Origins of Sleep Apnea – Phenotypes, Endotypes, and Pathogenesis
The way that CPAP operates on apnea-prone individuals is quite simple. Keeping the airway open prevents collapse. But sleep apnea develops in a number of different ways, each of which has its own characteristics, level of severity, and susceptibilities. Knowing the details of these often complex mechanisms can improve treatment outcomes and help prevent the development of comorbid conditions. While sleep apnea refers more generally to cessations in breathing, physiological responses and health outcomes are varied, now known to occur with varying degrees of severity in up to a billion people worldwide. Because of the growing prevalence of the disorder and its history of treatment difficulties, efforts are underway to provide more specialized care that focuses on the details of the condition and its potential effects on overall health. To provide specialized medicine, doctors first need more specialized knowledge of the disease, how it develops, who is the most susceptible, and why.
What is a Phenotype?
A phenotype is a presentation of a disease, but more specifically, it is a classification system used to categorize diseases based on what is observed. This includes morphology (physical characteristics), forms of development, behavior, and physiological traits, as well as any clinical aspects not otherwise defined. For example, one study published in the journal of Sleep Medicine Review defines obstructive sleep apnea (OSA) phenotypes as: “A category of patients with OSA distinguished from others by a single or combination of disease features, in relation to clinically meaningful attributes.” These features are listed mainly as patient attributes, symptoms, or health outcomes (including responses to treatment). Thus, a clinically meaningful attribute would be any expected outcome from CPAP therapy. Excessive daytime sleepiness (EDS), for example, is a common phenotypic trait because not everyone with OSA develops the symptom. Patients with EDS are often referred to as having “sleepy” OSA, and treatment for this type of syndrome may include additional medications or behavioral therapies prescribed along with CPAP. “Non-sleepy” OSA, on the other hand, would be treated with less emphasis on daytime symptoms. Another example is the distinction between REM-related and supine-related arousals. These patterns tend to stratify according to older women and younger men, respectively, and effective treatments must take into account the distinct symptomatic differences, as well as the challenges that each type will present.
Phenotypes are one type of classification for diseases and disorders. Other classifications include endotype, which emphasizes the mechanisms and origins of a disease, genotype, the genetic makeup of individuals with a particular condition, and regiotype, a classification based on environmental factors. Many types of classification exist for health conditions, but phenotype is used in a range of disciplines because it involves observable traits. By establishing a classification system based on these traits, healthcare providers can develop more effective approaches to diagnosis and treatment.
What is an Endotype?
An endotype is defined as a distinct functional mechanism of a disease or disorder. A complementary concept to phenotype, endotype is distinguished by its focus on pathogenesis, rather than observations or presentations. These phenomena, also referred to as pathobiological traits, are similar to phenotypes in the sense that they define a subtype of a condition, giving health providers an effective means of identifying common patterns in the development of a disease. In addition, endotypes are closely related to the concept of etiology, a term that refers specifically to mechanisms of causation or origination in a broader context of disease progression. Each endotype will have its own conditional pathology or etiology that describes how it develops (or is likely to develop). Specifically, etiology focuses on the backstory of a disease, for example, whether an illness is intrinsic — coming from within, extrinsic — coming from the environment, or Idiopathic — without known causes. In an endotypic pattern of development, etiology may refer to what is causing the disorder, while pathology more broadly refers to all the many “behaviors” of the specific endotype.
An example of this can be seen in the disorder of central sleep apnea (CSA), which is a form of sleep apnea without physical blockage of the airway and is often idiopathic. When CSA is idiopathic, it does not have a specific endotype, but does have a phenotype of observable characteristics. Sleep experts report that the great majority of CSA patients often experience OSA first, then later develop CSA when they begin treating the OSA with PAP therapy. This same pattern, or pathogenesis, can also develop into shallow breathing episodes known as Cheynes Stokes Respiration, representing a similar pattern but a separate condition. The diversity of forms has led some researchers to suggest that loop gain issues may be a contributing factor. While more studies are needed to better understand this phenomenon, a clear pattern has been recognized involving forms of idiopathic sleep disordered breathing (SDB) following treatment of OSA with CPAP.
Pathogenesis and Pathophysiology
Pathogenesis, like endotype, involves mechanisms of causation, but with a broader emphasis that includes disease origins (etiology) and ongoing development (pathology). For example, Pathogenesis is at times separated into acute, chronic, or recurrent patterns, a distinction that informs health providers of when and how often an individual experiences disease symptoms. The term pathophysiology combines this idea with the physiological states of a patient. Pathogenesis, it can be said, represents the physiological developments of a pathological state. In other words, pathogenesis helps in defining the many factors involved in a particular phenotype, including any potential causes, consequences, or associated conditions.
