Ischemic Lesion Formation in Solitary Tract Nuclei During Central Sleep Apnea With Heart Failure – Reply –　Adaptive Servo-Ventilation Therapy for Patients With Chronic Heart Failure in a Confirmatory, Multicenter, Randomized, Controlled Study

Dr Jaster referred to the importance of the afferent feedback from the heart via the sympathetic nervous system with respect to the formation of medullary ischemic lesions in the solitary tract nuclei and mentioned the potential development of severe cardiac arrhythmias via the disruption of brain automatic regulations. I read his comments with interest.

However, I would like to point out that the objective of our study¹ was not to prevent life-threating cardiac events as he mentioned but to confirm the cardiac function-improving effect of adaptive servo-ventilation (ASV) therapy in patients with chronic heart failure (CHF). Although not indicating the superiority of ASV therapy to guideline-directed medical therapy (GDMT) in the cardiac function-improving effect (the primary endpoint), our study showed a clinical status-improving effect and indicated a given level of clinical benefit in the studied patients with CHF through a significant improvement in the clinical composite response (CCR) as corroborated by improvements in New York Heart Association class and in activities of daily living against the GDMT group.

Furthermore, our study did not intend to treat sleep-disordered breathing as with the studies mentioned by him,^2,3 but was conducted based on the previously estimated mechanisms of ASV to improve pulmonary congestion, including a reduction in cardiac preload through reduced venous return⁴ and the inhibition of sympathetic nerve overactivity.^5–7 We conducted the post hoc analysis of our study according to the possible combination and backward elimination methods in order to examine the associations of explanatory variables with CCR. Consequently, the apnea-hypopnea index was not included in the best combination of explanatory variables (Table).

Table. Best Combination of Variables in the Overall Group According to the Backward Elimination Method

Variable	MLE	P value	OR	95% CI
Intercept	−0.967	0.076
Intervention, ASV	1.224	0.019	3.401	1.224–9.455
Age <65 years	0.978	0.047	2.660	1.014–6.976
BNP ≥280 pg/ml	1.020	0.051	2.772	0.995–7.723
DBP ≥65 mmHg	1.328	0.091	3.775	0.807–17.652
LVEF ≥30%	−1.064	0.043	0.345	0.123–0.968
E/e’ ≥16	−1.429	0.009	0.239	0.082–0.695

P values calculated using Wald test. Note: numbers of patients with and without improved clinical composite response were 40 and 50, respectively. ASV, adaptive servo-ventilation; BNP, B-type natriuretic peptide; CI, confidence interval; DBP, diastolic blood pressure; E/e’, ratio of the E wave velocity to the early velocity of mitral annulus maximal expansion; LVEF, left ventricular ejection fraction; MLE, maximum likelihood estimate; OR, odds ratio.

In addition, our understating is that the major cause of sudden death in patients with CHF is not ischemic lesions in the medulla oblongata but fatal ventricular arrhythmias with the underlying pathology of sympathetic overactivity as mentioned in the guideline.⁸ We consider that this comprehension is clinically supported by the fact that β-blockers are effective for reducing the risk of death and improving the cardiac function of patients with CHF.⁸ ASV, a nonpharmacological modality, has been shown to improve sympathetic overactivity,^5–7 and our study indicated a tendency of suppression of HF deterioration.¹ Therefore, we recognize the potential improvement in prognosis by ASV. Nevertheless, a well-controlled clinical study will be required to verify the potential.

Disclosures

Conflict of Interest: S.M., lecture fee from Teijin Pharma Limited.

• Shin-ichi Momomura, MD
• Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan

(Released online March 4, 2016)

References

• 1.    Momomura  S,  Seino  Y,  Kihara  Y,  Adachi  H,  Yasumura  Y,  Yokoyama  H, et al; for the SAVIOR-C investigators. Adaptive servo-ventilation therapy for patients with chronic heart failure in a confirmatory, multicenter, randomized, controlled study. Circ J 2015; 79: 981–990.
• 2.    Satake  H,  Sugimura  K,  Fukumoto  Y,  Fukuda  K,  Nakano  M,  Kondo  M, et al. Effect of respiratory therapy on the prognosis of chronic heart failure patients complicated with sleep-disordered breathing: A pilot efficacy trial. Circ J 2016; 80: 130–138.
• 3.    Cowie  MR,  Woehrle  H,  Wegscheider  K,  Angermann  C,  d’Ortho  MP,  Erdmann  E, et al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure. N Engl J Med 2015; 373: 1095–1105.
• 4.    Takano  T,  Endo  T,  Tanaka  K,  Seino  Y,  Nitta  T,  Matsuyama  Y, et al. Effects of positive end-expiratory pressure ventilation and extracorporeal ultrafiltration method in patients with refractory heart failure. Jpn Circ J 1986; 50: 359–367.
• 5.    Harada  D,  Joho  S,  Oda  Y,  Hirai  T,  Asanoi  H,  Inoue  H. Short term effect of adaptive servo-ventilation on muscle sympathetic nerve activity in patients with heart failure. Auton Neurosci 2011; 161: 95–102.
• 6.    Koyama  T,  Watanabe  H,  Tamura  Y,  Oguma  Y,  Kosaka  T,  Ito  H. Adaptive servo-ventilation therapy improves cardiac sympathetic nerve activity in patients with heart failure. Eur J Heart Fail 2013; 15: 902–909.
• 7.    Tamura  Y,  Koyama  T,  Watanabe  H,  Hosoya  T,  Ito  H. Beneficial effects of adaptive servo-ventilation therapy on albuminuria in patients with heart failure. J Cardiol 2015; 65: 412–417.
• 8.    Yancy  CW,  Jessup  M,  Bozkurt  B,  Butler  J,  Casey  DE Jr,  Drazner  MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128: e240–e327, doi:10.1161/CIR.0b013e31829e8776.