Author + information
- Nicholas E. Houstis, MD, PhD∗ ()
- ↵∗Address for correspondence:
Dr. Nicholas Houstis, Cardiology Division, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114.
The barriers to creating new treatments for heart failure with preserved ejection (HFpEF) have so far proven impenetrable. To prevail, the field may require a more rigorous understanding of HFpEF pathophysiology. This knowledge would serve interlocking objectives, from refining disease nosology to guiding discovery efforts. Knowledge of the cause(s) of symptoms and outcomes, coupled with the ability to measure them at scale, would enable the subtyping of patients by matching pathophysiology. Knowledge of these causal mechanisms would also enable rational therapy design, and, in a well selected population, improve the odds of a successful clinical trial.
A chief complaint among patients with HFpEF is exercise intolerance, a phenotype whose pathophysiology has been the subject of intense scrutiny. To this end, many investigators have applied a reductionist framework premised on defining exercise capacity as the rate of oxygen (O2) consumption at peak exercise (Vo2). Mechanisms of exercise intolerance are then taken to be defects in the individual steps of O2 transport and consumption that move O2 from the mouth to skeletal muscle mitochondria (the O2 pathway). This breakdown of Vo2 into its constituent O2 pathway steps has the attractive feature that it can be performed quantitatively. Another attractive feature is it can be performed hierarchically, although this requires care. For example, the most common approach is to decompose Vo2 in to 2 terms: . The first term, cardiac output, reflects convective O2 transport mediated by the heart. The second term, peripheral O2 extraction, lumps all noncardiac O2 pathway steps together, including alveolar ventilation, diffusive O2 transport in the lungs, O2 carried by hemoglobin, vascular redistribution of blood flow, diffusive O2 transport to skeletal muscle, and mitochondrial respiration. The measurements needed for this 2-term analysis can be performed with familiar tools of clinical cardiology, including cardiopulmonary exercise testing, echocardiography, and arterial and venous catheters. Unfortunately, the appeal of this approach to decoupling the cardiac and noncardiac components of VO2 is deceptive because the value of depends on cardiac output as well, a consequence of the competition between convective and diffusive transport of O2. To truly decouple the O2 pathway into independent steps requires finer measurements and a more exacting analysis. Such an approach was adopted by Zamani et al. (1), to analyze Vo2 in HFpEF in this issue of JACC: Basic to Translational Science.
Zamani et al. (1) sought to improve our understanding of the noncardiac causes of exercise intolerance in patients with HFpEF. Study participants performed 2 types of exercise: supine cycle ergometry with echocardiographic monitoring; and forearm exercise (isometric handgrip) with invasive monitoring. Cycle ergometry confirmed the widely recognized phenotype of reduced peak Vo2 in HFpEF. Moreover, using echocardiographic estimates of peak cardiac output, the investigators calculated peak and found that it too was reduced in HFpEF, as others have also demonstrated. The second exercise modality, isometric handgrip, was monitored with a catheter in the antecubital vein and a brachial artery flow probe. These tools permitted the measurement and estimation of O2 transport properties in the local muscle bed, including blood flow, arterial and venous blood gases, and Vo2. The investigators then used this high-resolution phenotyping to calculate the forearm muscle diffusion conductance for O2 (DM). Unlike prior efforts to characterize DM in HFpEF, the investigators’ estimate did not rely on assumptions regarding local blood flow and local venous O2 tension, because they measured these quantities directly. This forearm technique had the added advantage that it could be scalable to a broader population than is currently reachable with alternative techniques (e.g., the use of pulmonary artery catheters).
A key finding from Zamani et al. (1) was that forearm was reduced in patients with HFpEF relative to control subjects, but forearm DM was not. This finding prompts at least 2 important questions: 1) if forearm DM is similar between patients and control subjects, can it be extrapolated that locomotor muscle DM might also be similar between groups, contrary to previous estimates? (2); and 2) what explains the drop in forearm in lieu of a defect in DM?
Several observations likely preclude the extrapolation of the forearm findings to other muscle beds. First, at least 2 other studies used similar methodology to Zamani et al. (1) to estimate DM in distinct muscle beds (3,4). Among control participants from all 3 studies, the values of DM (normalized to muscle mass) in the forearm (1), whole arm (3), and single-knee extensors (4) differed widely. Similarly, muscle mass-normalized Vo2 in these 3 muscle beds was also distinct. Though it could be argued that the control groups from each of these studies were not identical, data from within the Zamani et al. (1) study itself casts doubt on the likelihood that DM is an invariant property across muscle beds. In particular, it was notable that in addition to DM forearm Vo2 (normalized to muscle mass) was also quite comparable between patients with HFpEF and control subjects. In other words, the drop in peak Vo2 observed in patients during cycle ergometry was not recapitulated by the forearm muscles. This strongly suggests that the O2 pathway determinants of Vo2 in locomotor muscle differ from those of forearm muscle in patients with HFpEF. Finally, previous work has shown that modulation of arm Vo2 and its determinants can be dissociated from whole-body Vo2 (cycle ergometry). Boushel et al. (3) performed an exercise training study in which they found peak Vo2 and DM in the arm (arm exercise) increased after training, whereas peak whole-body Vo2 remained unchanged.
If DM differs between patients with HFpEF and control subjects in some muscle beds but not others, this fact may have important implications. It would argue against the existence of a circulating factor that uniformly compromises microcirculatory structure or function—and thus DM—across all muscle beds. Rather, it is not difficult to imagine that differences in locomotor activity between patients and control subjects could explain differences in locomotor O2 transport and consumption. Forearm activity might simply be more similar between groups, thereby explaining the similarities in Vo2 and DM. Another possibility is that patients with HFpEF are not less mobile per se, but their locomotor muscles adapt less to a given amount of mobility—they are less trainable.
To explain the drop in forearm in patients with HFpEF in the absence of a defect in forearm DM, the investigators considered alternative O2 pathway steps. First, they noted that forearm blood flow trended higher in patients with HFpEF. An isolated rise in blood flow, ceteris paribus, would be expected to cause a fall in , together with a sublinear rise in Vo2. That Vo2 was unchanged suggested the existence of additional O2 pathway defects. The investigators entertained the possibility that anemia and or impaired mitochondrial function in HFpEF could contribute to the drop in forearm . To this end, they noted that patients with HFpEF were more obese than control subjects and the degree of adiposity was correlated with the drop in forearm . Furthermore, a strong epidemiological association between HFpEF and obesity has been previously recognized (5). Although it can be difficult to tease apart correlation from causation, the latter is made plausible by biological links between adiposity and anemia, muscle metabolism, and mitochondrial function.
The repeated failure of clinical trials in HFpEF strongly suggests that its pathophysiology remains insufficiently understood. The prototypical chronic symptom of this syndrome, exercise intolerance, is governed by mechanisms that are distributed over multiple organs, cell types, and subcellular systems. The resulting system properties of Vo2 in turn give rise to tremendous mechanistic heterogeneity among patients with HFpEF (2). In the face of this complexity, progress will likely require comprehensive high-resolution phenotyping combined with quantitative causal analysis. Careful studies such as the work by Zamani et al. (1) will ultimately pave the way to improving disease nosology and discovering new therapies.
↵∗ Editorials published in JACC: Basic to Translational Science reflect the views of the authors and do not necessarily represent the views of JACC: Basic to Translational Science or the American College of Cardiology.
Dr. Houstis has reported that he has no relationships relevant to the contents of this paper to disclose.
The author attests he is in compliance with human studies committees and animal welfare regulations of the author's institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
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