Evolution of a Geriatric Syndrome: Pathophysiology and Treatment of Heart Failure With Preserved Ejection Fraction

Bharathi Upadhya, MD; Barbara Pisani, MD; Dalane W. Kitzman, MD


J Am Geriatr Soc. 2017;65(11):2431-2440. 

In This Article

Evolution in Our Understanding of the Pathophysiology of HFpEF

Luchi first described HFpEF in 1982.[19] He noted that, in his patients aged 75 and older admitted with acute congestive HF, nuclear imaging studies, a relatively new development at the time, frequently showed a relatively normal LVEF, rather than a severely low LVEF, which was universally thought to be a requisite for HF.[19] Although this syndrome was first recognized in 1982, it was not until 2001 that it was mentioned in the ACC/AHA HF management guidelines, where it was termed "HF due to diastolic dysfunction." In the 2005 guidelines, the syndrome was referred to as the more generic and less pathophysiologically presumptive term "HF with preserved EF."[20] Since then, HFpEF has become accepted as a true and distinct clinical syndrome.[21] Thirty-five years after its initial description, the fundamental pathophysiological mechanisms of HFpEF remain incompletely defined.

One of the most commonly cited mechanisms of HFpEF has been LV diastolic dysfunction, consisting of abnormal LV active relaxation, LV passive stiffness, or both.[22] Although diastolic dysfunction is a pivotal factor in many cases of HFpEF, many individuals do not have echo-Doppler indices of severe diastolic dysfunction, at least at rest or that differ greatly from that expected based on age and comorbidities.[23,24] Nevertheless, most HFpEF studies have measured diastolic function only at rest rather than during exercise, when symptoms become manifest.[25] Significant LV hypertrophy was previously thought to be a uniform characteristic of HFpEF, but many individuals with HFpEF have concentric remodeling without hypertrophy or even normal LV geometry and mass.[26,27] In addition, a recent trial of well-characterized individuals with HFpEF showed that only 8% had LV hypertrophy at baseline and that 50% had significant or severe diastolic dysfunction at rest. In addition, although cardiac fibrosis is commonly present in individuals with HFpEF, the degree appears modest.[28]

These data have led to reconsideration of the initial hypothesis of hypertension-induced LV hypertrophy, diastolic dysfunction, and cardiac fibrosis as the sole or fundamental underlying pathophysiological mechanisms of HFpEF. In addition, the discovery of several novel contributing factors to HFpEF, including mild LV systolic dysfunction;[26,29] impaired LV and right ventricular (RV) systolic reserve;[30] impaired heart rate (HR) recovery and chronotropic incompetence;[31–33] abnormal ventricular vascular coupling;[34] low vasodilator reserve;[32,33] cardiac aging;[35] neuroendocrine dysfunction;[13] left atrial (LA) dysfunction;[36,37] impaired resting pulmonary arterial (PA) and RV function; abnormal PA vasodilatory reserve and abnormal RV-PA coupling;[30,38–40] altered pulmonary function and gas exchange, including low diffusion capacity;[41] impaired oxygen carrying capacity, peripheral oxygen extraction, and contributions from skeletal muscle dysfunction, including adipose infiltration, low muscle mass, capillarity, and mitochondrial density, drove the process (Figure 1).[42–45] As a result of this evolution in our pathophysiological understanding, this disorder underwent a name change approximately 10 years ago, from the presumptive term "diastolic HF" to the broader, more phenomenological term "HFpEF."[21]

Figure 1.

Relationship between (A) capillary-to-fiber ratio and (B) percentage of type I muscle fibers and peak oxygen uptake (VO2) in older adults with heart failure with preserved ejection fraction (▪) and age-matched healthy controls (▴).