Proposed HFpEF Phenotypes Point to Distinct Treatment Approaches

June 19, 2020

More drug trials for heart failure (HF) with preserved ejection fraction (HFpEF), it is sometimes noted, might turn out "positive" if HFpEF represented just one disease process.

It does not, however, and HFpEF has no approved medical therapy. But it's been a longstanding research goal to identify clinically useful HFpEF phenotypes that might each respond best to their own distinct treatment approaches.

A new analysis may have identified three variations of the single clinical entity HFpEF that are based on how some biochemical markers relate to traditional echocardiographic criteria.

The three proposed phenotypic patterns point to different potential management strategies, one of which may not necessarily involve drugs, propose the study authors.

"With these different phenotypes, one wonders what's driving them. And if there's something driving a certain kind of pathophysiology that could be identified by a biomarker, then you might be able to target therapy," David Kao, MD, University of Colorado Anschutz Medical Campus, Aurora, told theheart.org | Medscape Cardiology.

"One of the phenotypes has more of these biomarker abnormalities, and there's another one that's mostly atrial fibrillation," he said. "That one is probably driven by something completely different and therefore should be treated differently."

Kao led the post hoc analysis of clinical, echocardiographic, and biomarker data obtained from all 216 patients in the RELAX study and presented it last week in poster form at HFA Discoveries, the online version of the annual scientific meeting of the Heart Failure Association (HFA) of the European Society of Cardiology. The meeting was conducted virtually this year because of the COVID-19 pandemic.

The randomized, long-completed RELAX trial is noteworthy for having failed to show a benefit in functional capacity or clinical status for patients with HFpEF treated with the ground-breaking phosphodiesterase-5 (PDE-5) inhibitor sildenafil, as reported here in March 2013.

This new analysis relied on machine-learning techniques to discern structural, functional, and biochemical patterns that ultimately defined the three phenotypes: A (n = 45), B (n = 71), and C (n = 66).

Types A and B seem to have similar pathophysiologies, and type C may be an altogether different creature, Kao ventured.

Type A was characterized by prevalent grade II diastolic dysfunction — defined as increased left ventricular (LV) stiffness and elevated left atrial (LA) pressure — frequently with an abnormal E to e′ ratio (E/e′), the echocardiographic index for diastolic function based on mitral flow velocity.

Type B resembled a more severe form of type A, Kao proposed. It accounted for nearly all the grade III diastolic dysfunction in the population and was almost always accompanied by an abnormal E/e′.

Diastolic Dysfunction (DD) by Grade and Echo Measure for Three Proposed HFpEF Phenotypes
Parameter Type A (n = 45) Type B (n = 103) Type C (n = 68) P Value
DD grade I, % 14 0 8
DD grade II, % 86 0 3 <.001
DD grade III, % 0 68 3
Abnormal E/e′, % 74 91 0 <.001

Type B also included prevalent atrial fibrillation (AF) and moderate to severe LA enlargement, as well as the highest levels of endothelin-1, natriuretic peptides, cystatin-C, and cardiac troponin I by high-sensitivity assay (hsTnI). A third of type B cases showed an LV ejection fraction less than 55%.

Atrial and Ventricular Features for Three Proposed HFpEF Phenotypes
Parameter Type A (n = 45) Type B (n = 103) Type C (n = 68) P Value
LVEF ≤55%, % 4 32 34 <.001
Moderate to severe LA enlargement, % 38 80 55 .002
Atrial fibrillation, % 18 65 53 <.001
RV dysfunction, % 2 28 17 .0003

Indeed, type B accounted for almost half the LV systolic dysfunction and most right ventricular dysfunction. It also included the most severe diastolic dysfunction by grade and echo measures and the most severe LA enlargement. Its biomarker profile, more than those of the others, pointed to prevalent pulmonary artery resistance, myocyte injury, and extensive ventricular remodeling, Kao said.

Biomarker Levels for 3 Proposed HFpEF Phenotypes
Biomarker Type A (n = 45) Type B (n = 103) Type C (n = 68) P Value
hsTnI, pg/mL 8.3 11.6 6.7 <.001
NT-proBNP,* ng/L 441 1171 481 <.001
Endothelin-1, pg/mL 2.20 2.85 2.14 <.001
Cystatin-C, mg/L 1.33 1.45 1.15 .002
*N-terminal pro-brain-type natriuretic peptide

Diastolic dysfunction and biochemical abnormalities were mostly absent among type C cases, but they had prevalent AF and LA enlargement, Kao observed.

"So I suspect that type of HFpEF is just completely different, and really driven by the arrhythmia and the symptoms that come from that, rather than a primary myocardial cause."

That has immense treatment implications; catheter ablation might be an effective treatment for patients with type C HFpEF, and such patients may also be "the least likely to respond to antifibrosis drugs," Kao said.

The phenotypic patterns suggest such agents might more appropriately and effectively be aimed at patients with HFpEF of type A or type B.

Meds that fight myocardial fibrosis include spironolactone — which seemed to clinically benefit patients with HFpEF in a post hoc analysis of TOPCAT — and most renin-angiotensin-system (RAS) inhibitors, long-established mainstays for HF with reduced ejection fraction (HFrEF).

Had patients with HFpEF of the proposed type C been excluded from the major HFpEF trials, Kao speculated, the drugs tested in those trials might have registered a significant clinical benefit.

That doesn't necessarily mean all HFpEF with AF is a type C outlier. The arrhythmia was present in 65% of phenotype B cases, but those also tended to have grade III diastolic dysfunction and the highest E/e′ values.

"I think that speaks to the fact that all atrial fib isn't created equal," Kao said.

"In type B, the atrial fibrillation is probably secondary to all the other problems, like the diastolic dysfunction. In type C, I think the atrial fib was probably primary and driving the symptoms and the heart failure presentation, even though the heart otherwise wasn't that sick."

Kao discloses consulting for Codex.

HFA Discoveries 2020 from the Heart Failure Association (HFA) of the European Society of Cardiology.

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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