Patient experiences with obstructive and nonobstructive hypertrophic cardiomyopathy: a conceptual model of symptoms and impacts on quality of life

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder dened by left ventricular hypertrophy that cannot be explained by another cardiac or systemic disease. There is a general lack of knowledge about patients’ perspectives on the symptoms and day-to-day limitations they experience as a result of HCM. We therefore sought an in-depth understanding of patients’ experiences of obstructive (oHCM) and nonobstructive (nHCM) forms of the disease, including symptoms and their quality of life impacts, and to develop a conceptual model to capture them.


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Background Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder de ned by left ventricular hypertrophy that cannot be explained by another cardiac or systemic disease (1)(2)(3)(4). Globally, approximately 1/500 people in the general population is thought to be affected by HCM, but the number of diagnosed cases is less than 1/3000 (1,3,5). Patients are often diagnosed at a young age, sometimes even in childhood, and often incur a lifelong and progressive burden from the disease (6,7).
HCM is a clinically heterogeneous disease, with a diverse clinical presentation and course. It can be a debilitating and life-changing disease resulting in impaired functionality and reduced quality of life (8,9). The most commonly reported symptoms are shortness of breath, especially with physical exertion, fatigue, chest pain, palpitations from arrhythmias including atrial utter or atrial brillation, dizziness, and syncope (1,2,5,8,10,11).
Because of widely debated historical concerns about elevated sudden cardiac death risk associated with vigorous exercise in athletic individuals (12)(13)(14)(15), patients with HCM often limit their physical activity, which can, in turn, lead to other complications, such as obesity and depression (16)(17)(18)(19)(20). Patients with HCM have reduced exercise capacity and cardiorespiratory tness (21), which have been shown to be independent predictors of early mortality from heart failure and sudden cardiac death as well as disease progression (22)(23)(24)(25). First-line therapies for management of symptomatic HCM have not been shown to improve cardiorespiratory tness (26); the only noninvasive measure that has been shown to improve it is moderate-intensity exercise. (27). In symptomatic patients, impacts of HCM such as emotional distress and limited social functioning can lead to impaired quality of life (8,9).
HCM can be classi ed as obstructive (oHCM; also known as hypertrophic obstructive cardiomyopathy or HOCM) or nonobstructive (nHCM) based on the presence or absence of left ventricular out ow tract obstruction (1,2,11). It is estimated that two-thirds of patients with HCM have oHCM, and one-third of patients have nHCM (11). Relatively little is known from the patients' perspective about the symptoms and day-to-day limitations they experience over time from HCM, and whether experiences differ between oHCM and nHCM.
The objectives of this study were: to gain an in-depth understanding of patients' experience with oHCM and nHCM, including the symptoms and impacts of the disease that most profoundly affect patients' quality of life; and to develop a conceptual model capturing the symptoms and impacts of this disease that are most clinically meaningful when considering treatment outcomes.

Methods
Development of a conceptual model to better understand the symptoms and impacts experienced by patients with oHCM and nHCM involved a sequence of steps: a patient web survey to capture their insights; a targeted literature review (which included relevant guidelines and patient advocacy websites); one-to-one interviews with clinical experts; and one-to-one qualitative concept elicitation interviews with patients. All aspects of this study were conducted in accordance with relevant local guidelines for the protection of research participants, and all participants written informed consent prior to data collection. This study was conducted according to the Declaration of Helsinki . The qualitative patient interview   study protocol was approved by Ethical & Independent Review Services on March 21, 2017; amendments  were also made and resubmitted with approval on October 27, 2017; November 13, 2017; and December 20,2017. Elements of this study were also submitted to Copernicus Group Independent Review Board (IRB) for ethics review and approval prior to any contact with study participants. Study documents were submitted to the Copernicus Group IRB and received approval on December 28, 2017, with an amendment approved on January 23, 2018. This study was also submitted to Chesapeake IRB for ethics review and approval; approval from Chesapeake IRB was received on February 20, 2018.

