Disagreement between drug effects on autonomic function and mortality: another unreliable surrogate endpoint in heart failure?

Several classes of inhibitors of the renin–angiotensin system were developed as antihypertensive agents. Following the early observations of favourable haemodynamic effects of angiotensin-converting enzyme inhibitors (ACEIs) in patients with congestive heart failure, a series of major randomized outcome trials demonstrated morbidity and mortality benefits of these agents across the spectrum of patients with heart failure with reduced ejection fraction (HFrEF). Angiotensin receptor blockers (ARBs) were then also shown to have similar benefits with a suggestion of some incremental improvements when used together. However, in the trials that randomized patients to a proven dose of an ACEI plus either placebo or an ARB, the combination of the two inhibitors of the renin–angiotensin system resulted in more adverse drug effects without a meaningful improvement in clinical outcomes. This chapter reviews the fundamental underpinnings for use of either an ACEI or ARB to improve prognosis of patients with HFrEF.

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Controlled Trial of Physical Training in Chronic Heart Failure, Exercise Performance, Hemodynamics, Ventilation, and Autonomic Function.

Cardiopulmonary Physical Therapy Journal ◽

10.1097/01823246-199405010-00005 ◽

1994 ◽

Vol 5 (1) ◽

pp. 17

Author(s):

Ethel Frese

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Exercise Performance ◽

Physical Training ◽

Autonomic Function ◽

Controlled Trial

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2402Reduced heart rate variability is linked to clinical status in patients with a systemic right ventricle

European Heart Journal ◽

10.1093/eurheartj/ehz748.0155 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

T E Zandstra ◽

P Kies ◽

S Man ◽

A C Maan ◽

M Bootsma ◽

...

Keyword(s):

Heart Failure ◽

Heart Rate ◽

Congestive Heart Failure ◽

Autonomic Function ◽

Clinical Status ◽

Clinical Event ◽

Healthy Controls ◽

Significant Determinant ◽

Systemic Right Ventricle ◽

Event Score

Abstract Background Adult patients with congenital heart disease and a systemic right ventricle (sRV) are prone to develop heart failure. Decreased heart rate variability (HRV), a measure of autonomic dysfunction, is associated with morbidity and mortality in patients with congestive heart failure. The standard deviation of all intervals between normal sinus beats (SDNN) is a HRV parameter commonly reported as an indicator of autonomic function in these patients. Data about HRV and its clinical implications in patients with a sRV are scarce. Purpose To compare HRV parameters between patients with a sRV and healthy controls, and to assess their association with clinical status. Methods All available 24-hour Holter monitoring records of sRV patients under follow-up in our center and one record per healthy control subject were analysed. Holters with non-sinus rhythm were excluded. Time and frequency domain parameters were calculated and compared between both groups. Clinical landmarks such as arrhythmias or an episode of congestive heart failure, which occurred up until the time of the ambulatory ECG, were combined in a clinical event score. Determinants of SDNN were investigated with mixed model linear regression in the patients and with multivariate linear regression in the controls. Baseline characteristics, medication use, global longitudinal strain, validity as measured with bicycle exercise testing, and the clinical event score were taken into account. Results 113 Holters of 43 patients and 39 Holters of healthy controls were analysed. The patient group included 30 patients (70%) late after Mustard or Senning correction for transposition of the great arteries, and 13 patients with congenitally corrected transposition of the great arteries (30%). Age and gender were comparable in patients and controls. Several HRV parameters were significantly worse in patients compared with controls, including SDNN (138 in patients vs. 161 in controls, p=0.021). In the patients, clinical event score was the only significant determinant of a lower SDNN (p<0.001). In the controls, age was the only significant determinant of a lower SDNN (p=0.039). Conclusion Contrary to the healthy population, in patients with a sRV, HRV is associated with clinical status rather than age. This indicates that disease progression affects autonomic function more than ageing in this group. Further research is needed to clarify the relation between clinical outcome and autonomic function in sRV patients. Acknowledgement/Funding The Department of Cardiology of the LUMC received research grants from Medtronic, Biotronik, Boston Scientific and Edwards Lifesciences

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Sacubitril/Valsartan Improves Autonomic Function and Cardiopulmonary Parameters in Patients with Heart Failure with Reduced Ejection Fraction

Journal of Clinical Medicine ◽

10.3390/jcm9061897 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1897 ◽

Cited By ~ 1

Author(s):

Francesco Giallauria ◽

Giuseppe Vitale ◽

Mario Pacileo ◽

Anna Di Lorenzo ◽

Alessandro Oliviero ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Autonomic Function ◽