For studies of sleep apnea, pathogenesis is often described according to the most common mechanisms of causation. For OSA, this includes (1) upper airway anatomy and susceptibilities to collapse (2) ventilatory response to respiratory disturbances (also called loop gain), (3) arousal threshold (light sleeper vs. deep sleeper) , and (4) the overall stability of the respiratory control system. These traits are also risk factors in the form of pathophysiologic predisposition mechanisms. While this may sound technical, knowing how these mechanisms work is the first step to solving them. One area of study, for example, seeks a better understanding of the pathogenic relationship between sleep apnea and cardiovascular disease, including any genotypes that may contribute to these conditions. These types of patterns involving multiple health factors are often referred to as syndromes, though the specific qualifications of a syndrome, as opposed to a phenotype or endotype, may not be clearly defined. In some instances, a syndrome can be so closely related to a disorder’s pathogenesis that the words syndrome and disorder end up being used interchangeably.
Types and Sub-Types
Most people know the three main types of sleep apnea, but these are broad classifications representing separate disorders, each with a distinct set of symptoms and health effects. These include obstructive sleep apnea (OSA), by far the most common type of sleep apnea, central sleep apnea (CSA), which develops without a physical blockage of the airway, and complex or mixed sleep apnea, which is a combination of the other two types.
Over the past two decades, sleep apnea has been increasingly recognized as a complex disorder with a range of possible health effects, the most common of which is OSA related to weight gain, EDS, and treated effectively with CPAP. Other related phenotypes are defined according to additional symptoms, etiology or pathology, and a number of potential comorbid conditions. In addition to weight, other traits that can affect sleep apnea are age, sex, and to an extent, ethnicity. Studies show that males are 2 to 3 times more likely to have sleep apnea than females, and have longer apnea durations and higher levels of oxygen desaturation, despite a lower body mass index (BMI) on average. This predisposition is primarily due to anatomical differences such as an increase in fat deposits in the airway and around the abdomen. Thus, male patients with these specific types of weight gain can be considered phenotypes of obstructive sleep apnea. And the endotypic trait of airway collapsibility is affected both by fatty tissue in the airway itself and by reduced lung volume as a result of fat accumulation around the waist. While these traits are weight related, they are also related to specific male body types, making them phenotypic of males with weight gain, and endotypic in regard to the underlying mechanism (collapsibility). Classifications often overlap in this way, leading some researchers to use the term endophenotype when referring to features that overlap in some way. In fact, phenotypes are often related to several underlying endotypes. There is no consensus on which types should be recognized in a clinical sense. They are simply meant to be helpful, so the more that are recognized, the better access there is to information on common patterns.
In terms of age, there are similar traits of collapsibility that tend to increase up to 65 years, making older or senior-aged patients more susceptible. In these patients, a more specific endotype often arises involving the build up of fluid or tension in the upper airway. Older patients also tend to have a lower loop gain. Faster loop gain (or more sensitive ventilatory control) is associated with a greater likelihood of overcompensation, which can cause further problems in blood-gas exchange or fluctuating heart rates. Again, while these traits are observable to an extent, they are also related to the mechanisms of the disorder and are thus defined more specifically as endotypic features.
In studies on ethnicity, multivariate linear regression models have shown that African-American men younger than 40 years old have increased apnea-hypopnea index (AHI) scores by approximately 3.21 events per hour compared to white men with the same BMI, an increase reduced only slightly (2.79) for those between 50 and 59 years of age. According to the study authors, the precise mechanism (endotype) for these differences remains unclear, but they suggest that slight anatomic differences between males of different races may have an effect on upper airway collapsibility and neurochemical breathing control. By matching these various phenotypes with their corresponding endotypes, researchers can gain a better understanding of the overall pathogenesis of the disease, giving them valuable insights into more specialized treatment approaches.
What it Means for the Patient
Modern health care is becoming more and more proactive and specialized, combining precision diagnostics with more patient-centered approaches to healthcare. These multidisciplinary strategies make effective use of phenotypes, endotypes, and the biomarkers of pathogenesis, as they not only help to improve clinical practice and treatments, but also provide epidemiological details for more informed public policy decisions on disease prevention.
While the sleep apnea disorder can appear somewhat simple, it is extremely diverse in its manifestations, and each difference, whether subtle or more significant, represents a potential challenge to treatment and a therapeutic target. Since the pathophysiology of apnea varies between individuals and is composed of different mechanisms of causation, the recognition of clinically relevant phenotypes and endotypes are highly significant contributions to medical science.
American Journal of Respiratory and Critical Care Medicine – https://pubmed.ncbi.nlm.nih.gov/20538960/
Anesthesia and Analgesia – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429962/
Expert Review of Respiratory Medicine – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727690/
Journal of Clinical Sleep Medicine – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2546461/
Journal of Physiology – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214640/
Journal of Sleep Research – https://pubmed.ncbi.nlm.nih.gov/11869421/
Nature and Science of Sleep – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789079/
Physiological Reviews – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970937/
Principles and Practice of Sleep Medicine, 4th Ed. – https://www.sciencedirect.com/topics/medicine-and-dentistry/airway-resistance
Respirology – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161664/
Sleepeducation.org – http://sleepeducation.org/news/2019/08/06/six-facts-about-sleep-apnea
Sleep Medicine Reviews – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389934/
Therapeutic Advances in Chronic Disease – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549693/