Patient web survey
A patient web-based survey was conducted in 2015 to identify the key signs, symptoms, and impacts of HCM. An 80-question quantitative survey was developed to evaluate patients' experience of HCM by asking closed questions about the symptoms, treatment decisions and outcomes, and quality of life. The web-based survey was distributed via email to 2469 members of the Hypertrophic Cardiomyopathy Association (HCMA), an HCM advocacy, education, and patient-support group based in the United States of America (US).

Literature review
A review of published guidelines about HCM diagnosis or treatment was performed to identify HCMspeci c symptoms and their impacts. Three HCM guidelines were evaluated to further understand the patient experience: the 2011 American College of Cardiology Foundation/American Heart Association guideline (1), the 2011 Cardiac Society of Australia and New Zealand guidelines (3), and the 2014 European Society of Cardiology guidelines (4).
Secondary research on patient advocacy websites for the HCMA (28) and Cardiomyopathy UK (29) sought to pinpoint any experiences reported on patient forums.
Additionally, a targeted literature review was conducted using PubMed and the Excerpta Medica Database (Embase), coupling "hypertrophic cardiomyopathy" terms with keywords related to outcomes and quality of life. PubMed/Embase search terms were adapted from an existing review and developed with input from a medical research librarian. Published articles were included in the review when they contained details related to symptoms, symptom impacts, effects of therapies on symptoms, quality of life, or patient-reported outcome (PRO) measures reported in adult patients (≥ 18 years of age) with HCM, heart failure, or cardiomyopathy. The symptoms and impacts reported in the literature review and the websites were cross-referenced with those identi ed in the guideline search, and a list of HCM symptoms and impacts was generated.

Clinical expert interviews
Following the patient web survey and literature review, semi-structured, one-to-one telephone interviews with three clinical experts from the US and Europe were carried out between December 22, 2016 and January 4, 2017 to verify and build upon the ndings of the literature review. The three clinicians were selected because they are recognized experts in cardiology, speci cally in HCM patient care and research, and have experience that is largely representative of European and US clinicians working with HCM patients.
Each one-time interview was based on a brief, semi-structured guide, which included asking the clinician to describe aspects of the disease observed in clinical practice described in the clinician's own words. The clinicians were asked to provide information on how they diagnose HCM, and to detail their experiences with the clinical presentation of the disease, including the most frequently reported symptoms and the impacts these have on patients' lives. Interviewers asked follow-up questions as appropriate, and probed the clinicians regarding speci c symptoms and impacts if these had not been mentioned spontaneously.

