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Obstructive sleep apnea (OSA) is highly prevalent in patients undergoing total joint arthroplasty (TJA) and is a major risk factor for postoperative cardiovascular complications and death. Recognizing this, the American Society of Anesthesiologists urges clinicians to implement special considerations in the perioperative care of OSA patients. However, as the volume of patients presenting for TJA increases, resources to implement these recommendations are limited. This necessitates mechanisms to efficiently risk stratify patients having OSA who may be susceptible to post-TJA cardiovascular complications. We explore the role of perioperative measurement of cardiac troponins (cTns) and brain natriuretic peptides (BNPs) in helping determine which OSA patients are at increased risk for post-TJA cardiovascular-related morbidity.
Over 1 million total hip and knee joint arthroplasty (total joint arthroplasty [TJA]) surgeries were performed in the USA in 2012, with costs exceeding $25 billion [1,2]. Projection models predict a profound increase in the number of TJAs that will be performed by 2030, estimating a twofold and sixfold increase in total hip and knee arthroplasties, respectively . The average patient presenting for TJA is older and obese . Importantly, this demographic is also at increased risk for the common medical disorder of obstructive sleep apnea (OSA) [3–7]. Recent studies have identified the growing role of OSA as a major risk factor for adverse post-TJA cardiovascular complications, including death [8–16].
OSA is defined by recurring episodes of airway collapse during sleep, which terminate in a burst of sympathetic activity and a resulting arousal from sleep . These events result in cyclic, intermittent hypoxemia and sleep fragmentation, that lead to daytime sleepiness, multi-system physiologic perturbations and a host of adverse clinical conditions, that most commonly include cardiovascular complications [17–20]. Importantly, routine post-TJA clinical conditions (including noise [leading to sleep fragmentation], use of narcotics for pain control and supine positioning) exacerbate OSA symptoms and confer greater risk for post-TJA cardiovascular complications [9,10]. However, there is little information available that can be used to stratify which patients with OSA are especially at risk for post-TJA cardiovascular complications.
Given the expected increase in patients undergoing TJA, information that can be used for accurate and efficient cardiovascular-related risk stratification will be critical for effective post-TJA management of a patient with OSA. In this regard, the blood biomarkers cardiac troponins (cTns [cTnT or cTnI]) and brain natriuretic peptides (BNPs [BNP or N-terminal proBNP]) have shown promise for predicting risk of adverse cardiovascular-related 30-day morbidity or mortality in patients undergoing noncardiac surgery [21–47], TJA [48–58,59] and to a certain degree in OSA patients [60–73]. While these biomarkers have been studied in surgical patients and OSA patients, none of these studies directly evaluated the perioperative patient with OSA undergoing noncardiac surgery or TJA.
In this review, we evaluate the feasibility of using cTns and BNPs to risk stratify patients with OSA for cardiovascular complications post-TJA. We conclude that there is a logical link to be made in utilizing cTns and BNPs for predicting risk of cardiovascular-related adverse events in OSA patients undergoing TJA. However, given the lack of studies directly evaluating the populations of interest, more research is needed.
A literature search was conducted using the PubMed, Embase and Scopus electronic databases, and references of articles, limited to human studies, English language and primarily elective surgeries conducted within the past 10 years. Our findings are presented chronologically (see Tables 2–7), as more recent assays have been found to be more precise and sensitive, reducing S/N in sensing the biomarker within the assay . Our search strategy included MeSH and exploratory keywords including ‘troponin’, ‘brain natriuretic peptide’, ‘perioperative or postoperative complication’, ‘noncardiac’ or ‘non-cardiac’ ‘surgery’, ‘total hip’ or ‘knee’ ‘joint arthroplasty’ and ‘obstructive sleep apnea’. Our review excluded studies evaluating cTns and BNPs in cardiac surgery, as levels of cTns and BNPs are increased with cardiac instrumentation .
Current trends show a growing prevalence in obesity  and an aging population , both of which increase the risk of joint disease, and cardiovascular disease . Indeed, the group of patients undergoing TJA is unique as they typically have increased age, higher obesity levels and are also more likely to have pre-existing cardiovascular disease . These trends of increasingly prevalent risk factors for TJA provide strong evidence that support projection models by the Task Force for Orthopedic Surgeons that the frequency of TJA procedures will continue to increase exponentially over the next decade . The surgical procedure for TJA involves precise incisions through tissue of either the knee or hip, removal of eroded cartilage and bone, drilling into bone and compression of an artificial prosthesis into native bone structure [81,82]. Recovery in the immediate postoperative period requires increased pain control, periods of immobilization in the supine position and/or periods of limited or passive range of motion [81,82]. The most common post-TJA cardiovascular complications include pulmonary embolism (PE) and acute myocardial ischemia or myocardial infarction (MI) [1,83]. Patients undergoing major orthopedic procedures such as TJA carry a moderate risk (1–5%) of developing postoperative cardiac complications [84,85]. However, pre-existing cardiovascular co-morbidities in the older and obese patient presenting for TJA contributes to increased postoperative cardiac events that further complicate recovery . Importantly, the existence of OSA in the TJA demographic further potentiates the manifestation and incidence of adverse postoperative cardiovascular complications [8–16].
