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Mikic, L.; Ristic, A.; Markovic Nikolic, N.; Tesic, M.; Jakovljevic, D.G.; Arena, R.; Allison, T.G.; Popovic, D. Cardiopulmonary Exercise Testing in Hypertrophic Cardiomyopathy. Encyclopedia. Available online: https://encyclopedia.pub/entry/47188 (accessed on 23 April 2024).
Mikic L, Ristic A, Markovic Nikolic N, Tesic M, Jakovljevic DG, Arena R, et al. Cardiopulmonary Exercise Testing in Hypertrophic Cardiomyopathy. Encyclopedia. Available at: https://encyclopedia.pub/entry/47188. Accessed April 23, 2024.
Mikic, Lidija, Arsen Ristic, Natasa Markovic Nikolic, Milorad Tesic, Djordje G. Jakovljevic, Ross Arena, Thomas G. Allison, Dejana Popovic. "Cardiopulmonary Exercise Testing in Hypertrophic Cardiomyopathy" Encyclopedia, https://encyclopedia.pub/entry/47188 (accessed April 23, 2024).
Mikic, L., Ristic, A., Markovic Nikolic, N., Tesic, M., Jakovljevic, D.G., Arena, R., Allison, T.G., & Popovic, D. (2023, July 24). Cardiopulmonary Exercise Testing in Hypertrophic Cardiomyopathy. In Encyclopedia. https://encyclopedia.pub/entry/47188
Mikic, Lidija, et al. "Cardiopulmonary Exercise Testing in Hypertrophic Cardiomyopathy." Encyclopedia. Web. 24 July, 2023.
Cardiopulmonary Exercise Testing in Hypertrophic Cardiomyopathy
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In contrast to standard exercise testing and stress echoes, which are limited due to the ECG changes and wall motion abnormalities that characterize this condition, CPET allows for the assessment of the complex pathophysiology and severity of the disease, its mechanisms of functional limitation, and its risk stratification. It is useful tool to evaluate the risk for sudden cardiac death and select patients for cardiac resynchronization therapy (CRT), cardiac transplantation, or mechanical circulatory support, especially when symptomatology and functional status are uncertain. It may help in differentiating HCM from other forms of cardiac hypertrophy, such as athletes’ heart. Finally, it is used to guide and monitor therapy as well as for exercise prescription. It may be considered every 2 years in clinically stable patients or every year in patients with worsening symptoms. Although performed only in specialized centers, CPET combined with echocardiography (i.e., CPET imaging) and invasive CPET are more informative and provide a better assessment of cardiac functional status, left ventricular outflow tract obstruction, and diastolic dysfunction during exercise in patients with HCM.

cardiopulmonary exercise testing hypertrophic cardiomyopathy

1. Hypertrophic Cardiomyopathy—Pathophysiology to Target

Hypertrophic cardiomyopathy (HCM) is a disease of the cardiac muscle defined by the presence of increased left ventricular (LV) wall thickness that cannot be explained exclusively by abnormal loading conditions [1]. The latest guidelines [1][2] suggest that HCM is a disease defined by its phenotype, which, in adults, is defined as a wall thickness ≥15 mm in one or more LV myocardial segments. However, more limited hypertrophy (13–14 mm) can be diagnostic when present in family members of a patient with HCM or in conjunction with a positive genetic test. Hypertrophic cardiomyopathy is the most common inherited heart disease with a prevalence of 1:200 to 1:500 in the general population, equally distributed by sex [1][2]. In comparison to newer AHA/ACC guidelines, the ESC recommends a broader approach to the term HCM; many genetic and acquired disorders have a similar phenotype to LV hypertrophy. In adolescents and adults, 40–60% of cases are caused by autosomal dominant sarcomeric gene mutations, 25–30% have unknown etiology, and 5–10% of cases hide disorders such as amyloidosis, Anderson Fabry, Danon cardiomyopathy in adults, mitochondrial and metabolic diseases, RASopathies, sarcoid, hemochromatosis, and drug toxicity [1]. The AHA/ACC have different approaches to defining the condition and consider HCM specific to a historically well-described genetic disease caused by the mutation of one of the sarcomeric proteins dominantly affecting the septum [2]. Additional diagnostic challenges arise from secondary LVH, such as hypertensive cardiomyopathy, athletes’ heart, hypertrophy due to valvular or subvalvular LV obstructive lesions, or obstruction after antero-apical infarction and stress cardiomyopathy [2].
Most patients with HCM are asymptomatic for an extended period and can have a normal life expectancy [1][2][3]. As the disease progresses, patients can experience exertional fatigue and dyspnea, syncope, angina, and palpitations. The pathophysiological mechanisms behind these symptoms are complex and consist of LV outflow tract impairment, diastolic dysfunction, chronotropic incompetence, and microvascular and even peripheral muscle changes [4]. Almost thirty years ago, Lele and other authors described the inability to increase cardiac stroke volume as the most important cause of exertional incompetence in patients with HCM [5]. A combination of septal hypertrophy and the systolic anterior motion (SAM) of the mitral leaflet causes a systolic LV outflow pressure gradient and resting obstruction in approximately 30% of HCM patients [4][6][7]. That number rises to almost half of the patients during exercise—out of 11,672 patients studied from 69 different research articles, an LVOT gradient >30 mmHg was present at baseline in 31.4% of cases and increased to 49% during exercise [7]. Shah and colleagues found that 54 out of 87 symptomatic patients with no previously documented LVOT had latent LV outflow tract obstruction [8]

