Prevalence, Severity, and Prognostic Value of Sleep Apnea Syndromes in Cardiac Amyloidosis

Abstract

Study Objectives:

To assess prevalence, severity, and prognostic value of sleep-disordered breathing (SDB), in the three main cardiac amyloidosis (CA) types, i.e., light-chain (AL), transthyretin-related familial (m-TTR), or senile (WT-TTR).

Methods:

Patients consecutively referred for CA diagnosis work-up underwent cardiac assessment and nocturnal polygraphy. SDB was defined as apnea-hypopnea index (AHI) ≥ 5/h. Multivariate analysis was used to identify predictors of a major adverse cardiac event (MACE) defined as death, heart transplantation and acute heart failure.

Results:

Seventy CA patients were included (31 AL, 22 m-TTR, 17 WT-TTR). The mean ± standard deviation age and left ventricular ejection fraction were 71 ± 12 years and 49% ± 13% and median (interquartile range) N terminal pro brain natriuretic peptide (NT-proBNP) was 3,932 (1,607; 7,028) pg/mL. The prevalence of SDB was 90% without difference between amyloidosis types. SDB was central in 27% and obstructive in 73%. AL had less frequent severe SDB compared to m-TTR and WT-TTR (P = 0.015) but longer time with peripheral capillary oxygen saturation (SpO2) < 90% (P = 0.037). After a median follow-up of 7.5 (2.8; 14.9) months, 49% patients experienced MACE. Time with nocturnal SpO2 < 90% was the only independent predictor of MACE. The best-identified threshold was 30 min. Values > 30 min were associated with bad prognosis (Log-rank χ²: 8.01, P value = 0.005). Using binomial logistic regression, determinants of time with nocturnal SpO2 < 90% were New York Heart Association class (P = 0.011), and log-NT-proBNP (P = 0.04) but not AHI.

Conclusions:

In CA population, prevalence of SDB is high (90%) and dominated by the obstructive pattern. Bad prognosis in this population was driven by nocturnal desaturation, reflecting heart failure severity and respiratory involvement.

Citation:

Bodez D, Guellich A, Kharoubi M, Covali-Noroc A, Tissot CM, Guendouz S, Hittinger L, Dubois-Randé JL, Lefaucheur JP, Planté-Bordeneuve V, Adnot S, Boyer L, Damy T. Prevalence, severity, and prognostic value of sleep apnea syndromes in cardiac amyloidosis. SLEEP 2016;39(7):1333–1341.

Significance.

Sleep-disordered breathing is frequent and associated with poor prognosis in patients with heart failure. Cardiac amyloidosis is a severe condition, its entire understanding including co-morbidities that have additional prognostic impact, is of crucial importance. This is the first study to focus on sleep consequences of cardiac amyloidosis, highlighting that SDB is highly prevalent in these patients. The attention of physicians should be drawn to the need of SDB screening in this population. Moreover, this study provides a first potential therapeutic target to consider in this particular population that is nocturnal desaturation. Further studies are needed to establish the prognostic value in each type of cardiac amyloidosis, as to evaluate the effects of SDB treatment on outcomes.

INTRODUCTION

Sleep-disordered breathing (SDB) and the related clinical syndrome, sleep apnea (SAS), are common in patients with chronic heart failure (CHF).^1,2 SDB is increasingly being recognized as an independent risk factor for the development of HF and may aggravate the natural course of CHF.^3–6 Prevalence studies of SDB have shown its occurrence in up to 70% to 80% of CHF patients with either altered or preserved ejection fraction.^7,8 SAS can be obstructive (OSA), resulting from upper airway collapse, or central (CSA), resulting from exaggerated respiratory control responses to changes in PaCO₂ that lead to breathing instability.^9,10 The two forms of SAS can also coexist in patients with congestive HF.¹¹ In OSA, this leads to abrupt increase in left ventricle (LV) afterload through the combined effects of elevation in systemic blood pressure, generation of exaggerated negative intra-thoracic pressure and activation of the sympathetic nervous system consecutive to the recurrent arousals from sleep.¹² CSA causes intermittent hypoxia, generation of reactive oxygen species, inflammation, and sympathetic activation. This may lead to arrhythmia, pulmonary and systemic hypertension, myocardial ischemia, and remodeling.^13–17 Therefore, both OSA and CSA have harmful consequences on the heart and CHF prognosis.⁵ CHF in turn, can also cause and exacerbate CSA and OSA: rostral fluid displacement worsens CSA but also OSA because of pharyngeal edema increasing obstruction in the upper respiratory tract.¹⁸ Thus CHF and SDB maintain a vicious circle depending on the characteristics and specificities of both of them.

