Introduction

In spite of recent triumphs in pharmacological and device therapy, chronic heart failure (CHF) remains a major public health problem. CHF is associated with high morbidity, frequent hospitalizations and readmissions, huge economical cost and excess mortality. Therefore, identification of co-morbidities which contribute to progression of CHF, particularly if treatable is our current challenge and need to be pursued systematically and aggressively.

Among multiple co-morbidities, sleep-related disordered breathing (SRBD), is the most common and least recognized by cardiologists. Yet, SRDB consisting of apneas (cessation of breathing for 10 seconds or longer) and hypopneas (reduction in breathing for 10 seconds or longer) are associated with acute and chronic pathophysiological processes which ultimately result in excess cost, morbidity, readmissions, and mortality.1-4

There are two major types of apnea:

1. Central sleep apnea (CSA) is due to temporary failure in the pontomedullary pacemaker generating breathing rhythm. This is analogous to sinus node arrest for at least 10 seconds. During central apnea, there is no brain stem inspiratory neural output through the nerves innervating the diaphragm and intercostals pump muscles. Therefore, polygraphically, central apnea is characterized by the absence of naso-oral airflow and thoracoabdominal excursions (Fig 1). Mechanistically, central apneas occur when the prevailing PCO2 decreases below a certain level referred to as apneic threshold PCO2. Due to cessation of breathing, PCO2 rises and when it exceeds the apneic threshold PCO2, breathing resumes.
2. Obstructive sleep apnea (OSA) is due to upper airway occlusion secondary to neuromuscular failure, primarily involving hypoglossal nerve and genioglossus muscle. Normally, during sleep, genioglossus muscle activity decreases and during inspiration due to the negative airway pressure, the tongue falls backward. In susceptible individuals, this results in upper airway closure (obstructive apnea, Fig 2) or narrowing (obstructive hypopnea). Obesity is the major risk factor for OSA, in part due to excess fat deposition in the pharynx. Not surprisingly, HF patients with OSA are commonly obese and snore habitually.5,6

Overlapping Symptoms of Heart Failure and Sleep Apnea

These two chronic disorders share symptoms, both nocturnal and diurnal, making it difficult to tell them apart or if they are comorbid. Heart failure patients without sleep apnea have difficulty maintaining sleep, which may be fragmented by nocturia, orthopnea and paroxysmal nocturnal dyspnea, waking up the patient with shortness of breath. Similarly, patients with sleep apnea without heart failure have frequent awakenings, nocturia and may wake up short of breath due to the apnea.

Finally, patients with sleep apnea or heart failure, independent of each other, also share similar day time symptomatology such as waking up unrefreshed, fatigue and lack of energy, and at times, excessive daytime time sleepiness.

Overlapping Neurohormonal and Biological Markers of Sleep Apnea

Not only do the symptoms of HF and SA overlap, but also the two disorders share similar pathological molecular signatures. In both disorders, there is evidence of increased sympathetic activity, oxidative stress and inflammation. In both disorders, endothelial dysfunction is manifested with impairment in vasodilatation and decreased availability of NO, whereas TNFα, IL6, and endothelin are increased.

Pathophysiological Consequences of Sleep Apnea Adversely Affect Progression of Heart Failure

In regards to sleep apnea (Fig 3), both CSA and OSA, is associated with three immediate adverse biological consequences: A) arterial blood gas abnormalities consisting of repetitive episodes of hypoxemia/hypercapnia which occur due to apnea, followed by reoxygenation/hypocapnia associated with recovery from apnea, and B) large negative swings in intrathoracic pressure and C) arousals. These consequences are qualitatively similar for both OSA and CSA, but more pronounced with OSA.

These nocturnal events occurring night after night, eventually adversely affect various cardiovascular functions and structure.1 These adverse effects should be most detrimental in the presence of established left ventricular systolic and diastolic dysfunction and coronary artery disease.

In regards to sympathetic activity which has a profound effect on the natural history of heart failure, multiple studies have shown that both OSA and CSA, independent of HF, are associated with increased sympathetic activity as measured by an increase in both plasma and urinary catecholamines, heart rate variability and muscle sympathetic nerve activity.

The underlying mechanisms of apnea- related increased sympathetic activity while asleep have to do with altered blood gas chemistry, arousals, and the apnea itself. Therefore, patients with heart failure who suffer from sleep apnea, in spite of presence of beta blockers, may not be protected from the overwhelming hyperadrenergic state of sleep apnea and be prone to nocturnal arrhythmias,7 the precursor of sudden death.

Prevalence of Sleep Apnea in Consecutive Patients of Heart Failure

The prevalence of sleep apnea in ambulatory patients with HF, both with reduced and preserved ejection fraction is quite high and HF is the leading risk factor for sleep apnea.