2. Exercise Testing to Assess HCM

Cardiopulmonary exercise testing (CPET) combines standard exercise testing measurements (i.e., blood pressure, ECG, and symptom assessment) with ventilatory expired gas analysis. The use of CPET provides enhanced information on the severity of the disease and its mechanism(s) of functional limitation compared to that of standard exercise testing and stress echocardiography, which are limited due to the ECG changes and wall motion abnormalities that are common in HCM in the absence of coronary artery disease [2].
A cycle ergometer or a treadmill is an acceptable exercise modality for CPET in patients diagnosed with HCM [2]. CPET is used to quantify cardiorespiratory fitness, discover the pathophysiological mechanism underlying exercise intolerance and formulate a function-based prognostic stratification [9][10]. CPET provides a detailed and comprehensive way to approach the complex pathophysiology of HCM and can be a useful tool in assessing prognosis and treatment, especially in recognizing patients with a higher risk for sudden cardiac death and HF development [7][11]. CPET is also a useful tool in differentiating HCM from other forms of LV hypertrophy, such as athletes’ heart, as well as in the evaluation of athletes with a confirmed diagnosis of HCM [12]. Moreover, CPET is used to monitor therapeutic efficacy in this patient population [13].
A number of monitored and calculated CPET parameters may be helpful in targeting HCM diagnosis and assessing its risks, including but not limited to the following: (1) blood pressure; (2) HR and ECG changes (3) maximal or peak oxygen consumption (VO2); (4) percentage of age- and sex-predicted maximal/peak VO2; (5) ventilatory anaerobic threshold (VAT); (6) oxygen O2 pulse (i.e., amount of oxygen extracted by tissues per heartbeat); (7) ventilatory efficiency (i.e., minute ventilation (VE)/carbon-dioxide (CO2) production slope); (8) partial pressure of end-tidal CO2 pressure (PETCO2); and (9) pattern of breathing, or respiratory reserve at the end of exercise (BR) [10][11].