Amyloidosis is a systemic disease characterized by continuous accumulation of insoluble proteins in the extracellular matrix of different tissues and organs such as the heart, kidney, nerve, but also tongue and upper respiratory tract.¹⁹ The three major forms are immunoglobulin light-chain-related amyloidosis (AL), mutated transthyretin-related amyloidosis (m-TTR), and wild-type transthyretin-related amyloidosis (WT-TTR).²⁰ Cardiac involvement is frequent in all these forms and carries poor prognosis.²¹

In the context of amyloidosis, CHF presents specificities, which may relate to pathophysiological mechanisms of SDB. Indeed, the deposition of amyloid proteins in the extracellular matrix of the oropharyngeal soft tissue, macroglossia, arrhythmia, or autonomic neuropathy, are comorbidities and risk factors of SDB.^22,23 The present study was, therefore, carried out in order to establish the prevalence, severity and prognostic value of SDB in three main types of CA.

METHODS

Study Design and Patient Assessment

This prospective epidemiologic observational study included patients who were referred to our amyloidosis network for a diagnosis work-up of amyloidosis between July 1, 2006, and March 1, 2014. Inclusion criteria were age > 18 years and diagnosis of CA. Each patient underwent basic clinical evaluation, for which baseline demographic characteristics, medical history, sleep history, cardiovascular risk factors, and medication taken were reported. An electrocardiogram (ECG) and a transthoracic echocardiography (TTE) were performed for each patient at inclusion. Standard assessment was completed by biological tests including cardiac biomarkers. Informed consent was obtained from each patient. This study complied with the 1975 Declaration of Helsinki and was approved by our local ethics committee.

Sleep Study

Patients were screened for SDB consecutively and prospectively. An overnight polygraphy was performed in the cardiology ward using a digital recording system (Embletta, ResMed, Saint Priest, France). Oro-nasal airflow was measured from a mouth thermistor and nasal pressure; chest and abdominal movements were assessed by inductance plethysmography. Pulse oximetry, snoring, actimetry, and body position were also recorded. Patients were asked to fill out the Epworth Sleepiness Scale. The polygraphic recordings were scored on the basis of visual analysis by an experienced investigator (A.C-N) blinded to the cardiac assessment. Only recording ≥ 4-h duration without any missing traces were considered for analysis. The number of apnea-hypopnea events per hour (AHI) was determined after the exclusion of periods that had movements, which were considered to be wakeful periods. Generally accepted definitions and scoring methods were used. The oxygen desaturation index (ODI) was defined as the number of episodes per hour of sleep with oxygen desaturations ≥ 4%. Obstructive and central events were scored as previously described.⁷ According to the American Society of Sleep Medicine, a diagnosis of SDB was considered if the AHI was ≥ 5/h. The severity of SDB was classified as mild (5 ≤ AHI < 15 events/h), moderate (15 ≤ AHI ≤ 30 events/h), and severe (AHI > 30 events/h). SDB was considered central if > 50% of apnea-hypopnea events were central (absence of respiratory efforts); it was considered obstructive if > 50% of apnea-hypopnea events were obstructive (presence of respiratory efforts). Desaturation time was defined as the duration of sleep with oxygen saturation (SpO₂) < 90%.

Morphological Exams

Experienced operators performed echocardiograms before sleep assessment, in accordance with the recommendations of the American Society of Echocardiography²⁴ and the European Association of Echocardiography,²⁵ using a Vivid 7 system (GE Vingmed, Horten, Norway).