The strongest risk factor for OSA is obesity [3–5,7]. Other major risk factors include advanced age , male gender and postmenopausal status in women . Data from 2013, estimate that 34% of middle-aged men and 17% of middle-aged women suffer from at least mild OSA, and 13 and 6%, respectively, suffer from moderate-to-severe disease . These estimates represent a clear increase in prevalence compared with the previous decade, reflecting the rising obesity levels in the population . In-laboratory polysomnography (PSG) is the gold standard diagnostic tool for OSA, however, an unattended portable home sleep testing (HST) is accepted as a less expensive method of diagnosis for patients with a high pretest probability of OSA . The primary measure of OSA severity is the apnea-hypopnea index (AHI) , the average number of apneas and/or hypopneas per hour of sleep (based on PSG) or recording time (when using HST). The AHI can be used to define disease severity as normal (AHI<5), mild (AHI≥5 and <15); moderate (AHI≥15 and ≤30) or severe (AHI>30) . The main treatment for OSA is positive airway pressure (PAP), which works as a pneumatic splint to maintain airway patency, reduce arousals and restore oxygenation .
OSA has been shown to contribute to a wide variety of cardiovascular manifestations (see Figure 1), including coronary ischemia [18,66], myocardial infarction [18,66], arrhythmias [19,88], heart failure , hypertension , venous thromboembolism [91–94] and stroke . Complex pathophysiological mechanisms, some that remain unclear, contribute toward the pathogenesis of cardiovascular events among OSA patients. These include the development of severe negative intrathoracic pressure as a result of arduous respiratory efforts to overcome upper airway collapse, sympathetic activation during episodes of apnea, sleep fragmentation and increased rapid eye movement (REM) activity, intermittent hypoxemic stress, dysregulation in neurohumoral, carotid chemoreflex (augmented) and baroreflex (reduced) function, inflammation, endothelial dysfunction, metabolic dysregulation and thrombosis [17,20,96,97]. Over time, recurrent swings in negative intrathoracic pressure can lead to increased cardiac preload and left ventricular afterload, increased cardiac work load, ventricular wall stress, unmet myocardial oxygen demand in the presence of alveolar hypoxia and hypercapnia and ultimately myocardial stress, ischemia, injury or infarction [17,20,97]. Furthermore, increased cardiac work, altered cardiac stretch and cardiac mechanoreceptors, systemic hypoxemia, respiratory acidosis (from carbon dioxide retention) and sympathetic hyperactivity contribute to dysregulated cardiac automaticity and arrhythmias [17,20,97]. Increased sympathetic activity and REM activity also contribute to blood pressure surges, fluctuating vagal tone, decreased heart rate variability, disruption in cardiac automaticity and arrhythmias [17,65,96].
In addition to these pathophysiological mechanisms, cycles of intermittent hypoxia that occur in OSA activate vascular inflammatory pathways, and produce pro-inflammatory cytokines, reactive oxygen species and increased expression of adhesion molecules, which in turn contribute to endothelial dysfunction and atherosclerosis [17,96]. Increased levels of pro-coagulant factors (such as plasminoger-activator inhibitor type-1, fibrinogen or platelet activity and aggregation) [91,93,94] are linked to OSA severity and circadian variation contributing to early morning fibrinolytic activity [98,99] and cardiovascular events [100–104]. These same mechanisms associated with cardiac myocyte stress have been shown to be triggers for the release of cTns and BNPs [75,105], making these biomarkers a potential indicator for OSA-related cardiovascular risk.
The co-existence of common clinical conditions in the perioperative treatment of TJA patients (see Box 1) further potentiates the effects of OSA [12,13,106–119]. The use of general anesthetics, opioid pain control, benzodiazepines and supine patient positioning during and post-TJA all act to promote and prolong airway closure, worsening desaturation and increasing the frequency of sympathetic bursts that accompany the termination of sleep-disordered breathing events [8–11,14,83,120–124]. Additionally, standard patient care activities, noise, light, pain and surgical stress  not only disrupt sleep architecture, but also increase sympathetic activity  and inflammation . Taken together, this may render patients with OSA who undergo TJA at even greater risk for postoperative cardiovascular complications compared with patients without OSA. Several studies have found that most postoperative complications typically occurred within the first 24–72 h of surgery, a period of time during which disruptions from these clinical conditions are more prominent [10,107,108,111,114,117,119].
OSA: Obstructive Sleep Apnea; REM: Rapid Eye Movement (REM); TJA: Total Joint Arthroplasty.
In 2001, a pivotal study published by Gupta and colleagues observed that 39% of patients diagnosed with OSA experienced post-TJA complications compared with only 19% of controls without OSA . Patients having OSA were more likely to experience adverse postoperative events in general; however, given that both patients having OSA and controls without OSA experienced an adverse event, the event in the patient having OSA (approximately 22% compared with 9% in controls) was commonly cardiovascular related and included myocardial infarction, myocardial ischemia, arrhythmias and pulmonary embolus . Other post-TJA complications experienced by both groups were not limited to acute hypercapnia or episodic hypoxemia, delirium, wound infections and nerve palsy . Further, subanalyses revealed that patients with OSA developed 15% more serious post-TJA complications (including cardiac events requiring patient transfer to an intensive care unit [ICU]), had significantly longer length of stay (LOS), unplanned ICU days and total ICU days compared with patients without OSA . Illustrating the efficacy of proper treatment, none of the 33 patients who used PAP therapy developed any complications in the first 24 h . A larger, subsequent study in the US Nationwide Inpatient Sample database of 258,445 TJA patients showed that patients with OSA developed more hypoxia, had increased rates of pulmonary embolism and in-hospital mortality and higher postoperative hospital charges . Other studies of post-TJA patients with OSA also observed increased adverse cardiovascular complications including development of pulmonary embolism [9,12,124], cardiac complications (nonmyocardial infarction)  and need for intubation/use of mechanical ventilation [12,13]. Additionally, the increased use of economic resources such as unplanned transfer to the ICU [11,13], longer hospital stays [8,13] and increased hospital costs  have been reported. Recognizing the growing impact that OSA has on adverse postoperative complications, the American Society of Anesthesiologists (ASA)  has urged providers to implement special considerations such as PAP therapy or enhanced monitoring in the postsurgical management of patients with OSA.
