Diastolic Stress Testing

We read with great interest 2 recent state-of-the-art review articles by Ha et al. (1) and Obokata et al. (2) published in iJACC. Both reviews advocate for the use of cycle exercise in patients with unexplained dyspnea for optimal diagnosis of diastolic dysfunction, particularly when resting assessments remain equivocal. The first review by Ha et al. (1) highlights the clinical application of both invasive and noninvasive diastolic stress testing, whereas the review by Obokata et al. (2) provides a comprehensive summary of the pathophysiology and phenotyping of heart failure with preserved ejection fraction (HFpEF), with particular emphasis on utilizing cycle exercise echocardiography. Thanks to their seminal work, and important contributions from others, submaximal, cycle exercise is now recommended by both the American Society of Echocardiography and the European Association of Cardiovascular Imaging for optimal diagnosis of diastolic dysfunction.

One important limitation raised by both reviews involves the technical challenges often associated with cycle exercise, particularly in patient populations with limited acoustic windows, even at rest. As expected, dynamic lower body exercise increases both respiratory and movement artifact, which is exacerbated in patients with increased body adiposity or poor acoustic windows. This is further compounded by orthopedic limitations that often accompany patients. Moreover, as discussed by Ha et al. (1), there are also technical challenges associated with assessing diastolic function at high heart rates.

In light of these limitations, our group has advocated using isometric handgrip echocardiography (IHE) as an alternative diastolic stress testing modality, as it avoids the previously mentioned limitations, while reproducibly increasing left ventricular afterload and myocardial oxygen demand (3,4). Of course, we are not the first to suggest this, with investigators adopting this approach decades ago to invasively study stress induced changes in diastolic hemodynamics. In our hands, using a similar noninvasive imaging approach described by Ha et al. (1) and Obokata et al. (2), IHE at 40% of maximal voluntary contraction for 3 to 5 min is able to differentiate between normal and abnormal diastolic function in a group of asymptomatic elderly individuals, a response that parallels that observed in HFpEF (Figure 1) (4). We have also shown that IHE has a similar myocardial oxygen demand as low-level cycle exercise (20 W), as defined by rate pressure product, and evokes a comparable rise in the ratio between early mitral inflow velocity and early annular tissue velocity (3).

FIGURE 1. Illustration Highlighting Potential Mechanisms and Early Evidence Promoting IHE as a Diastolic Discriminator.

(A) Isometric handgrip echocardiography (IHE) performed at 40% of maximal voluntary contraction for 3–5 min reproducibly leads to an increase in arterial blood pressure (BP) and heart rate by stimulating the exercise pressor reflex (top), which acts as a diastolic stressor via 2 dominant mechanisms (bottom). First, the increase in heart rate and BP challenges the myocardial oxygen supply-demand balance, which can compromise adenosine triphosphate (ATP) production. Second, the elevated afterload stress can lead to impaired calcium handling, leading to delayed and prolonged myocardial relaxation. (B) Similar to 20-W cycle exercise, IHE leads to a rise in the ratio between Doppler-derived early mitral inflow velocity and early annular tissue velocity (E/e′) in a subset of elderly asymptomatic individuals, termed responders (top). This rise in E/e′, induced by IHE, mirrors the response observed in clinically diagnosed heart failure with preserved ejection fraction (HFpEF) patients (n = 3), which is not seen in young healthy individuals (below). Data are expressed as mean ± SD. Adapted with permission from Samuel et al. (3–5). NCX = sodium-calcium exchanger.

The mechanism(s) by which diastolic dysfunction is unmasked by IHE and cycle exercise are likely different, and is worth consideration (5). Specifically, IHE causes a greater rise in systolic pressure that is expected to pose greater challenge on calcium handling and associated actin-myosin cross-bridge cycling. When ventricular-arterial stiffness is increased, as occurs in HFpEF, the IHE-mediated increase in systolic pressure is associated with delayed cardiac relaxation and increased end-diastolic pressure.

Although cycle exercise echocardiography offers significant value in identifying many patients with diastolic dysfunction–which is otherwise hidden at rest–IHE is a convenient alternative that avoids many of the technical limitations of cycle exercise, while still serving as a robust diastolic discriminator. Therefore, we reason that IHE should be considered when planning diastolic stress testing in the laboratory and the clinic.