Methodology was previously reported.²⁶ Briefly, inter-ventricular septum thickness (IVST) was measured on the M-mode parasternal long-axis view at end-diastole. Left ventricular ejection fraction (LVEF) was measured by the Simpson biplane method. Early (E) and Late (A) transmitral diastolic peak flow velocities were measured using pulsed-wave Doppler recordings from the apical 4-chamber view. Pulse-wave tissue Doppler imaging (TDI) of the mitral annulus was obtained from the apical 4-chamber view and was recorded at the septal and lateral mitral annulus. Early diastolic mitral annular velocity (e') was measured, and the early diastolic mitral peak flow velocity/e' ratio (E/e') was calculated. Tricuspid annular plane systolic excursion (TAPSE) was obtained from the M-mode apical 4-chamber view. Systolic pulmonary artery pressure (PAP) was estimated from the maximal peak velocity of tricuspid regurgitation (TR). The average of 3 consecutive cycles was used for each measurement. LV peak systolic longitudinal strain (LS) was assessed for patients with sinus rhythm using speckle-tracking analysis on 2D images from the 3 apical views. 99Tc-bisphosphonate bone scintigraphy and cardiac MRI were performed as previously described.^27–29

Cardiac Amyloidosis Diagnosis

Diagnosis of amyloidosis was made as previously described.^29,30 Briefly, it was based on histological findings, based on Congo red positive deposits from endomyocardial tissue or extra-cardiac biopsies. Type of amyloidosis was established from clinical evidence (past and familial medical history), biomarkers (serum and urine immunoglobulin measurements), immunohistochemistry, and bisphosphonate cardiac uptake at scintigraphy. TTR gene sequencing was performed to differentiate m-TTR and WT-TTR. The diagnosis of cardiac amyloidosis was made when amyloidosis was associated to a hypertrophic cardiomyopathy defined by an IVST ≥ 12mm.

Outcomes and Follow-up

The follow-up began at the completion of sleep assessment. The primary endpoint was major adverse cardiac event (MACE) defined as the composite of death, heart transplant, and acute heart failure (AHF). Status and dates of event were obtained from the patients' usual follow-up visits, by patient phone call, or using medical records. None of the patients was lost to follow-up.

Statistical Analysis

Data were expressed as absolute and relative frequencies (counts and percentages) for categorical variables and as mean ± standard deviation for continuous variables, except for N terminal pro brain natriuretic peptide (NT-proBNP) and creatinine, which were expressed as median (25^th, 75^th percentiles). Non-normal distributed variables (NT-proBNP and creatinine) were log-transformed for further analyses. Comparisons between nominal variables were made using χ² test or Fisher exact test. Continuous variables were compared between 2 groups using Mann-Whitney test, and with Kruskal-Wallis tests for 3-group comparisons. Clinical, biological, echocardiographic, and polygraphic variables were compared depending on the presence or not of MACE at 12 months. Patients without event and a follow-up less than 12 months were excluded of this analysis to avoid bias due to the duration of follow-up. Univariate cox proportional hazard analysis including all the patients with no limitation in follow-up duration was performed to identify predictors of MACE. Variables with a P value < 0.15 were retained for Cox proportional hazard multivariable analysis. Hazards ratios (HRs) and 95% confidence intervals (95%CIs) were derived from the regression model using the Wald method. To assess the best cutoff values for predicting MACE within 12 months, receiver-operating characteristics (ROC) curves were plotted followed by a Youden test. Cumulative event curves were drawn using Kaplan-Meier survival method according the best cutoff values determined by the Youden test. Differences between curves were tested for statistical significance by the log-rank test. To identify the determinant of the independent predictors binomial logistic regression was used and selected variable were included in the model (age, gender, type of amyloidosis, NYHA, SBP, log NT-proBNP, LVEF, IVST, E/e', AHI). A P value < 0.05 was considered to be statistically significant. All statistical analyses were performed using the SPSS software (version 19.0 for Windows 2010 SPSS Inc.).