Given the evidence linking TJA, OSA and adverse postoperative cardiovascular outcomes, we review how the use of the blood biomarkers cTns and BNPs could represent additional information that may augment current perioperative risk stratification for a cohort of at-risk TJA patients with OSA. The literature provides notable differences among various studies evaluating cTns and BNPs in OSA patients. These differences from the studies generally relate to the clinical variability in biomarker measurement techniques as well as differences in study design. These are detailed in the ‘Limitations and challenges’ section.
Troponin is a protein complex involved in muscle contraction that is comprised of three distinct subunits: troponin T (cTnT), troponin I (cTnI) and troponin C (cTnC) . The troponin T (largest subunit; 37–39 kiloDalton) and troponin I (26 kiloDalton) isoforms are specifically involved in cardiac muscle contraction, while the troponin C isoform is involved in cardiac as well as skeletal muscle contraction. With myocardial injury, ischemia or necrosis, cardiac cell membrane integrity is interrupted and cardiac troponins T and I are released from myocytes into the blood stream. Elevation in either cTnT or cTnI is universally accepted as a highly sensitive laboratory measure in the diagnosis of myocardial infarction . Cardiac troponins (cTnT or cTnI) can be detected in the blood within 2–4 h of myocardial damage and may persist for up to 21 days [75,105]. Increased serum and plasma levels of troponin can also be seen during open heart surgery, percutaneous coronary intervention, pulmonary embolism, end-stage renal disease, pericarditis, myocarditis, aortic dissection, acute heart failure, strenuous exercise, chest wall trauma, cardiac contusion, chemotherapy, malignancy, inflammation, stroke, sepsis, subarachnoid hemorrhage and rhabdomyolysis [105,127]. In addition to underlying disease states, the variability in sample processing, differences in manufacturing methods and variation in the generation of cTn product measured (e.g., fourth generation cTnT or high sensitivity cTnT [hs-cTnT]) may all affect interpretation of results [105,128].
Most of the studies that have investigated the role of perioperative measurement of cTns evaluated patients undergoing noncardiac surgery, rather than solely on TJA, and were assessing for myocardial injury [23,26,28] and infarction [21–27] (see Table 1). These studies have a great deal of heterogeneity in the specific assays and timing of troponin measurement, as well as specific populations within the larger grouping of noncardiac surgery. Thus, this review focuses on several of the larger and more applicable studies. However, overall, several studies have shown that elevated cTn levels predicted or were associated with 30-day mortality [23,27,29–31] and long-term (up to 5 years) morbidity  or mortality [21,24,33,34]. These studies share similarities in their limitations, strengths and weaknesses, and the majority of such findings are grouped under the ‘Limitations and challenges’ section unless as discussed below.
One of the largest studies to date, the Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION), evaluated levels of cTnT (using a fourth generation assay) drawn 6–12 h following surgery and during the first three postoperative days within 15,133 older adult patients (aged ≥45 years) undergoing noncardiac surgery . The investigators found that higher peak levels of cTnT over the follow-up period were associated with increased risk of 30-day mortality . Specifically, compared with the 1% of patients with cTnT levels ≤0.01 ng/ml, 4% of patients with cTnT levels of 0.02 ng/ml, 9.3% of patients cTnT levels between 0.03 and 0.29 ng/ml and 16.9% of patients with cTnT levels ≥0.30 ng/ml died within 30 days of surgery . Forty five percent of these deaths were vascular in origin. Risk factors associated with increased 30-day mortality and increased cTnT levels included advanced age, the need for emergent surgery or major general surgery and the presence of recent coronary arterial disease. Neither OSA diagnosis (based on interviews and medical record review) nor major orthopedic surgery (20.4% of surgeries studied) was significantly associated with either 30-day mortality or increased cTnT. The authors concluded that given that the median time from elevation of cTnT at 0.02 ng/ml to death was 13.5 days, there could be sufficient time for the initiation of special considerations and potential interventions in the perioperative phase in order to minimize mortality . Despite the large sample size of the study, several specific limitations include the lack of cTnT collected before surgery, the lack of association between cTnT to changes in renal function such as the estimated glomerular filtration rate in the perioperative period, and a record of any interventions that may have occurred with findings of a critical value of cTnT .
In a subsequent analysis of 15,065 patients in the same cohort, the VISION investigators found that 8% of patients met criteria for myocardial injury (evidenced with cTnT optimal discriminatory point levels > 0.03 ng/ml) within the first 2 days following surgery . Myocardial injury was not only an independent predictor of 30-day mortality, but was also the population with the highest attributable risk toward primarily cardiovascular-related perioperative complications . However, 58% of those patients who had evidence of myocardial injury did not meet criteria for the universal definition of myocardial infarction and only 15.8% of patients who met criteria for myocardial injury exhibited symptoms of cardiac ischemia . A limitation in this study included the potential of missed cases of ischemic events as the study analyzed a higher optimal discriminatory threshold level of the cTnT assay (peak of 0.04 ng/ml compared with 0.03 ng/ml). Similarly, in a study of 8351 patients who underwent elective noncardiac surgery, the PeriOperative ISchemic Evaluation (POISE) trial, increased cTn (unspecified generation) levels, drawn 6–12 h following surgery and during the first three postoperative days, were associated with myocardial ischemia in patients who suffered both symptomatic and asymptomatic postoperative MI . Most events related to myocardial infarction or ischemia occurred within 48 h postsurgery .