3. Aerobic Capacity—Peak VO2

Peak VO2 is a central CPET parameter and has great prognostic value in HCM [9][10][14]. Percentages that are <80% of the predicted VO2 for the patient’s age, gender, and height are considered abnormal [15], which is common in the HCM population. Cui et al. analyzed 752 patients diagnosed with HCM and found that the mean peak VO2 was 18.0 mLO2·kg−1·min−1, which was 60% of the predicted value. The primary causes attributed to low peak VO2 were impaired cardiac output (73.7%), limited HR reserve (52.0%), and obesity (48.2%) [14]. Interestingly, a resting LV outflow tract gradient correlated poorly with peak VO2, which was confirmed by recent studies as well [7][16]. Patients were followed for a median of 9.0 years and it was found that an adjusted peak VO2 and an abnormal O2 pulse increase were independently associated with long-term survival after myectomy. Through analyzing more than 50 publications in HCM cohorts and, collectively, 11,672 HCM patients (48 ± 14 years old, of which 65.9% were men and 34.1% women), Bayonas-Ruiz et al. found that the mean peak VO2 was 22.3 ± 3.8 mLO2·kg−1·min−1 and concluded that it is a disease with an exercise capacity reduced by at least 20% that of what is expected in an apparently healthy individual [7]. There was no significant difference in peak VO2 between patients with severe vs. milder hypertrophy, nor between subgroups with obstructive vs. non-obstructive HCM. However, the mean peak VO2 was 6.2 mLO2·kg−1·min−1 less in patients who died during the follow up period compared to those who survived [7]. Masri et al. studied 1005 HCM patients (50 ± 14 years, 64% male) and found that a peak VO2 < 50% of the predicted value was independently associated with overall mortality and SCD [17]. Similarly, in a study of 156 patients with HCM (mean follow-up at 27 ± 11 months), Finocchiaro et al. concluded that a peak VO2 <20 mLO2·kg−1·min−1 or <80% of the predicted value was associated with a worse prognosis [18]. Coats et al. followed 1898 patients with HCM (47 ± 15 years, 67% male) who underwent CPET at the beginning of the follow up period during the time period between 1998 and 2010. In this study, aerobic capacity was shown to be a strong predictor for death and heart transplantation (primary end points). The patients who had a peak oxygen consumption of ≤15.3 mL/kg/min had a 14% or 31% chance of dying or having a heart transplant in a 5 or 10 year period, respectively [11]. In a prognostic study by Sorajja et al., with a 4.0 ± 3.2 year follow up, a population of 182 minimally symptomatic patients with obstructive HCM (53 ± 15 years; 65% male, 35% female) who had a peak VO2 less than 60% of the predicted value had a 41% chance of dying or having severe symptoms in a 4 year period [19]. The fact that, in the earlier mentioned study by Masri et al., only 8% of patients with HCM achieved >100% age-gender predicted peak VO2 [17] can be a valuable clinical measure in the differentiation between physiologic LV hypertrophy in athletes and HCM, especially in the so called “gray zone” [20]. Recently, 58 athletes with HCM evaluated at the Mayo Clinic were found to have a mildly reduced exercise capacity (83% of predicted); however, a reduced peak VO2 did not correlate with symptom status or clinical outcomes [12]. The fact that two recent clinical trials that evaluated the usage of the new therapeutic drug mavacamten in the treatment of obstructive HCM, EXPLORER, and PIONEER HCM used the change in peak VO2 as both primary and secondary endpoints, or only the secondary endpoint, indicates the importance of functional testing in the management of HCM [21][22].

4. Ventilatory Anaerobic Threshold

The ventilatory anaerobic threshold represents the moment in exercise where ventilation starts to exponentially rise due to the transition toward an anaerobic metabolism with a relative increase in carbon dioxide (CO2) production compared to VO2 [9]. The ventilatory anaerobic threshold typically occurs between 45% to 65% of the measured peak VO2 in healthy untrained individuals and, in general, at a higher percentage in trained subjects. The later VAT occurs (i.e., the closer the VAT and peak VO2 approximate), the greater one’s capacity for submaximal exertion will be [9]. The already cited study of Coats et al. found that for each 1 mLO2·kg−1·min−1 reduction in VAT, there was a 29% increase in the risk of death or heart transplantation in an HCM cohort [11]. A recent meta-analysis by Bayonas-Ruiz et al. revealed an average VAT of 14 mLO2·kg−1·min−1 in patients with HCM and demonstrated significant prognostic value [22].

5. Oxygen Pulse

Oxygen pulse is viewed as a surrogate for stroke volume, and as such, a flattening of the O2 pulse curve during exercise is considered a strong prognostic parameter in all HF phenotypes [23]. In patients diagnosed with HCM, abnormal temporal behavior of the O2 pulse during exercise is strongly related to an inadequate stroke volume increase and correlates with a reduced peak VO2 and VAT, as well as an increased VE/VCO2 slope, identifying more advanced disease irrespective of the LV outflow tract obstruction [16]. In a study by Mapelli et al., 96 out of 312 patients with non-end-stage HCM (70% of which were males, aged 49 ± 18 years), that is, 31%, presented with abnormal O2-pulse temporal behavior, irrespective of their LVOTO values.