A. Heart failure with reduced left ventricular ejection fraction

Sleep studies of consecutive patients with stable HFrEF have been reported from various countries with either polysomnography or polygraphy (without electroencephalography).1-3 

The most detailed systematic prospective study in HFrEF involved 100 (of 114 consecutive) ambulatory male patients with stable, treated HF.6 Each patient spent two nights in the sleep laboratory, with the first night for habituation. Polysomonography was performed during the second night. 49% of the patients had an AHI of 15 ≥ per hour of sleep. In the general population, only 9% of men have an AHI≥15/h. For reference, an AHI of 5 to < 15, 15 to < 30 and 30 or more are considered mild, moderate and severe sleep apnea, respectively.

In our study, 10% of the patients were taking β-blockers. However, in spite of wide spread use of β-blockers, the prevalence of sleep apnea in CHF has remained quite high. Combining results of studies from consecutive CHF patients from around the world shows that 52% have an AHI ≥ 15/hour (Fig 4).3 In most of these studies, 80% to 90% of the patients were on a β-blocker. In these studies, 31% had CSA and 21% had OSA; however, this distribution varies considerably among various reports, in part due to difficulties involved in differentiating central and obstructive hypopneas from each other. 

B. Heart failure with preserved ejection fraction

In the largest study8 of 244 consecutive patients (87 women) with well documented HFpEF, Bitter and colleagues used echocardiography and right and left heart catheterization to define the causes of heart failure: 33% had coronary artery disease, 44% had systemic hypertension and 23% had hypertrophic/restrictive cardiac disease. Using polygraphy, 48% of the patients had an AHI ≥ 15/hour, prevalence similar to patients with HFrEF. 25% of the 244 patients had OSA and 23% had CSA (Fig 4).

In summary, in the era of beta blockers, sleep apnea is a major co morbidity in heart failure with a prevalence of 52%. Yet, sleep apnea remains under-diagnosed. We recently reviewed data of randomly selected Medicare beneficiaries.4 These were patients with HF newly diagnosed in the first quarter of 2004 that were not coded with the diagnosis of HF or SA in 2003. Among a study population of 30,719, only 1,263 (4%) were clinically suspected to have SA, and 553 (2% of the total cohort) received SA testing. Not surprisingly, 97% of the 553 were diagnosed with sleep apnea. As noted earlier, we estimate that about 52% of the cohort, i.e., about 15,000 patients suffered from sleep apnea. Meanwhile, as will be discussed later, the heart failure patients who were treated for sleep apnea had a significantly improved survival compared to the remaining patients.4

Impact of sleep apnea on mortality of heart failure and effect of treatment. Given the acute and chronic adverse effects of SRDB on cardiovascular system it should not be of surprise that sleep apnea could independently contribute to excess mortality of patients with heart failure.1-4,10-15 We have suggested9that there is a bidirectional relation between heart failure and sleep apnea (Fig 5). 

Impact of OSA on mortality and effect of treatment with CPAP

A prospective study11 reported a significantly greater death rate in 37 untreated heart failure patients with OSA than in the 113 patients without (or with mild) OSA. The death rate was significant after controlling for confounding factors. Furthermore, the authors reported no deaths among the 14 heart failure patients with OSA who were treated with CPAP devices, the treatment of choice for OSA. However, n was small and this difference was significant at .07 p value.

In a French study, comparing 50 patients with AHI < 5/hour to 236 patients with AHI ≥ 5 hour Damy and colleagues15 reported excess mortality associated with OSA. Furthermore, the authors reported that treatment of OSA with positive airway pressure device was associated with improved survival in 62 patients compare to the 48 untreated patients with AHI ≥ 20/hour. 

In a study AHI from Japan,12 in patients with HFrEF and moderate to severe OSA (n=65), use of a CPAP device was associated with significant reduction in the rate of hospitalization and mortality when compared to 23 untreated OSA patients. The improved survival was only in CPAP adherent patients. 

In the only study from US, of several thousand Medicare beneficiaries,4 we reported improved survival (Fig. 6), less hospitalization and cost of couple of hundred treated patients compared to several thousand untreated HF patients after accounting for a number of confounders 

Impact of CSA on mortality and effect of treatment with CPAP and Adaptive servo-ventilation devices. Regarding CSA and mortality, there are multiple studies and most1,10,16 show that CSA is associated with excess mortality in HFrEF. We followed 88 heart failure patients with (n=56, mean AHI=35/hour) or without (n=32, mean AHI=2/hour) CSA with a median follow-up of 51 months.(2) After controlling for 24 confounding variables, CSA was associated with excess mortality (hazard ratio=2.14, p=0.02). The average survival of heart failure patients without CSA was 90 months compared to 45 months of those with CSA (Fig. 7). 