Other studies have found increased levels of cTnI or cTnT (including hs-cTnT), drawn preoperation and or for any of the first three mornings postoperation [21,23,24,26,28,32], or for at least two consecutive days postoperation [22,25,34] were helpful in identifying risk for postoperative cardiac complications for up to 1 month [23,25,26,28,29], 1 year  and up to 5 years [21,24,34] following surgery. In addition to increased postoperative morbidity, both cTnI and cTnT or hs-cTnT have been associated with identifying increased risk of mortality. A systematic review and meta-analyses found that increased cTn levels following surgery were an independent predictor of mortality within 1 year . Furthermore, increased postoperative cTnI [23,24,28,29] and cTnT or hs-cTnT [21,27,30,31,34] levels predicted or are associated with decreased 5-year , 1–3 year [21,23,24] and 30-day survival [27,29–31].
The majority of the data in orthopedic surgery patients are from those undergoing emergency procedures, such as those necessitated by hip fractures [48–55], rather than elective arthroplasty. Data from this select population may not be generalizable to patients undergoing elective TJA. Reasons not only include differences in clinical and patient characteristics, but also because levels of cTns drawn from patients undergoing emergency TJA may be higher than those having elective TJA, as muscle injury associated with fractures may further raise levels of cTns . Specifically, cTns rise following elective TJA in only 0.0–8.9% of patients, but do so after hip fractures in 22–52% of patients . Several of these studies also found that increased perioperative (either pre- and or post-) cTn levels predicted postoperative cardiac complications that may not correlate to electrocardiographic changes , however did correlate with in-hospital cardiac events [50,55] and 1-year mortality [49,50]. Nevertheless, one study found that in older adults (age 85 ± 9.6 [mean ± SD] years) with multiple comorbidities, cTnI levels did not predict 6-month mortality or cardiac complications .
Very few studies evaluated cTns following elective TJA. These results are summarized in Table 2. In a mixed group of elective (approximately 51% of all surgeries performed in this study) and emergent hip surgery, increased cTnI was associated with in-hospital myocardial ischemia, acute coronary syndrome and other cardiac events . Importantly, increased cTns were evident in patients who did not exhibit clinical symptoms of underlying cardiac perturbations, but who had a history of co-morbid cardiovascular risk factors that were likely to increase risk of cardiac events . Further, increased cTnI levels were associated with mortality at 1-year and a tenfold risk of cardiac events at 1 year; however, this was primarily observed in nonelective TJA patients . Thus, these biomarkers could represent an additional mechanism for identifying at-risk patients, beyond standard medical history and clinical symptoms.
Studies observing the association between cTns and OSA have been conflicting. Increased levels of cTns have been found to be independently associated with severity of OSA and in patients with OSA having a history of coronary artery disease (see Table 3) [60,66,67,72,129,130]. However, several studies have also found no association between levels of cTns and OSA [65,131–134]. One of the largest nationally conducted cross-sectional studies of middle aged to older adults (involving 1645 patients with a mean age of 60 years), the Atherosclerosis Risk in Communities (ARIC) and the Sleep Heart Health Study (SHHS) studies, found increased levels of hs-cTnT were independently associated with both OSA severity and risk of death or occurrence of heart failure in all OSA classified groups . The association of increased levels of hs-cTnT and OSA in this study remained significant after adjusting for 17 major confounders including age, BMI, smoking status, alcohol intake, hypertension, diabetes, chronic lung disease, pulmonary function tests, estimated glomerular filtration rate, systolic blood pressure and blood levels of total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides and insulin .
Studies have suggested that the association between cTns and OSA is higher specifically in patients with OSA who have a known history of existing heart disease or a constellation of known cardiovascular risk factors [60,61,66,72,129,130]. In a 2014 cross-sectional study using only OSA patients from the Akershus Sleep Apnea Project (ASAP) cohort (AHI >5), Einvik and colleagues found that after adjustment for age, gender, CAD and a host of factors associated with cardiovascular risk, increased OSA severity and nocturnal desaturations were independently associated with increased levels of hs-cTnI . The authors concluded that over time repeated episodes of hypoxemia could have contributed to changes in myocardial structure that consequently contributed to the release of cTns . Additionally, the authors state, the use of a high-sensitive assay could have been more useful in detecting the smaller sized cTnI molecule . However, after controlling for potential confounding variables (such as age, sex, hypertension, diabetes and other cardiovascular risk factors) other studies have not corroborated this finding [131,132]. Using data from the ASAP cohort, Randby and colleagues examined three groups of OSA patients and observed that the prevalence of elevated hs-cTnT increased in proportion with severity of OSA ; however, this association was no longer significant after adjusting for covariates such as age, sex, hypertension and diabetes . Interestingly, in a 2014 cross-sectional study using only OSA patients from the ASAP cohort (AHI >5), Maeder and colleagues did not find any differences in levels of hs-cTnI in a group with severe OSA compared with a group with mild OSA . Hall et al. also did not observe any significant differences in levels of hs-cTnT or a single molecule cTnI when comparing patients with varying severity of OSA to controls without OSA .
Further illustrating the discrepancies in the literature examining cTns in OSA, a recent study by Shah and colleagues has focused on the phenomena of ischemic preconditioning developing over time from repeated cycles of hypoxia and re-oxygenation. This confers an element of cardio-protection and results in decreased cardiac injury and hs-cTnT (third generation) levels in patients with OSA . However, further studies are necessary to confirm this hypothesis.
Data evaluating the impact of PAP therapy, the mainstay treatment of OSA, on cardiac cTns are limited and mixed. Current evidence (see Table 3) primarily suggests that PAP adherence does not affect cTns [133–135] in the overall OSA population. However, one study showed a change in the levels of cTn, an increase in hs-cTnT levels with CPAP use .