Patient concept elicitation interviews
One-to-one qualitative concept elicitation interviews with 27 patients in the US the United Kingdom (UK), France, and Italy were conducted in 2017 and 2018 to con rm or add to the ndings from the web survey, literature review, and expert clinician interviews. Participants were recruited through referrals from established physician and nursing panels and through patient advocacy organizations. Each participant's physician was contacted to complete a clinical form detailing the participant's HCM diagnosis and treatment.
Participants who met the following inclusion criteria were invited to take part in these concept elicitation interviews: male or female patients between 18-75 years of age with a documented clinical diagnosis of HCM (hypertrophied and non-dilated left ventricle in absence of systemic or other known cause); New York Heart Association (NYHA) functional class > I; have experienced at least one HCM symptom (e.g. shortness of breath, chest pain, tiredness) within the six months prior to enrollment; willing and able to provide written informed consent to participate in research; able to read, speak, and understand English, French, or Italian su ciently to complete all assessments; and willing and able to participate in a telephone interview session, including adherence to the interview instructions and completion of questionnaires. Patients were excluded if they had a major health problem that complicates their HCM (e.g. severe pulmonary disease or highly symptomatic severe disease other than HCM); were hospitalized for any reason at time of study enrollment; had major surgery, including thoracic or cardiac procedures within 8 weeks prior to enrollment; had a history of obstructive coronary artery disease (i.e. one or more stenoses > 70% of luminal diameter); or had undergone interventions such as myectomy or septal alcohol ablation.
Interviews were conducted in patients' local languages and consisted of concept elicitation about the key symptoms and impacts of HCM on patients' daily lives, with the aim of understanding the language patients use to talk about these experiences. A semi-structured interview guide was used to maintain consistency across different interviewers. Interviewees were rst asked to spontaneously describe the process of diagnosis, symptomatology at the time of diagnosis, and treatment history. Subsequently, interviewers further probed the participants about their experience using a list of signs, symptoms, and impacts of HCM derived from the patient web survey, literature review, and clinician interviews. For each sign, symptom, and impact reported, participants were asked about the timing, frequency, location, triggers, sources of relief, and level of disturbance to their life.
All interviews were audio-recorded and transcribed, and non-English language (i.e. French or Italian) transcripts were translated into English for further analysis. All transcripts were cleaned of any personal identi able information prior to coding. Qualitative interview data were analyzed using ATLAS.ti™ software version 7.5 (ATLAS.ti Scienti c Software Development GmbH, Berlin, Germany). Key concepts identi ed from the interview transcripts were translated into relevant codes and used to maintain a coding dictionary and a grid to assess concept saturation: the point at which further interviews stop identifying new concepts.
A database was developed, tested, and validated to hold the quantitative sociodemographic information provided prior to and during the interview, and a quantitative list of signs, symptoms, and impacts mentioned by patients during the interviews. Data were entered into the database and reviewed by project scienti c staff. Tables summarizing the data were developed and populated. Means, standard deviations, and ranges were calculated for continuous variables, and frequencies and percentages were calculated for categorical values. A two-sample t-test was used to compare the mean number of symptoms reported between patients with oHCM and nHCM.

Conceptual model development
Participant-reported HCM symptoms and impacts were compared with those identi ed in the literature and clinician interviews. The key concepts identi ed as underlying the patient experience contributed to the development of a conceptual model of the most relevant HCM symptoms and impacts that addresses both obstructive and nonobstructive forms of the disease.

Patient web survey
A total of 3089 adult patients were invited to complete the survey, with 2469 surveys successfully delivered. Of these, 474 responses to the survey were received, of which 444 responses (94%) were complete, self-reported an HCM diagnosis, and were analyzed. Among all respondents, 58.0% reported a diagnosis of oHCM (i.e. "have you been diagnosed with left ventricular out ow tract obstruction?"), 33.1% reported a diagnosis of nHCM, and 8.8% did not know their speci c HCM condition. Overall, fatigue (74%), shortness of breath upon exertion (73%), and light-headedness (70%) were reported as the symptoms experienced most often. Other symptoms reported by more than half the respondents included palpitations (54%), dizziness after exertion (54%), and exercise intolerance (57%). Chest pain was reported by 39% of respondents and fainting by 24%.
When asked about the impact of their symptoms on physical activity, 21% reported no limitation, 42% reported slight limitation, 31% reported marked limitation, and 6% reported being unable to be physically active without discomfort.
Patients with oHCM reported experiencing a greater number of symptoms than did patients with nHCM: 84% of oHCM patients reported experiencing four or more symptoms characteristic of HCM, versus 55% of nHCM patients. When asked to de ne the severity of their symptoms using descriptions based on the NYHA functional classi cation scale, 43% of patients with oHCM reported moderate-to-severe symptoms (i.e. NYHA Class III or IV), compared with 27% of nHCM patients. About 70% of patients with oHCM reported that their symptoms had somewhat or signi cantly worsened since their diagnosis, and that their symptoms had a greater impact on their ability to work.
The time between rst experiencing symptoms and being diagnosed with HCM was reported as < 3 months by 36.5% of respondents, 3 months to 1 year by 14.1%, 1-3 years by 11.2%, 3-5 years by 6.6%, and > 5 years by 18.7%; 12.9% of respondents reported having never experienced symptoms.

