inverse relationships are strongest in younger males and older females.NEW & NOTEWORTHY Our data reveal for the first time that associations between aerobic fitness and resting muscle sympathetic nerve activity are sex and age specific; inverse relationships are evident in younger males (<50 yr) and older females (≥50 yr), but absent in younger females (<50 yr) and older males (≥50 yr).

Attenuated Sympathetic Blood Pressure Transduction in Patients With Treated Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is associated with reduced cardiac ß-adrenergic signal transduction in response to chronic elevations in neurally released and circulating norepinephrine. Whether elevations in muscle sympathetic nerve activity (MSNA) are accompanied by attenuated α-adrenoceptor-mediated vasoconstriction remains unclear. Therefore, the objective of the current work was to compare transduction of sympathetic firing into blood pressure (BP) in treated patients with HFrEF and healthy controls. METHODS: Twenty-three treated patients with HFrEF (4 females, left ventricular ejection fraction: 28±2%) and 22 healthy controls (6 females) underwent a 7-minute resting measurement of continuous beat-to-beat BP (finger photoplethysmography), heart rate (electrocardiography), and MSNA (microneurography). Sympathetic-BP transduction was quantified using both signal averaging, whereby the BP response to each MSNA burst was serially tracked over 15 cardiac cycles and averaged to derive the peak change in BP, and cross-spectral analysis of low-frequency (0.04-0.15 Hz) MSNA and BP oscillations. RESULTS: Compared with controls, patients with HFrEF had less sympathetic-BP transduction (0.7±0.3 versus 0.2±0.3 mm Hg; P<0.01), and lower low-frequency oscillations in MSNA (120±56 versus 64±32 arbitrary units2; P<0.01) and BP (3.1±1.6 versus 2.0±1.7 mm Hg2; P<0.01). In subgroup analysis, resting sympathetic-BP transduction was lower in patients with HFrEF with normal resting MSNA compared to healthy controls (0.7±0.3 versus 0.4±0.3 mm Hg; P=0.01) and further attenuated (0.1±0.1 mm Hg; P=0.03) in patients with HFrEF with elevated resting MSNA. CONCLUSIONS: Treated HFrEF is associated with lower sympathetic-BP transduction, even when MSNA is not elevated, and diminishes further with disease progression. These adaptations may serve to limit the adverse consequences of oscillatory surges in sympathetic vasoconstrictor discharge on stroke volume.

Methodology for the nocturnal cardiac arrhythmia ancillary study of the ADVENT-HF trial in patients with heart failure with reduced ejection fraction and sleep-disordered breathing.

Background: Sleep disordered breathing (SDB) may trigger nocturnal cardiac arrhythmias (NCA) in patients with heart failure with reduced ejection fraction (HFrEF). The NCA ancillary study of the ADVENT-HF trial will test whether, in HFrEF-patients with SDB, peak-flow-triggered adaptive servo-ventilation (ASVpf) reduces NCA. To this end, accurate scoring of NCA from polysomnography (PSG) is required. Objective: To develop a method to detect NCA accurately from a single-lead electrocardiogram (ECG) recorded during PSG and assess inter-observer agreement for NCA detection. Methods: Quality assurance of ECG analysis included training of the investigators, development of standardized technical quality, guideline-conforming semi-automated NCA-scoring via Holter-ECG software and implementation of an arrhythmia adjudication committee. To assess inter-observer agreement, the ECG was analysed by two independent investigators and compared for agreement on premature ventricular complexes (PVC) /h, premature atrial complexes/h (PAC) as well as for other NCA in 62 patients from two centers of the ADVENT-HF trial. Results: The intraclass correlation coefficients for PVC/h and PAC/h were excellent: 0.99 (95%- confidence interval [CI]: 0.99-0.99) and 0.99 (95%-CI: 0.97-0.99), respectively. No clinically relevant difference in inter-observer classification of other NCA was found. The detection of non-sustained ventricular tachycardia (18% versus 19%) and atrial fibrillation (10% versus 11%) was similar between the two investigators. No sustained ventricular tachycardia was detected. Conclusion: These findings indicate that our methods are very reliable for scoring NCAs and are adequate to apply for the entire PSG data set of the ADVENT-HF trial.

Warmer summer nocturnal surface air temperatures and cardiovascular disease death risk: a population-based study.

BACKGROUND: In recent summers, some populous mid-latitude to high-latitude regions have experienced greater heat intensity, more at night than by day. Such warming has been associated with increased cause-specific adult mortality. Sex-specific and age-specific associations between summer nocturnal surface air temperatures (SAT) and cardiovascular disease (CVD) deaths have yet to be established. METHODS: A monthly time series analysis (June-July, 2001-2015) was performed on sex-specific CVD deaths in England and Wales of adults aged 60-64 and 65-69 years. Using negative binomial regression with autocorrelative residuals, associations between summer (June-July) nocturnal SAT anomalies (primary exposure) and CVD death rates (outcome) were computed, controlling for key covariates. To explore external validity, similar associations with respect to CVD death in King County, Washington, USA, also were calculated, but only for men aged 60-64 and 65-69 years. Results are reported as incidence rate ratios. RESULTS: From 2001 to 2015, within these specific cohorts, 39 912 CVD deaths (68.9% men) were recorded in England and Wales and 488 deaths in King County. In England and Wales, after controlling for covariates, a 1°C rise in anomalous summer nocturnal SAT associated significantly with a 3.1% (95% CI 0.3% to 5.9%) increased risk of CVD mortality among men aged 60-64, but not older men or either women age groups. In King County, after controlling for covariates, a 1°C rise associated significantly with a 4.8% (95% CI 1.7% to 8.1%) increased risk of CVD mortality among those <65 years but not older men. CONCLUSION: In two mid-latitude regions, warmer summer nights are accompanied by an increased risk of death from CVD among men aged 60-64 years.

The 2021 Carl Ludwig Lecture. Unsympathetic autonomic regulation in heart failure: patient-inspired insights.

Defined as a structural or functional cardiac abnormality accompanied by symptoms, signs, or biomarkers of altered ventricular pressures or volumes, heart failure also is a state of autonomic disequilibrium. A large body of evidence affirms that autonomic disturbances are intrinsic to heart failure; basal or stimulated sympathetic nerve firing or neural norepinephrine (NE) release more often than not exceed homeostatic need, such that an initially adaptive adrenergic or vagal reflex response becomes maladaptive. The magnitude of such maladaptation predicts prognosis. This Ludwig lecture develops two theses: the elucidation and judiciously targeted amelioration of maladaptive autonomic disturbances offers opportunities to complement contemporary guideline-based heart failure therapy, and serendipitous single-participant insights, acquired in the course of experimental protocols with entirely different intent, can generate novel insight, inform mechanisms, and launch entirely new research directions. I précis six elements of our current synthesis of the causes and consequences of maladaptive sympathetic disequilibrium in heart failure, shaped by patient-inspired epiphanies: arterial baroreceptor reflex modulation, excitation stimulated by increased cardiac filling pressure, paradoxical muscle sympathetic activation as a peripheral neurogenic constraint on exercise capacity, renal sympathetic restraint of natriuresis, coexisting sleep apnea, and augmented chemoreceptor reflex sensitivity and then conclude by envisaging translational therapeutic opportunities.