In a small study of 21 patients with severe OSA and presence of CAD, Valo and colleagues found that levels of hs-cTnT drawn before and after sleep were not affected by one night of CPAP use . Further, in this study, electrocardiogram monitoring of ST segments were conducted throughout the night of sleep to document any evidence of myocardial ischemia . Although use of CPAP reduced ST segment depression during the lowest point of oxygen desaturation with sleep, this finding was not significant. The authors concluded that attenuation of ST segment depression could have been more evident at alternate time-points of sleep such as during post-apnea tachycardia or with an alternate measurement interval. Similarly, Maeder et al. and Cifci et al. did not find an association between hs-cTnI or cTnI levels and use of CPAP over one night or 6 months, respectively [134,136]. In a CAD naive population, Colish and colleagues found no change in levels of a third-generation cTnT from baseline following 1 year of CPAP therapy in patients with severe OSA. However, in this study both echocardiography and cardiac magnetic resonance imaging revealed that CPAP use contributed to improvements in cardiac remodeling properties and reversal of systolic and diastolic changes as seen with pulmonary hypertension in as early as 3 months, with continued improvements at 1 year .
In an interesting finding, Barcelo and colleagues found an unanticipated increase in hs-cTnT levels after treatment with PAP for 12 months, compared with controls without OSA . Subjective assessment of PAP adherence was not explicitly described in this study, and as such this may impact interpretation of the results. The study was conducted in a male population with OSA and hypertension (including elevated glucose and triglycerides in the OSA group), but excluded patients with prior myocardial infarction, unstable angina, stroke and most of other cardiovascular-related co-morbidities. Potential mechanisms by which PAP therapy may in fact raise hs-cTnT levels have been suggested and include cardiac adaptation, turnover of cardiomyocytes and a reversible change in the membrane permeability of cardiomyocytes, along with variations in intrathoracic pressures leading to increased hs-cTnT levels. The rise in this biomarker may therefore signal a repair process or evidence of cardiac stress that could occur with PAP therapy within this particular subgroup .
Brain natriuretic peptide (BNP) belongs to a group of vasodilator and anti-proliferative neurohormonal natriuretic polypeptides that are produced primarily by the cardiac ventricles (and in lesser amounts by the brain and adrenal glands) in response to stretching of cardiac myocytes or increased cardiac wall stress . ProBNP, a biologically inactive prohormone, is secreted by the ventricles in response to ventricular dysfunction and cleaved into the physiologically active BNP and the biologically inactive N-terminal fragment (NT-proBNP) . BNP has a half-life of approximately 20 min, and is cleared actively and passively through the renal system. NT-proBNP has a plasma half-life of approximately 2 h, and is cleared primarily through the renal system (as well as through muscles and the liver) . BNP and NT-proBNP increase with age, and are found in higher levels in women and in lower levels in patients who are obese . BNPs are established hallmark biomarkers in the detection of acute or chronic congestive heart failure. Their levels are independently associated with major cardiovascular events such as myocardial infarction, stroke and unstable angina in patients aged 50–89 years , and 1-year mortality in patients with congestive heart failure or acute coronary syndrome . Elevated BNP levels can also be seen with valvular heart disease, atrial fibrillation, pulmonary embolism, severe pulmonary hypertension, inflammatory cardiac disease, acute or chronic renal failure, liver cirrhosis, sepsis, trauma, endocrine disorders, severe neurological disorders such as stroke and subarachnoid hemorrhage .
Studies measuring BNPs in patients undergoing noncardiac surgery have investigated the role in the perioperative period for risk prediction or associations with adverse postoperative myocardial events [35–44], prolonged hospital stay  and mortality [24,46,47] (see Table 4). Most of the studies evaluating BNPs had levels drawn within 2 weeks prior to the day of surgery, typically at one time-point, however recent studies have incorporated perioperative BNP levels (levels drawn preoperatively and up to 5 days following surgery) [36,38,43,45,46]. Preoperative BNPs have been found to be an independent predictor or associated with increased postoperative cardiac events [35–44,47,142] or mortality [24,41,46,47] in noncardiac surgery, including cardiac morbidity at 30 days following discharge from hospitalization . Additionally, postoperative BNPs [36,45] were associated with cardiac events, but not always , and predictive for mortality over a 2-year follow-up . These findings were typically representative of patients who were aged 60 years and older with cardiovascular co-morbidities.
Compared with cTns, studies evaluating BNPs in noncardiac surgeries have fewer number of patients enrolled. A study by Dernellis and colleagues, with the most number of patients (1590) noted increased preoperative BNP levels independently predicted cardiac death as well as a host of adverse cardiac events . The majority of patients (40%) underwent elective orthopedic-related surgeries . Further, in Dernellis’ study, increased preoperative BNP levels were superior to clinical categorization for ascertaining risk for adverse postoperative events including cardiac death . The authors of this study utilized findings regarding BNP levels to alter the clinical management and treatment of patients thus confounding the study results . In a study of older patients (median age of 70 years) with a host of cardiac diseases, Goei et al., observed that after adjusting for cardiac risk factor, procedure type and location of surgery, increased levels of preoperative NT-proBNP increased the odds (by fourfold) of predicting postoperative cardiovascular events including cardiac death within 30 days following surgery . Increased presence of cardiac risk factors was associated with increased risk of cardiac events . The authors noted that the longer half-life of NT-proBNP compared with BNP may make NT-proBNP superior to BNP in select cohorts in the screening for cardiac risk .