Literature review
The literature search yielded a total of 256 abstracts and titles for potential consideration. A total of 220 studies were excluded; the main reasons for exclusion were irrelevant patient population or no mention of PROs, symptoms, or impacts. After full-text review of the remaining 36 articles, 28 studies were excluded; the main reason for exclusion was no mention of PROs. The nal set of eight articles included for review comprised ve cross-sectional studies, one qualitative study, one cohort study, and one cost-effectiveness study.
The articles describing the experiences of patients with HCM identi ed in the literature review revealed shortness of breath or dyspnea, chest pain (angina) (30,31), and syncope (30)(31)(32) to be the primary complaints/symptoms of patients with HCM.
The patient advocacy websites also indicated that symptoms such as chest pain, light-headedness, blackouts/dizziness, and fatigue were common in HCM (28,29). In addition, the websites noted arrhythmia, cardiac arrest, and endocarditis as other symptoms experienced by some patients with HCM (28,29).
These symptoms identi ed by the literature review were considered highly impactful on the mental health, physical functioning, and overall quality of life of patients (16,18,(31)(32)(33)(34). Depression was also commonly reported in several studies (32, 33) and on the patient advocacy websites (28,29). The most commonly reported impact measured in the literature review was anxiety, which was mentioned in four studies (32)(33)(34). It was also noted on the patient advocacy websites (28,29).
Overall, the review was consistent in identifying shortness of breath/dyspnea, light-headedness and blackouts/syncope, palpitations/tachycardia, fatigue, and dizziness as the most common symptoms among patients with HCM. Furthermore, anxiety, depression, and reduced physical functioning with shortness of breath were identi ed as being particularly impactful on patient quality of life and functioning.
Although the presence of left ventricular out ow tract obstruction (oHCM) was associated with more severe symptoms and greater risk of heart failure and cardiovascular death (2), there was limited information in the literature describing differences in symptom experiences between patients with oHCM and those with nHCM. This topic was explored further in the clinician and patient interviews.

Clinical expert interviews
The clinical expert interviews showed the three clinicians to be highly consistent in their views of the symptom burden of HCM and how these symptoms impact patients' lives. They reported that symptoms are experienced by most patients diagnosed with HCM, particularly those with oHCM, and that the most commonly reported symptoms were shortness of breath with exertion or after a meal, chest pain (angina), palpitations, and syncope/feeling faint or dizzy. The three clinical experts reported that the symptoms of HCM are often nonspeci c, overlap with one another, can vary from day to day, and can show similarities with side effects of treatment or symptoms of a comorbidity. Because of these challenges, they said that symptoms alone are rarely used to diagnose HCM in their practices, and physical and imaging assessments are required.
When asked to what extent the most frequently reported symptoms were consistent with their assessment of the cardinal symptoms of HCM, all clinicians referred to the di culty in untangling the symptoms of HCM from treatment side effects or comorbid issues such as obesity. For example, fatigue, hypertension, and sexual impairment were listed as symptoms that could be due to treatment, and shortness of breath was listed as a symptom that could also be due to excess weight.
Of these commonly experienced symptoms, shortness of breath and dizziness/light-headedness were considered by two of the three clinical experts as the most bothersome to patients. Chest pain (angina), feeling faint (syncope), tiredness/fatigue, and palpitations were also ranked by one of the three clinical experts as among the most bothersome for patients. Exertion was considered to be the predominant trigger for symptoms (with the exception of chest pain [angina], which can occur spontaneously). Limitations to physical activity were considered to have the greatest impact on patients' lives, and the clinicians reported that many patients avoid exercise out of fear of sudden death. The experts cited anxiety as the most common psychological impact related to patients' HCM symptom burden.
The clinicians were asked to describe how the experience of patients with oHCM and nHCM are similar or different, and their responses are summarized in Table 1. The clinicians reported that, in general, patients with oHCM experience very similar symptoms to patients with nHCM, but patients with oHCM may experience more symptoms simultaneously, more severe symptoms, and more consistent and sustained symptoms than do patients with nHCM. • All clinicians stated that there were psychological impacts associated with HCM and that it was most common for patients to have anxiety, especially after the initial diagnosis  Table 2. The mean age of the patients was 44.6 years, and the most common comorbid conditions were anxiety (40.7%), hypertension (29.6%), and depression (25.9%). Patients rated the severity of their HCM symptoms that day as very mild (15.4%), mild (30.8%), moderate (46.2%), severe (3.8%), or very severe (3.8%). Clinical con rmation of obstructive status was missing for seven patients; four of these patients self-reported oHCM diagnoses, and self-reported obstructive status was unknown/missing for three patients. COPD chronic obstructive pulmonary disease; HCM hypertrophic cardiomyopathy; SD standard deviation; UK United Kingdom; US United States; yrs years a Other included self-employed/PhD student, and craftsman b Obstructive HCM was clinician-con rmed for seven patients and self-reported by four additional patients; all 11 were considered to have obstructive HCM for the qualitative analyses c Not mutually exclusive Table 3 summarizes the frequency of HCM symptoms reported by interview participants. A total of 29 different symptoms were reported and complete content saturation was reached after 23 interviews. The most commonly reported symptoms included tiredness (89%), shortness of breath (89%), shortness of breath with physical activity (89%), and dizziness/light-headedness (89%). Other symptoms commonly reported included chest pain (angina) (70%), chest pain (angina) with physical exertion (70%), and palpitations ( uttering or rapid heartbeat) (81%). "Couldn't stand very well" (trouble standing) 2 (7) Low heart rate 2 (7) Overheating 2 (7) Nausea