RESULTS

Baseline Characteristics

Baseline characteristics of the 70 patients included are shown in Table 1 according to CA etiology. 31 patients had AL, 22 m-TTR, and 17 WT-TTR (Figure 1). Briefly, WTTTR patients were older, more often male, and presented significant lower LVEF than the other groups. Prevalence of neuropathy was higher in m-TTR patients. The proportion of patients with an implanted device (pacemaker or defibrillator) was also higher in this group. AL patients presented higher heart rate (HR) and more frequent ECG low voltage and higher NYHA III-IV class. NT-proBNP level tended to be higher in AL. Macroglossia was observed only in AL patients (n = 3). Twenty-seven of the 30 patients without any cardiac implantable device had also a cardiac MRI, which showed the presence of late-gadolinium enhancement (LGE) for all of them.

Table 1.

Baseline characteristics of all patients classified by the cardiac amyloidosis type.

Figure 1.

Study plan: Sleep-disordered breathing in cardiac amyloidosis population of the study. AL, light-chain amyloidosis; m-TTR, transthyretin-related familial amyloidosis; WT-TTR, wild-type transthyretin-related amyloidosis.

Polygraphic Data in the Overall Population

Prevalence of SDB (AHI ≥ 5/h) was 90% (n = 63). Comparisons of the clinical characteristics between patients with and without SDB are shown in Table S1 of the supplemental material. No significant difference was observed. Among the 63 SDB patients the mean AHI was 20.2 ± 14.2/h; and 27% (n = 17) presented a CSA and 73% (46) an OSA, without difference between CA type (Figure 2A).

Figure 2.

Sleep-disordered breathing (SDB) according to cardiac amyloidosis etiology. (A) Type of SDB according to cardiac amyloidosis etiology (χ², P = 0.79). (B) Severity of SDB by nocturnal desaturation time according to cardiac amyloidosis etiology (*P = 0.037). (C) Severity of SDB by AHI according to cardiac amyloidosis etiology (*P = 0.015). AHI, apnea-hypopnea index; AL, light-chain amyloidosis; m-TTR, transthyretin-related familial amyloidosis; SDB, sleep-disordered breathing; WT, wild-type transthyretin-related amyloidosis.

Polygraphic Data Depending on Amyloidosis Type

Polygraphic variables regardless of CA type are presented in Table 2. Apnea-hypopnea index tended to be lower in AL patients than other groups (P = 0.09), however AL patients presented longer desaturation time compared to the other groups (P = 0.037, Figure 2B). Distribution of patients by SDB class according to CA etiology is shown in Figure 2C; frequency of severe SDB was different in the 3 CA types (41% in WT-TTR, 23% in m-TTR and 7% in AL, P = 0.015).

Table 2.

Baseline polygraphic data according to the cardiac amyloidosis type.

Clinical Variables Depending on SDB Type

Interestingly, LVEF was lower in CSA patients (39.2 ± 9.8) compared to non-SDB (46.9 ± 16.2) or OSA patients (53.6 ± 11.8; P < 0.001). The presence of implanted devices was more frequent in OSA (n = 26, 57%), than CSA (n = 12, 71%) or non SDB patients (n = 2, 29%, P = 0.04).

Survival Data and Analysis Depending on MACE

The overall median follow-up period was 7.5 (2.8; 14.9) months, and 18.0 (15.0; 26.0) months in the free-event group. At 12 months, MACE occurred in 26 (54%) of the 48 patients analyzed with at least one year of follow-up, with death for 13 (50%), heart transplantation for 1 (4%), and acute heart failure for 12 (46%) patients. Table 3 showed comparisons of baseline characteristics depending on presence of MACE at 12 months. Only time spent with SpO₂ < 90 was significantly higher in patients with MACE compared to those without. Over the whole follow-up period, 34 (49%) patients had at least one cardiac event. Primary event was death for 15 (21%), cardiac transplantation for 1 (1%), and acute heart failure for 18 (26%).

Table 3.