Several studies utilizing perioperative BNPs have focused on vascular surgery patients. In a study of 788 patients undergoing vascular surgery, Biccard et al. observed increased preoperative BNP levels were superior to alternate biomarkers such as C-reactive protein and cTnI in predicting overall risk for adverse postoperative cardiac events independent of the clinical oriented Revised Cardiac Risk Index (RCRI) . Utilizing a Holter heart monitor in the perioperative period to detect presence of myocardial ischemia in 318 of their patients, the authors found no significant findings between BNP and Holter monitor analysis . In a smaller study, also of vascular patients, increased preoperative BNP levels along with the RCRI were independent predictors of postoperative cardiac events as evidenced by elevated levels of cTnI . Further, in this study, increased levels of preoperative BNP improved the overall risk classification for postoperative cardiac complications . A study by Yang and colleagues in high-risk vascular patients observed that the use of preoperative levels of NT-proBNP was not significantly different compared with the use of RCRI in screening for cardiac risk; however, NT-proBNP levels predicted postoperative cardiac events such as heart failure, MI and cardiovascular death . Further, to improve the power of detecting asymptomatic cardiac events, the authors validated the use of NT-proBNP levels in conjunction with the use of myocardial stress thallium test .
Other studies evaluating preoperative BNPs have also observed that increased levels were associated or predicted the following: adverse postoperative cardiac complications within 30 days following abdominal surgery , and up to 6 weeks post vascular surgery ; a 3.4-fold odds of having myocardial injury post-vascular surgery ; and, increased risk of postoperative cardiac events in patients aged 68 ± 8 years undergoing nonvascular surgeries . In addition to increased postoperative morbidity, preoperative BNP has been associated with predicting postoperative mortality and long-term survival in vascular and laparotomy patients ; whereas, preoperative NT-proBNP has been associated or predicted postoperative all-cause mortality over a 2-year follow-up in a vascular surgery cohort , and a 3.5-fold odds of death , 6.9-fold odds of cardiovascular related mortality following vascular surgery .
Fewer studies have found utility in the use of postoperative BNPs in the perioperative patient. Rajagopalan and colleagues observed, increased postoperative levels of NT-proBNP in vascular surgery patients predicted mortality over a follow-up of 2 years; however, NT-proBNP levels were not associated with postoperative cardiac events . Borges and colleagues found, in intermediate and high-risk vascular patients, although both preoperative and postoperative levels of NT-proBNP were associated with postoperative cardiac events in the unadjusted model, preoperative but not postoperative levels was associated with a fourfold odds of adverse major postoperative cardiac events after adjusting for clinical factors . The authors concluded although postoperative NT-proBNP levels were increased, there was lack of significance potentially attributed to the perioperative release of surgery-related catecholamine contributing to subtle postoperative myocardial ischemia and elevation of NT-proBNP levels in a higher cardiac risk cohort . This finding was similar to a study by Schutt et al., who observed increased preoperative NT-proBNP but not postoperative NT-proBNP levels were associated with postoperative cardiac events; however, increased postoperative levels of NT-proBNP were common in all patients .
There are several meta-analyses and systematic reviews of studies evaluating BNPs in the surgical population; and they consistently demonstrate that BNPs, in particular when drawn preoperation compared with postoperation, are independent predictors of both short- and long-term adverse cardiac events, including cardiac deaths and all-cause mortality [143,144]. In addition, BNPs were found to be useful as a stratification tool to assess risk for postoperative cardiovascular complications . A meta-analysis of vascular surgery patients found that increased preoperative BNP levels (including NT-proBNP) were associated with increased risk of 30-day postoperative cardiac events, cardiac-related mortality and all-cause deaths up to 180 days . Using preoperative BNPs significantly improved the preoperative predictive risk classification of the traditionally utilized RCRI . Furthermore, higher postoperative BNP levels obtained from 1 h to 7 days postoperation following noncardiac surgery (primarily vascular surgery but also included emergent and elective orthopedic surgery), were independently associated with nonfatal myocardial infarction, cardiac failure, cardiac mortality, cardiac arrest and all-cause mortality . Another meta-analysis evaluating the role of BNPs following major noncardiac surgery found that increases in both preoperative BNP and NT-proBNP identified patients at risk for myocardial injury, nonfatal myocardial infarction, all-cause mortality and cardiac death . Further in this study, preoperative BNP was also associated with increased risk for major adverse cardiovascular events and all-cause mortality that occurred within 6 months following surgery . Last, a recent systematic review and meta-analysis found that in the noncardiac surgery patient population, increased postoperative BNP levels were the strongest predictors of nonfatal MI and death at 30 days and ≥180 days following surgery, adding prognostic value in risk stratification for postoperative complications .
Data regarding the role of BNPs in predicting future cardiovascular risk in TJA, like the data regarding cTns, largely comes from patients having emergency procedures (e.g., those following acute fractures) with a cohort that includes non-TJA surgeries [57,58,148] rather than elective procedures . As with cTns, four studies showed that a rise in NT-proBNP levels after emergency TJA predicts in-hospital cardiac events [129,134] and increased 1- [128,129] and 2-year  mortality in patients aged 60–86 years, but did not predict 6-month mortality or cardiac complications in older adults aged 85 ± 9.6 years , who may have other competing co-morbidities.
Table 5 summarizes data from studies that evaluated BNPs following elective TJA. These studies suggest that increased BNPs predicted in-hospital myocardial ischemia, injury and fatal cardiovascular events.
BNPs added value in scenarios where patients did not report clinical symptoms of a cardiac condition, but who had a history of cardiovascular risk factors. Thus, BNPs may be more valuable than standard clinical symptoms in predicting cardiovascular risk. In the singular study of older patients (aged 73.12 ± 10.05 years) with hypertension who underwent elective TJA, Park and colleagues observed increased postoperative but not preoperative levels of BNP predicted length of hospital stay that was ≥ 30 days; however, BNP levels were not associated with adverse postoperative cardiac events . The majority of patients in Park and colleagues’ study were women who did not have extreme cardiovascular risk factors (such as stroke and ischemic heart disease) .