6. Ventilatory Efficiency and PETCO2

Ventilatory efficiency represents cardiopulmonary coupling through an assessment of VE and VCO2. A VE/VCO2 slope >30 is an established abnormal threshold in the general population [9]. In patients diagnosed with HCM, diastolic dysfunction can lead to a retrograde increase in pulmonary pressure [1][9]. In this situation, as VE increases, there is lack of a concomitant matching in pulmonary circulation (i.e., a lack of perfusion of normally unperfused areas due to increased pressures) and the VE/VCO2 slope is abnormally elevated; the degree of the VE/VCO2 slope reflects the degree of increased pulmonary pressure. The progression of pulmonary hypertension indicates a greater HCM severity. Similarly, another marker of ventilation–perfusion mismatch is PETCO2, which is normally >37 mmHg in apparently healthy individuals at peak exercise. In the 2012 clinical recommendations for CPET in specific populations, Guazzi et al. made a semiquantitative classification of HCM severity using the following parameters: (1) the VE/VCO2 slope; (2) percentage of predicted peak VO2; and (3) PETCO2. The greater the VE/VCO2 slope (or ratio during exercise) and the lower the percentage of predicted peak VO2 and PETCO2, the greater the likelihood of increased pulmonary pressure and, with it, the severity of HCM [9]. In a study cohort of 623 HCM patients (49 ± 16 years old, 69% male, 3.7 year follow up), Magri et al. investigated CPET parameters that can predict SCD risk, finding a VE/VCO2 slope >31 to be the most accurate among CPET parameters in predicting the SCD end point (sensitivity 64%, specificity 72%) [24]. In an earlier mentioned study by Coats at el, the risk of death or heart transplantation was increased by 18% for each unit increase in the VE/VCO2 slope [11]. A VE/VCO2 slope >34 and left atrial enlargement were defined as the main predictors of overall mortality, heart transplantation, and deterioration to septal reduction in a study by Finocchiaro et al. [18]. In a study by Velicki et al. who analyzed a total of 41 patients with nonobstructive HCM who were recruited into the ongoing SILICOFCM study, the VE/VCO2 slope was found to be the most sensitive CPET parameter for gauging the therapeutic efficacy of a 16 week sacubitril/valsartan treatment [25].

7. Blood Pressure Response to Exercise

During both standard exercise testing and CPET, blood pressure measurement is essential and obligatory. Systolic blood pressure should rise, with an upper normal threshold of 210 mmHg in males and 190 mmHg in females during exercise, while diastolic blood pressure is normally unchanged or slightly decreased [9]. An abnormal blood pressure response to exercise (ABPRE) is defined as hypotension or the inability to increase blood pressure (>20 mm Hg) with exercise [26], which can be explained by impaired stroke volume and/or vagal driven vasodilatation [4]. This parameter is well recognized as a marker of hemodynamic instability and increased risk factor for SCD in patients with HCM younger than 40 years [1][2][7][26]. In a metanalysis by Bayonas-Ruiz et al., the mean prevalence of ABPRE in HCM patients was 20%, and this proportion was higher in severe groups (>20 mm) than in mild hypertrophy groups (17.9% vs. 13.6%) [7]. Both European and American guidelines point out ABPRE as a risk factor for SCD in young adults with HCM [1][2]. However, ABPRE is not included in the provided risk scores for SCD and indications for ICD implantation in primary prevention [1]. This is explained by the fact that the positive predictive accuracy of this parameter is too low to allow for the identification of a high-risk patient based only on an abnormal test result. On the other hand, it has a high negative predictive accuracy for HCM-related mortality in the absence of other risk factors and can be used as a screening test for the identification of low-risk patients [26]. Circulatory power (i.e., peakVO2 x peak systolic BP) was shown to be useful in monitoring therapeutic efficacy, as demonstrated in the EXPLORER-HCM mavacamten study [13].

8. Chronotropic Competence

Electrocardiogram monitoring, typically 12 leads, is an inevitable part of both standard exercise testing and CPET, providing the ability to monitor HR and rhythm by an appropriately qualified health professional, which is of particular importance in patients diagnosed with HCM [9]. The minimal normal HR response to exercise, for an individual not on beta-blockade, is approximately 80–85% of maximal predicted HR for a given age (usually calculated as 220—age) [9]. HR increases linearly with time, work rate, and VO2 at approximately 10 beats per 3.5 mLO2·kg−1·min−1 [9][10]. HR recovery should be ≥12 beats within the first minute of exercise cessation [10]. Chronotropic incompetence plays a role in the exercise limitation of patients with HCM, likely due to remodeling of the sinoatrial node or impaired cell signaling [27][28]. Efthimiadis et al. studied 68 HCM patients (age 44.8 ± 14.6 years, 45 males), who underwent CPET and discovered that half of the cohort demonstrated chronotropic incompetence [27]. This abnormal response was associated with a higher functional disability, history of atrial fibrillation, signs of fibrosis at nuclear magnetic resonance imaging, and the usage of antiarrhythmic drugs, especially beta-blockers [27]. During a 4.2 year follow up of 681 patients with HCM (48 ± 16 years old, 68% male), Magri et al. found that a peak HR < 70% was a risk factor for HF related events and found this abnormal response held prognostic significance in HCM patients [29].

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