Left Ventricular ◽

Exercise Stress ◽

Left Ventricular Ejection ◽

Peak Exercise ◽

Ventricular Ejection Fraction ◽

Reduced Ejection Fraction

Background: Heart rate recovery (HRR) is a marker of vagal tone, which is a powerful predictor of mortality in patients with cardiovascular disease. Sacubitril/valsartan (S/V) is a treatment for heart failure with reduced ejection fraction (HFrEF), which impressively impacts cardiovascular outcome. This study aims at evaluating the effects of S/V on HRR and its correlation with cardiopulmonary indexes in HFrEF patients. Methods: Patients with HFrEF admitted to outpatients’ services were screened out for study inclusion. S/V was administered according to guidelines. Up-titration was performed every 4 weeks when tolerated. All patients underwent laboratory measurements, Doppler-echocardiography, and cardiopulmonary exercise stress testing (CPET) at baseline and at 12-month follow-up. Results: Study population consisted of 134 HFrEF patients (87% male, mean age 57.9 ± 9.6 years). At 12-month follow-up, significant improvement in left ventricular ejection fraction (from 28% ± 5.8% to 31.8% ± 7.3%, p < 0.0001), peak exercise oxygen consumption (VO2peak) (from 15.3 ± 3.7 to 17.8 ± 4.2 mL/kg/min, p < 0.0001), the slope of increase in ventilation over carbon dioxide output (VE/VCO2 slope )(from 33.4 ± 6.2 to 30.3 ± 6.5, p < 0.0001), and HRR (from 11.4 ± 9.5 to 17.4 ± 15.1 bpm, p = 0.004) was observed. Changes in HRR were significantly correlated to changes in VE/VCO2slope (r = −0.330; p = 0.003). After adjusting for potential confounding factors, multivariate analysis showed that changes in HRR were significantly associated to changes in VE/VCO2slope (Beta (B) = −0.975, standard error (SE) = 0.364, standardized Beta coefficient (Bstd) = −0.304, p = 0.009). S/V showed significant reduction in exercise oscillatory ventilation (EOV) detection at CPET (28 EOV detected at baseline CPET vs. 9 EOV detected at 12-month follow-up, p < 0.001). HRR at baseline CPET was a significant predictor of EOV at 12-month follow-up (B = −2.065, SE = 0.354, p < 0.001). Conclusions: In HFrEF patients, S/V therapy improves autonomic function, functional capacity, and ventilation. Whether these findings might translate into beneficial effects on prognosis and outcome remains to be elucidated.

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Abnormalities of cardiac autonomic function and 11C-hydroxyephedrine PET coincide in heart failure

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(96)82562-9 ◽

1996 ◽

Vol 27 (2) ◽

pp. 406 ◽

Cited By ~ 1

Author(s):

Liisa-Maria Voipio-Pulkki ◽

Risto Vesalainen ◽

Mikko Pietilä ◽

Tuomas Jartti ◽

Heikki Ukkonen ◽

...

Keyword(s):

Heart Failure ◽

Autonomic Function ◽

Cardiac Autonomic Function

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Impact of sleep disordered breathing severity on the hemodynamics, functional status and autonomic function of chronic heart failure patients

Heart Lung and Circulation ◽

10.1016/j.hlc.2007.11.087 ◽

2008 ◽

Vol 17 ◽

pp. S34-S35

Author(s):

Chin Chwan Austin Ng ◽

Chin Moi Chow ◽

Helen Wong ◽

Andrew Sindone ◽

Glen Davis ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Functional Status ◽

Sleep Disordered Breathing ◽

Autonomic Function ◽

Heart Failure Patients ◽

Disordered Breathing

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Adrenomedullin-epinephrine cotreatment enhances cardiac output and left ventricular function by energetically neutral mechanisms

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00887.2011 ◽

2012 ◽

Vol 302 (8) ◽

pp. H1584-H1590

Author(s):

Thor Allan Stenberg ◽

Anders Benjamin Kildal ◽

Ole-Jakob How ◽

Truls Myrmel

Keyword(s):

Heart Failure ◽

Blood Flow ◽

Cardiac Output ◽

Acute Heart Failure ◽

Coronary Blood Flow ◽

Drug Effects ◽

Left Ventricular ◽

Experimental Myocardial Infarction ◽

Energetic Cost ◽

Lv Function

Adrenomedullin (AM) used therapeutically reduces mortality in the acute phase of experimental myocardial infarction. However, AM is potentially deleterious in acute heart failure as it is vasodilative and inotropically neutral. AM and epinephrine (EPI) are cosecreted from chromaffin cells, indicating a physiological interaction. We assessed the hemodynamic and energetic profile of AM-EPI cotreatment, exploring whether drug interaction improves cardiac function. Left ventricular (LV) mechanoenergetics were evaluated in 14 open-chest pigs using pressure-volume analysis and the pressure-volume area-myocardial O2 consumption (PVA-MV˙o2) framework. AM (15 ng·kg−1·min−1, n = 8) or saline (controls, n = 6) was infused for 120 min. Subsequently, a concurrent infusion of EPI (50 ng·kg−1·min−1) was added in both groups (AM-EPI vs. EPI). AM increased cardiac output (CO) and coronary blood flow by 20 ± 10% and 39 ± 14% (means ± SD, P < 0.05 vs. baseline), whereas controls were unaffected. AM-EPI increased CO and coronary blood flow by 55 ± 17% and 75 ± 16% ( P < 0.05, AM-EPI interaction) compared with 13 ± 12% ( P < 0.05 vs. baseline) and 18 ± 31% ( P = not significant) with EPI. LV systolic capacitance decreased by −37 ± 22% and peak positive derivative of LV pressure (dP/d tmax) increased by 32 ± 7% with AM-EPI ( P < 0.05, AM-EPI interaction), whereas no significant effects were observed with EPI. Mean arterial pressure was maintained by AM-EPI and tended to decrease with EPI (+2 ± 13% vs. −11 ± 10%, P = not significant). PVA-MV˙o2 relationships were unaffected by all treatments. In conclusion, AM-EPI cotreatment has an inodilator profile with CO and LV function augmented beyond individual drug effects and is not associated with relative increases in energetic cost. This can possibly take the inodilator treatment strategy beyond hemodynamic goals and exploit the cardioprotective effects of AM in acute heart failure.

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