Comparison of baseline clinical, echocardiographic, polygraphic, and biological variables in patients with or without MACE at 12 months.

Independent Predictors of MACE

The univariate and multivariate cox proportionate hazard model is shown in Table 4. Briefly, only desaturation time was independently associated with MACE in our CA population. The best prognosis cutoff value identified by ROC curves followed by Youden test was 30 min (AUC 0.70; 95%CI, 0.55–0.85; P = 0.022).

Table 4.

Multivariate model predicting a major adverse cardiac event (MACE) in cardiac amyloidosis.

Kaplan-Maier estimators of the cumulative risk of MACE according to desaturation time (≤ or > 30 min) are presented Figure 3. Patients with desaturation time > 30 min presented an event rate significantly higher (log-rank value 8.01, P value = 0.005). Using binary regression logistic model, NYHA (P = 0.011) and log NT-proBNP (P = 0.040) were identified as determinants of time spent with SpO₂ < 90 above 30 min (Table 5).

Figure 3.

Kaplan-Meier curves for time to major adverse cardiac event (MACE) according to nocturnal desaturation time with SpO2 < 90%.

Table 5.

Binary logistic regression depending on time of desaturation below 90%, classified in class (> 30 min vs. ≤ 30 min) in the overall population.

DISCUSSION

In this prospective epidemiologic observational study, we found that SDB was highly prevalent in CA, whatever the etiology. The time spent with SpO₂ < 90% was independently associated with occurrence of MACE and determined by the severity of HF.

Prevalence of Sleep-Disordered Breathing in Cardiac Amyloidosis

A high prevalence of SDB was shown in numerous CHF populations. However, there are very few data on SDB in amyloidosis, mostly case reports which focused on patients with macroglossia and redundant oropharyngeal and hypopharyngeal soft tissues.^31–33 To our knowledge, this is the first study to evaluate SDB in the specific context of CA including the three main types. The first major finding is the very high prevalence of SDB (90%), with 27% of CSA. In a series of CHF patients from various etiologies, a previous study⁷ has shown a similar prevalence of SDB (about 80%), with a similar pattern (30% CSA and 70% OSA). This indicates that macroglossia and the deposition in pharyngeal soft tissue are not the exclusive causes of CA-related SDB; first because they cannot explain CSA; secondly because of the low prevalence of macroglossia in our cohort (6%), compared to the high prevalence of SDB (90%), including OSA (66%). This is also consistent with the high prevalence of SDB in TTR CA, without difference between AL and TTR CA, despite the absence of oropharyngeal deposition in TTR patients for pathophysiological reasons. We can however specify that all three AL patients presenting macroglossia were suffering from OSA.

The prevalence of SDB seems to be lower in other hypertrophic cardiomyopathies (HCM), where it ranges from 32% to 71%.^34–36 This might be explained by the fundamental different pathophysiological mechanisms that lead to genetic or amyloid HCM. Indeed, cardiac involvements are very different in CA and genetic HCM, which can lead to different levels of CSA. Moreover, extracardiac factors, such as macroglossia, pharyngeal soft tissue thickening, peripheral neuropathy, or dysautonomia, might play a role in the occurrence of SDB associated with amyloid HCM.^22,23 Nevertheless in our cohort, presences of neuropathy or implantable devices were not different between SDB and non-SDB patients. Thus, our data suggest that the presence of SDB in association with a HCM, especially with a central pattern, might evoke an amyloid etiology, even if this hypothesis needs to be confirmed by further studies. Moreover, in comparison to a French cohort of stable CHF patients,⁷ our results indicate a lower mean AHI and a longer desaturation time in CA despite similar prevalence of SDB in the both cohorts, suggesting a predominant impact on desaturation in the specific context of CA that could partly explain our results on prognosis.