(19)
Headaches 2 (7) HCM hypertrophic cardiomyopathy Participants with oHCM reported all the same major symptoms as those with nHCM. Among the oHCM participants, 20 symptoms were reported, of which 85% were reported in the rst four interviews.

Overheating 1 (4)
Feet swelling 1 (4) HCM hypertrophic cardiomyopathy; nHCM nonobstructive HCM a Two nHCM patients did not provide a list of symptoms; the obstruction status of three patients was unknown Table 5 describes impacts of the disease on aspects of the patients' lives identi ed during the concept elicitation interviews. A total of 15 impact concepts were identi ed. Concept saturation was achieved within the rst 23 interviews. The most commonly reported impacts included limitations to physical activities (78%), emotional impacts (78%), feeling anxious or depressed (78%), and impacts on work (63%). Can't take certain cold medicines 1 (4) HCM hypertrophic cardiomyopathy

Conceptual model development
The HCM symptoms reported by patient interview participants were largely consistent with the ndings from the patient web survey, the literature review, and the interviews with the expert clinicians. The patient interviews provided additional speci cs on the frequency and importance of these symptoms, and the impact they have on patients' lives.
A conceptual model that organizes and prioritizes the most relevant concepts (both symptoms and impacts) in the HCM patient population was developed (Fig. 1). The conceptual model identi es shortness of breath, palpitations, fatigue/tiredness, dizziness/light-headedness, and chest pain as the core symptoms of both oHCM and nHCM. These symptoms have physical, emotional, and social impacts on patients, including limitations on their activities of daily living.

