Author + information
- Published online February 14, 2018.
- aJohn Ochsner Heart and Vascular Institute, Ochsner Clinical School-University of Queensland School of Medicine, New Orleans, Louisiana
- bBrigham Health Heart and Vascular Center and the Center for Advanced Heart Disease, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Carl J. Lavie, Cardiac Rehabilitation, Exercise Laboratories, John Ochsner Heart and Vascular Institute, Ochsner Clinical School, The University of Queensland School of Medicine, 1514 Jefferson Highway, New Orleans, Louisiana 70121-2483.
The evaluation of exertional dyspnea is frequently encountered by general and specialist clinicians in cardiovascular diseases (CVD). Experts in noninvasive cardiology and cardiac imaging are involved in such evaluations, including the assessment of heart failure (HF), particularly HF with preserved ejection fraction (HFpEF). As the prevalence of obesity, hypertension, and diabetes has risen, so has the incidence of HFpEF, leading to its becoming a prevalent HF phenotype associated with alarming morbidity and mortality (1,2). The diagnosis of this distinct phenotype is difficult and several biomimics exist, including morbid obesity, chronic obstructive pulmonary disease, and hypertensive effects on the heart with effort. Thus, astute clinicians rely on a combination of techniques, including history and physical examination consistent with HF, as well as an electrocardiogram or echocardiogram that demonstrates evidence of left atrial enlargement and evidence of other structural heart disease. In some cases, a natriuretic peptide biomarker may provide ancillary confirmation, and many such patients with exertional dyspnea are also evaluated with pulmonary function testing and other exertional assessments, sometimes combined with Doppler echocardiography.
In addition to a comprehensive clinical phenotyping effort, our practice has frequently used cardiopulmonary stress testing to evaluate patients with uncertain etiology of exertional dyspnea. This form of physiological testing quantifies functional capacity (a potent predictor of prognosis and survival) and provides information on the degree of circulatory impairment, ventilatory impairment, deconditioning, and various combinations of these disorders (3–5). However, a fairly large number of adult patients are unable to exercise vigorously, leading to an inconclusive test scenario that argues for the development of a simpler clinical diagnostic test.
In the this issue of iJACC, Kosmala et al. (6) attempted to establish both a diagnostic and prognostic value of a strategy for the prediction of abnormal diastolic response to exercise (AbnDR) using a combination of clinical, biochemical (especially galectin-3, a marker of cardiac fibrosis), and resting echocardiographic markers (peak early diastolic mitral inflow velocity/peak early diastolic mitral annular velocity ratio [E/e′] and assessment of myocardial deformation and rotational mechanics) in patients with exertional dyspnea and mild diastolic dysfunction but resting E/e′ <14. In a study of 171 patients followed for just over 2 years for CVD hospitalizations and death, AbnDR, defined as exertional E/e′ >14, was present in 60%, which was predicted by resting E/e′, left ventricular (LV) untwisting rate, and galectin-3. In those patients with E/e′ >11.3 and galectin-3 <1.17 ng/ml, the investigators concluded that this allowed exercise testing to be avoided, and these parameters performed as well as AbnDR by stress echocardiography for predicting major CVD events. They concluded that implementation of this 2-step approach (Doppler echocardiographic evaluation of resting E/e′ and assessment of the biomarker galectin-3) allowed for appropriate diagnosis and prognostic assessment of patients with HFpEF, especially for the many patients who are unable to perform an exercise stress test.
Overall, this study observes that measures of myocardial deformation coupled with a biomarker test are able to signify significant structural heart disease in patients with unexplained exertional dyspnea. Despite the potential for LV untwisting to impact LV filling pressure response to exercise, the investigators probably appropriately did not include this in their proposed clinical algorithm due to poor test-retest reproducibility, as well as the fact that LV untwisting is not routinely assessed in modern-day echocardiography. Nevertheless, a simple assessment of E/e′ and galectin-3 is theoretically possible and could potentially be used as a cost-effective correlate of AbnDR.
Besides the limitations mentioned by Kosmala et al. (6), including the exclusion of patients with atrial fibrillation and myocardial ischemia, there are several other “stretch weaknesses” that prevent inclusion of this simple clinical algorithm into current practice. First, the assumption that AbnDR or abnormal diastolic stress tests (increase in E/e′ to >14) equates to HFpEF is a “stretch,” considering the differences between diastolic dysfunction, diastolic HF, and HFpEF (1). In fact, in a recent study of 118 patients with unexplained dyspnea, E/e′ did not reflect LVFP or assist in identifying patients with HFpEF (7). Second, the assumption that AbnDR identifies or establishes the source of dyspnea is also a “stretch.” If one evaluated a group of patients with unclear dyspnea, often abnormalities of the heart during effort will be identified, as supported by the present study, which correlate weakly with underlying evidence of structural heart disease and myocardial fibrosis and abnormal heart motion (LV untwisting), which in turn correlate with increased CVD outcomes. Therefore, the findings in this study are best described as evidentiary markers of CVD risk in patients with unclear causes of dyspnea, rather than precisely defining the cause of dyspnea. Importantly, in a population of dyspneic patients who are assumed to be suffering from HFpEF, one would have liked to see evidence that the clinical diagnostic findings correlate as predictors for HF hospitalizations, rather than all CVD hospitalizations and death. No mention of the causes of these CVD hospitalizations or causes of death were provided, leaving one to wonder whether HF was truly diagnosed by the constellation of testing performed.
As Kosmala et al. (6) appropriately point out, they are not proposing that their 2-step clinical algorithm replace stress echocardiography, which is clearly valuable for the assessment of myocardial ischemia, as well as assessment for exercise-induced diastolic dysfunction common in HFpEF. Additionally, diastolic stress echocardiography may be helpful for potential diagnosis and treatment only after ischemic heart disease, dynamic mitral regurgitation, LV outflow tract obstruction, and chronotropic incompetence has been excluded. Therefore, performing only E/e′ at rest combined with a biomarker test may not be an adequate clinical algorithm in these patients. Also, recent major guidelines from the American Society of Echocardiography and European Association of Cardiovascular Imaging (8) state that the diagnosis of HFpEF by stress testing should show baseline septal e′ velocity of <7 cm/s or lateral of <10 cm/s with an exercise average E/e′ of >14 or septal E/e′ of >15, along with an exercise peak tricuspid regurgitation velocity of 2.8 m/s. Although there is no mention of tricuspid regurgitation gradient at rest or with exercise in the current study, presumably this was also assessed.
If clinicians begin to diagnose HFpEF simply based on this simple 2-step clinical algorithm (baseline E/e′ and galectin-3 evaluation) and this in turn leads to treatment of the dyspnea with a diuretic, one could at the very least be missing the opportunity to treat the underlying abnormality, such as valvular or ischemic heart disease or other CVD. This highlights the importance of convergent (things that are presumed to be related are in fact related) and divergent (things not presumed to be related that are unrelated) validity. It is clear that the current work does not yet fully satisfy the elements of this construct validity. Larger studies that better define specific CVD endpoints, particularly HF-related outcomes, will be needed before such a simplified or similar clinical algorithm is routinely adopted into every-day clinical practice.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Dr. Mehra has been a consultant for Abbott, Medtronic, Janssen (a division of Johnson and Johnson), Mesoblast, Portola, and NupulseCV, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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