Prognostic Value of Desaturation Time

The second main finding of this study is that time spent with SpO₂ < 90% but not the AHI was associated with MACE after multivariate analysis. Yet, the severity of SDB in CHF is commonly assessed by the AHI and by the presence of CSR, while several studies have reported their prognostic values.^37–39 Conversely, Gottlieb et al. reported that hypoxia but not the AHI was associated with nocturnal BNP increase,⁴⁰ and the prognostic impact of nocturnal desaturation on the occurrence of sudden death has also been reported.⁴¹ In addition, Gellen et al. showed very recently that the severity of nocturnal desaturation was strongly associated with poor outcomes and improved risk stratification in CHF patients.⁴² Moreover they also reported an increased occurrence of adverse event in association with time spent with SpO₂ < 90%, in line with the present results. In the same way, a recent large retrospective cohort showed a signifi-cant association between nocturnal desaturation and cardiovascular outcomes and all-cause mortality.⁴³ Then, it appears that in the specific context of HF, AHI might not be the best severity marker of disordered breathing activity, since hypoxemia is associated with MACE, contrary to AHI. Yet, in congestive CHF, hypoxemia is not only a consequence of CSA related-breathing instability: the supine position is known to worse the hemo-dynamic conditions and the pulmonary congestion by shifting rostral fluid from legs toward the chest,¹⁸ both conditions that compromise blood oxygenation independently of repetitive cessation of ventilation that are apneic episodes. Furthermore, desaturation related to supine position might strongly reflect hemodynamic compromise and therefore represents a more powerful marker of disease severity.

Hypoxemia in Cardiac Amyloidosis

Hypoxemia appears as the strongest prognostic factor in CA-related SDB. Oxygen desaturation in CA-related SDB might be due to several reasons. First, it can be related to the interrupted breathing by apneic-hypopneic episodes. In fact, AL CA patients presented longer desaturation time than other CA etiologies while having a lower AHI suggesting that hypoxemia was more related to pulmonary congestion. Conversely WTTTR patients had shorter nocturnal time with SpO₂ < 90% but tended to have higher AHI than AL. Indeed, we showed that desaturation time was significantly associated with signs of severe HF (increased NYHA class and NT-pro-BNP levels). This means that desaturation time appears to be more a congestion marker in CA-related SDB patients than a specific marker of SDB and particularly in AL. This finding can also explain why the type of amyloidosis was not an independent prognostic marker in the present study as previously observed,²¹ as AL patients showed more severe heart failure (superior NYHA IIIIV and NT-proBNP levels) than the two other CA.

Our data suggest that adverse outcomes in CA-related SDB patients are strongly driven by congestion-related oxygen de-saturation, just like in CHF with reduced ejection fraction.⁴²

Limitations

The main limitations of this study are the single reference center recruitment and the small sample size, both reflecting the low incidence of CA. However, this is the first study of SDB in CA, including three main types of amyloidosis. The reference standard for diagnosing SDB was unattended overnight polygraphy instead of attended polysomnography at the sleep laboratory. Polygraphy does not accurately measure total sleep time. However, we used the self-reported sleep time as the denominator for computing the AHI. The absence of total sleep time determination may have led to underestimation of the AHI and the time spent with SpO₂ < 90%. In addition, polygraphy does not accurately measure arousal/fragmented sleep or periodic limb movements, which might occur in CA patients. For these reasons, the underestimation of AHI might have led to underestimate its prognostic impact, which would require to be further evaluated a full polysomnography. Nevertheless, the prognostic value of nocturnal desaturation is well established.

CONCLUSIONS

Sleep-disordered breathing, including both OSA and CSA, are frequent in CA patients. Nocturnal time spent with SpO₂ < 90% rather than AHI is an important prognostic marker that reflects both respiratory involvement and congestion. Sleep study should be performed in CA patients to refine their prognosis. Impact of nocturnal desaturation treatment in this population needs to be assessed.

DISCLOSURE STATEMENT

This was not an industry supported study. This work was supported by the non-profit organization AREMCAR (Association pour la Recherche et l'Etude des Maladies Cardiovasculaires). Dr. Damy has received grant research support and is consultant for ResMed. The other authors have indicated no financial conflicts of interest. This work was performed at AP-HP Henri Mondor Teaching Hospital, Créteil, France.