Regarding treatment of CSA, there are some differences when compared to OSA. As noted above, it is unanimously agreed that CPAP devices are the treatment of choice for OSA. However, in contrast to OSA, CSA is not uniformly suppressed by CPAP. Various therapeutic options for treatment of CSA have been reviewed in detail elsewhere.1,2 Three options, cardiac transplantation, phrenic nerve stimulation and positive airway pressure therapy are discussed briefly.1,2

After cardiac transplantation CSA is generally eliminated indicating that heart failure is the cause of CSA.17 Unfortunately, however, few months after transplantation, more than a third of the patients develop OSA in association with excess weight gain.17 This is an important issue, but completely unrecognized), as these patients have a high prevalence of hypertension, poor quality of life and perhaps rejection.17

Phrenic nerve stimulation provides a unique opportunity acting as a bridge connecting cardiologists and sleep physicians together. This stimulator is placed transvenously like a pacemaker by an electro-physiologist, either in the brachiocephalic vein on the right or in the left pericardiophrenic vein where the phrenic nerve passes over the wall of the vein. With breath by breath stimulation of the phrenic nerve, virtually all central apneas are eliminated and arousal and desaturation improve.18 A long-term randomize clinical trial is pending.

Regarding treatment with positive airway pressure devices, CPAP suppresses CSA in about 50% of these patients (which is in contrast to OSA discussed above). In those whose CSA is suppressed by CPAP, survival improve considerably,16 whereas, and not surprisingly, survival remains poor in those whose CSA is not suppressed by CPAP. For the latter, we recommend adaptive servoventilation devices. These unique devices provide variable ventilatory support and are equipped with a back up rate to abort any impending apneas.15 Two observation studies have shown significantly improve survival in patients who used these devices.13,14 Two randomize clinical trials are in progress.

Pearls

Periodic breathing is common co morbidity in heart failure, both HFrEF and HFpEF. Periodic breathing includes both obstructive and central sleep-related breathing disorders and is characterized by repertoires of apneas, hypopnea, and the recovery hyperpnea. These SRDB cause arousals, hypoxemia-reoxygenation, hypercapnia-hypocapnia, and changes in intrathoracic pressure. All of these adversely affect sleep and cardiovascular function and eventually may contribute to progressive remodeling of myocardial structure and electrical conducting system leading to pump failure and arrhythmias and finally excess mortality. Several studies have demonstrated that both CSA and OSA are associated with increased mortality. Meanwhile few long-term studies with positive airway pressure treatment of sleep apnea in heart failure have shown that effective treatment of both CSA and OSA improves mortality of patients with heart failure. Randomized clinical trials are in progress.

Key Learning Points

• HF remains a malignant disorder
• 50% of HF patients, both HFREF and HFPEF, have SA.
• SA is not associated with EDS
• SA, both OSA and CSA, is associated with mortality
• OSA is easily treated by CPAP
• CSA is suppressed by CPAP in 50% of the patients
• ASV is recommended in CPAP non-responders
• Effective treatment of SA with positive airway pressure devices improves mortality. The key point is adherence

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References

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2. Javaheri S. Sleep-related breathing disorders in heart failure. In: Heart Failure, A Companion to Braunwald’s Heart Disease, edited by Douglas L. Mann. WB Saunders, Philadelphia 2010; 471-487.
3. Javaheri S. Cardiovascular Disorders. In: Atlas of Clinical Sleep Medicine. Edited by Kryger MH, WB Saunders, Philadelphia 2010.
4. Javaheri S, Caref B, Chen E, Tong KB, Abraham WT. Sleep apnea testing and outcomes in a large cohort of Medicare  beneficiaries with newly diagnosed heart failure. Am J Respir Crit Care Med 2011; 183:539-546.
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6. Javaheri S. Sleep disorders in systolic heart failure:  A prospective study of 100 male patients. The Final Report. Int J Cardiol 2006; 106:21-28.
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15. Damy T, Margarit L, Noroc A, Bodez D, Guendouz S, Boyer L, Drouot X, Lamine A, Paulino A, Rappeneau S, Stoica MH, Dubois-Rande JL, Adnot S, Hittinger L, Pia d’Ortho M. Prognostic impact of sleep-disordered breathing and its treatment with nocturnal ventilation for chronic heart failure. Eur J of Heart Fail 2012;14:1009-1019.
16. Artz M, Floras, JS, Logan, AG, et al. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure.Circulation 2007; 115:3173-3180.
17. Javaheri S, Abraham W, Brown C, et al: Prevalence of obstructive sleep apnea and periodic limb movement in 45 subjects with heart transplantation. Eur Heart J2004;25:260-266.
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Keywords: Chronic Disease, Comorbidity, Disease Progression, Heart Failure, Morbidity, Patient Readmission, Public Health

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