Discussion
This comprehensive approach to identifying the most relevant concepts (symptoms and their impacts) in HCM generated a conceptual model of the patient experience with the disease. The conceptual model is based on multiple sources of evidence (literature review, including relevant guidelines and patient advocacy websites; clinical expert interviews; patient web survey; and patient concept elicitation interviews) and indicates a substantial patient burden associated with HCM and its symptoms. This is the rst study to describe a conceptual model speci c to patients with this important disease.
The model identi es shortness of breath, palpitations, fatigue/tiredness, dizziness/light-headedness, and chest pain as the core symptoms of both oHCM and nHCM. The model also identi es limitations to physical activities, emotional impacts of feeling anxious or depressed, and impacts on work, sleep, and family relationships as the key impacts of HCM on areas of patients' lives. These HCM symptoms and impacts should be considered in clinical assessments of disease severity and progression. Given that therapies are aimed at reducing the burden of symptoms, thereby improving quality of life along with improving outcomes, response to currently available and any future treatments for HCM in terms of these core symptoms and their impacts should be further investigated.
Symptoms and impacts are similar for oHCM and nHCM, and although some differences emerge between the two forms (e.g. number and severity of HCM symptoms, heterogeneous disease progression), the conceptual model presented here is appropriate for both.
Historically, therapy has focused on relieving symptoms and patients with HCM are often treated with drugs indicated for broader cardiovascular disorders, such as heart failure (e.g. beta-blockers, calcium channel blockers, or disopyramide). Pharmacologic management options for HCM recommended by current guidelines produce limited and variable improvement in patients' symptoms and functional status. The development of this HCM-speci c conceptual model re ects the core symptoms and impacts of this disease from the perspectives of patients and clinical experts; it is expected to help in the management of patients' symptoms by formalizing patient experience as a reference for clinicians to use for assessment of disease burden and progression. Full awareness of core symptoms and their impact on quality of life is key to shared decision-making with regard to treatment options. Such a conceptual model can further provide a basis for a PRO measure to evaluate treatment e cacy for investigational drugs in clinical trials and in clinical practice.
Strengths of this study include the facts that a combination of qualitative and quantitative approaches was applied, clinicians and patients from multiple countries were included, and consistent and similar ndings emerged across the various sources consulted. Despite being applied to a rare disease, this study generated a large, meaningful dataset that re ects diverse patient experiences. Limitations of this study include the relatively small number of clinical experts and patients interviewed (a factor related to the disease's rarity) and the fact that some patients' obstructive status (i.e. oHCM or nHCM) was unknown or self-reported without clinical con rmation of that diagnosis. Conclusions A conceptual model was developed that identi es the core symptoms of HCM (those that patients reported as most frequent and most important: shortness of breath, palpitations, fatigue/tiredness, dizziness/light-headedness, and chest pain), as well as the impacts those symptoms have on patients' lives (including limitations to physical activities, emotional impacts, and impacts on work, sleep, and family relationships). In accordance with recommended guidelines for the development of PRO measures (35), the symptoms and impacts of HCM presented in this conceptual model can be used as a framework for developing a targeted PRO instrument that re ects the patient experience with HCM, and that would be useful for assessing outcomes in clinical practice or clinical trials. Such a PRO instrument can measure the impact of an intervention on one or more aspects (concepts) of patients' health status, which include purely symptomatic responses, more complex concepts (e.g. ability to carry out activities of daily living), and extremely complex concepts (e.g. quality of life, which is widely understood to be a multidomain concept with physical, psychological, and social components). Data generated with a PRO instrument can provide evidence of a treatment bene t from patients' perspectives (35). Ethics approval and consent to participate All aspects of this study were conducted in accordance with relevant local guidelines for the protection of research participants, and all participants provided informed consent. The study protocol was approved by a US institutional review board.

Consent for publication
All patients and clinicians who participated in this study provided consent for publication of their information and responses.

Availability of data and materials
The datasets used and analyzed for the current study are available from the corresponding author upon reasonable request.

Competing interests
Author AS is an employee of MyoKardia. Authors EB, AD, and EZ are employees of Evidera, which received nancial support from MyoKardia in connection with the implementation of the literature review and clinician and patient interviews. Author MR is an employee of IQVIA, and has a consulting agreement with MyoKardia. Author SS has a consulting agreement with MyoKardia.

Funding
This study and preparation of the manuscript were supported by MyoKardia.

Authors' contributions
Authors EZ and AD were involved in conducting the literature review and development of the method and analyses of the patient and clinician interviews. AD and EB were involved in conducting the patient interviews. EZ, AD, and EB all contributed to analyses of the patient interviews. MR contributed as an advisor to all aspects of the research. All authors contributed to the development of the HCM conceptual model. All authors contributed to critical interpretation of the ndings and drafting/revision of the manuscript content, have approved the nal version of this manuscript, and take responsibility for the integrity of this research study.