The majority of studies evaluating BNPs in patients with OSA found no association between levels of BNP and OSA severity [62,64,66,69–71,73,133,134,149,150], although some studies have found an association  (see Table 6). Association between BNP levels and OSA severity appears most useful in select sub-groups including a cohort of only women, or in patients with varying severity of coronary artery disease (CAD).
Notably, in the largest study conducted to date with 1645 patients, the ARIC-SHHS study did not find an association between NT-proBNP levels and the severity of OSA in their subjects, despite adjusting for 17 confounders . The authors concluded that the association between OSA severity and NT-proBNP was confounded by BMI. Although, statistical adjustment for BMI reduced the negative association between OSA and NT-proBNP levels, this finding was not significant following further adjusted analysis . Similarly, in a community cohort with stable cardiovascular risk from the Framingham Offspring Study, Patwardhan and colleagues also did not find an association between OSA severity and BNP nor NT-atrial NP (a marker belonging to the natriuretic peptide family that is sensitive to stimuli contributing to cardiac atrial stretch) . The authors conclude that timing of the blood draws (between 8 and 9 in the morning), sample selection bias or the prolonged time between when BNP levels were drawn and PSG (median of 79 days) could have all affected the final findings . In a cohort of patients with some cardiovascular co-morbidities, Vatany and colleagues observed, NT-proBNP levels decreased following a night's sleep compared with the morning-after levels but this finding was not significant .
Studies evaluating the utility of BNP levels and OSA severity in patients with background CAD have been informative. Valo and colleagues observed in patients with untreated OSA, NT-proBNP levels did not significantly change when compared before sleep to after sleep; however, levels in patients with OSA and background CAD were higher than in those with OSA without a history of CAD . Maeder et al., observed overnight BNP but not NT-proBNP levels had a larger relative (but not absolute) reduction following sleep in patients with moderate/severe OSA compared with those with mild/no OSA . Patients with moderate/severe OSA were mostly male and on a beta-blocker medication . The authors postulate that the lack of affect observed in NT-proBNP levels may be attributed to differences in half-life between the two BNPs (longer for NT-proBNP) and distinct individual biological variability that may be present . In patients with stable CAD, NT-proBNP levels were not only increased but correlated with severity of coronary stenosis . Other studies have found although there were no differences in levels of BNP between moderate compared with severe OSA groups, BNP levels grouped by quintile were associated with improvement in cardiac architecture such as left ventricular hypertrophy . In a interesting community-based study evaluating the effect of OSA severity and levels of morning BNP in a women only cohort, Ljunggren and colleagues observed that mean BNP levels (drawn in the morning following sleep) increased as the severity of OSA increased (further associated with oxygen desaturation index levels implying a dose–response relationship) . The authors conclude BNP levels could have been affected by episodes of hypoxia during sleep .
The effects of PAP therapy on BNP levels have been mixed, with a number of studies demonstrating PAP did not significantly alter levels of BNPs [64,73,133,134] versus other studies observing PAP decreased levels of BNPs [62,69,135,149] (see Table 6). However, some evidence seems to suggest that significant changes in BNP levels with PAP therapy occurs, particularly in patients with OSA and known left ventricular dysfunction or who have pre-existing cardiovascular risk factors.
In evaluating a number of biomarkers including BNP and NT-proBNP levels drawn pre-and post-one night of CPAP in a cohort with moderate-to-severe OSA, Maeder and colleagues did not observe significant findings . Zhao and colleagues observed a reduction in high sensitivity C-reactive protein levels but not in NT-proBNP levels following 3 months of CPAP in a cohort of patients with CAD and severe OSA who were previously CPAP naive . In an interesting discussion, the authors observe how medications used to treat CAD may blunt or reverse OSA-related cardiac strain, thus potentially contributing to the lack of association seen with NT-proBNP levels . Cifci et al., also did not observe an association between pro-BNP levels and OSA severity or the use of CPAP following 6 months of therapy. The authors acknowledge adherence to CPAP was evaluated subjectively  and may have a role in their findings.
Other studies have observed that although BNP levels were unaffected, initiation of CPAP  or nasal CPAP  improved cardiac structure and cardio-respiratory physiology including left ventricular mass size and pulmonary hypertension (improvements seen at 3 months and up to 1 year)  or peak maximal oxygen consumption and heart rate recovery (following approximately 8 months of PAP therapy) . This phenomena was also observed by Hubner and colleagues, who did not find any association between NT-proBNP levels and OSA severity either before or after nasal or bi-level CPAP; however, NT-proBNP levels were associated with impaired left ventricular ejection fraction and systemic arterial hypertension . NT-proBNP levels were reduced following nasal CPAP in a handful of patients but this finding was not significant quite possibly due to the small number of patients in this subgroup .
Last, several studies have observed changes in BNP levels that were associated with PAP use. Valo and colleagues observed, not only did a night of CPAP therapy reduce NT-proBNP levels in patients with severe OSA with presence of CAD, it decreased ST-segment depression monitored at the time of peak oxygen desaturation during sleep . Koga et al., observed BNP levels decreased following 3 months of nasal CPAP . Further, prevalence for global left ventricular dysfunction decreased significantly in the treated OSA group . Finally, although Tasci and co-workers did not observe any changes in baseline NT-proBNP levels between hypertensive and normotensive OSA groups compared with controls without OSA, use of CPAP reduced NT-proBNP levels in both groups, especially in the hypertensive group .
Overall, studies of cTn and BNP levels utilized as risk stratification tools or predictors of outcomes in patients with OSA undergoing TJA are lacking. Recommendations for the use of cTn and BNP levels in the diagnosis of acute coronary syndromes or other etiologies have been established by the National Academy of Clinical Biochemistry laboratory medicine practice guidelines , and the European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Heart Federation Task Force for Universal Definition of Myocardial Infarction . However, the routine use of cTns and BNPs to stratify risk for cardiovascular events following surgical procedures remains in its early stages and is currently being explored as delineated in this review.
There are many limitations in existing research that must be considered prior to the use of cTns or BNPs for outcomes in the patient with OSA presenting for TJA. These limitations and challenges derived from the studies presented can be categorized into the following: clinical use of biomarkers and study design.
Earlier studies utilized different generations of cTn or BNP assays that may have had a role in the preciseness of the assay results and thus offer conflicting results. Additionally, fundamental differences in the size of cTnI versus cTnT to facilitate the subtle detection of myocardial injury may be an issue. Pathophysiological differences in the release or clearance mechanisms of both cTns and BNPs could affect detection of circulating concentrations. Further, the interchangeable use of either plasma or serum samples, the timing of when the biomarker is drawn in consideration of sleep architecture, the inconsistent number of blood samples obtained during each study, variation in time points of blood sample collection, variation in elapsed time from collection to performance of the assay contributing to the stability or degradation of proteins, lack of synchronous collection of biomarkers during PSG recordings and consideration in half-life difference between BNP and NT-proBNP may have effected study results and comparison of studies.
Most of the studies consisted of small sample sizes, exhibited selection bias, lacked subject randomization, lacked objective measures to evaluate myocardial function such as echocardiography, varied in the severity and duration of OSA of the subject population, lacked control for adherence to PAP therapy, and varied in the presence of baseline cardiovascular disease or risk factors. Additionally, the nature of disease manifestation leading to surgery itself may have an effect on results.
Other limitations to be addressed include differentiating whether cTns or BNPs could guide medical care and whether these markers are better utilized as a surrogate marker for cardiovascular risk stratification in the preoperative or postoperative setting. Most importantly, studies would have to explore the variability in preoperative or perioperative cTns or BNPs and if these levels are predictive of worse postoperative cardiovascular outcomes in specific subgroups of surgical patients.
Given the evidence illustrating the association of cTns and BNPs and cardiovascular events in patients undergoing noncardiac and TJA surgeries, and in select patients with OSA, future studies should explore the role of cTns and BNPs as potential tools to stratify patients with OSA having TJA who are at increased risk for cardiovascular morbidity. Studies should focus on several key areas. First, they should assess whether cTns and BNPs could be used as part of a preoperative risk stratification algorithm in order to predict postoperative cardiovascular complications. Second, studies should explore whether using novel clinical management pathways that incorporate perioperative cTns and BNPs in TJA patients with OSA can reduce postoperative cardiovascular complications, as well as healthcare utilization, length of stay and medical costs. Such studies should explore the impact of perioperative cTns and BNPs for the perioperative patient with OSA in TJA concomitant with use of the guidelines recommended by the ASA, American College of Cardiology/American Heart Association (ACC/AHA) or the European Society of Cardiology/European Society of Anaesthesiology (ESC/ESA), AASM and American College of Physicians [84,85]. Both the ACC/AHA and ESC/ESA have explored the role of sleep apnea and the use of biomarkers, separately, in evaluating risk of the development of postoperative cardiovascular complications.
Finally, future studies evaluating the potential independent association between perioperative cTns or BNPs in OSA patients who undergo TJA and the risk for developing primary cardiovascular (e.g., acute myocardial infarction or nonmyocardial infarction cardiac complications), pulmonary (e.g., pulmonary embolism) and infectious complications (e.g., pneumonia, sepsis and periprosthetic joint or wound infection) would be helpful [1,83].
Data from studies presented here examining levels of cTns and BNPs suggest that these markers appear useful in identifying the subset of patients who are most likely to experience postoperative cardiovascular complications while undergoing noncardiac surgery, including TJA. In particular, results suggest these biomarkers may perform best in patients who are older (age>60) and/or have underlying cardiovascular disease or risk factors. However, we have very limited and inconclusive evidence about the role of these biomarkers in predicting cardiovascular risk in the subgroup of patients who have OSA at the time of surgery. This gap in our knowledge exists in the face of rising numbers of patients with background OSA who have elective TJA. The limited evidence we do have, however, hints that patients who are older and have a higher risk or presence of cardiovascular disease (attributes that are common in TJA and OSA) are more likely to have increased postoperative cardiovascular morbidity or mortality. Some evidence, albeit conflicting, also suggests that this increased risk is associated with elevations in cTns and or BNPs. Further data are needed to confirm whether these biomarkers, measured perioperatively in the patient with OSA undergoing TJA, may indeed differentiate patients at highest risk for adverse postoperative cardiovascular complications and death.
Present trends show that patients having TJA are older and more obese than in prior years, a group that is at particular risk for OSA and its potential downstream cardiovascular complications, which are higher still following surgery. Given that preliminary data support a role for biomarkers in predicting this cardiovascular risk, future studies should address a further exploration and refinement of the role of these biomarkers in patients having TJA.
The authors thank Mr Craig Diena at the Center for Sleep and Circadian Neurobiology, Perelman School of Medicine, University of Pennsylvania, for his assistance in manuscript preparation.
Financial & competing interests disclosure
M Melanie Lyons was funded by NIH grant T32HL07713. I Gurubhagavatula received loan of positive airway pressure devices (ResMed, Inc.) for use in a research protocol regarding management of OSA for a pilot study of sleep apnea in Philadelphia police officers. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Papers of special note have been highlighted as: •• of considerable interest