Deconstructing HFpEF: Permanent AF, LA Changes May Indicate Unique Phenotype

September 15, 2020

The cause of heart failure with preserved ejection fraction (HFpEF) may often have a lot to do with the left atrium, despite its name that is fixated on ventricular function, suggests a mechanistic study with implications for treating a condition that has defiantly crushed repeated clinical trial attempts at drug therapy.

A unique HFpEF phenotype was potentially identified among patients evaluated for dyspnea at a major center over a 15-year period, investigators report. Among its constellation of features were progressive left atrial (LA) structural and functional changes, permanent atrial fibrillation (AF), progressive pulmonary vascular disease, and right-heart failure, investigators report.

In their analysis, 278 patients with HFpEF were followed for 10 years after undergoing a full suite of invasive hemodynamic measurements, exercise testing, and echocardiographic evaluations. Just over a third of them also had some form of AF, and overall their outcomes tracked with AF burden. Survival was highest in the 65% of patients with HFpEF but no AF, mid-range in those with paroxysmal AF, and lowest in patients with permanent AF.

Left ventricular (LV) diastolic dysfunction seemed not to be a part of the proposed phenotype. Ventricular mass and stiffness as well as echo measures of diastolic function didn't vary much by AF burden in the patients with HFpEF.

It's increasingly said that the heterogeneous nature of HFpEF likely accounts for the consistent failure of large drug trials to identify a treatment that improves its mortality, and that future trials zeroing in on distinct HFpEF phenotypes may be more likely to succeed.

The current study may define just such a phenotype, one that could well be common, Barry A. Borlaug, MD, Mayo Clinic and Foundation, Rochester, Minnesota, told | Medscape Cardiology. Perhaps two-thirds of people with HFpEF develop AF at some point, and it usually indicates an advanced stage of heart failure, he said.

The proposed LA-myopathy version of HFpEF seems mechanistically different from other forms, so "we need to think about how we might leverage that knowledge therapeutically," said Borlaug, who is senior author on the study's September 1 publication in the Journal of the American College of Cardiology, with Yogesh N.V. Reddy, MBBS, MSC, of the same institution, as lead author.

The current study, which points to HFpEF with permanent AF as a "clinically and pathophysiologically distinct phenotype," used an extensive array of tests to provide "comprehensive insight into the spectrum of AF-HFpEF stages — an analytical approach that has not yet been done in this way," notes an accompanying editorial from Wojciech Kosmala, MD, PhD, Wroclaw Medical University, Poland.

The finding that LV mass "did not correspond to AF status and remained similarly abnormal across all AF categories" is novel and "may change the current approach to AF preventive strategies in HFpEF."

LA Remodeling Begets AF, Worsening LA Remodeling

Borlaug and his colleagues saw that LA changes progressed in tandem with AF burden. Left atrial dilatation in the HFpEF patients with permanent AF — in contrast to those without AF or only the paroxysmal form — was associated with greater total heart volume and bilateral deterioration in ventricular function. Paroxysmal AF typically progressed into permanent AF.

Borlaug believes that, in general, the LA structural changes precede AF and probably stem from "longstanding exposure to high left-atrial pressures, causing over-distension and remodeling of the left atrium." The process is likely accelerated by coexisting conditions like inflammation and obesity, he said.

The current study's longitudinal data "shows that just having the atrial myopathy predicted the development of atrial fibrillation" among people with no AF history at baseline, Borlaug said. "That suggests that it's clearly a precursor."

Still, the process seems to be bidirectional. "The atrial fibrillation also accelerates the myopathy," such that both AF and LA remodeling progressively worsen.

That process may explain why permanent AF often doesn't respond well to rhythm-control measures. For patients with longstanding permanent AF, "maybe the ship has sailed, maybe it's too late for a lot of them," Borlaug said. But for those with paroxysmal or even "early permanent" AF, maybe treatment could "reverse-remodel the atrium, make it smaller, make it more electrically stable."

The findings also suggest that "maybe we should be a bit more aggressive" in performing catheter ablation earlier in the progression of AF, before it becomes resistant, he said. Indeed, a key message of the study is that earlier treatment of the AF itself and measures aimed at LA unloading, whether pharmacologic or device-based, may stem LA myopathy and possibly, therefore, improve AF and HFpEF progression.

15-Year Experience

The analysis included 278 patients with HFpEF — of whom 65% had no history of AF, 18% had paroxysmal AF, and 17% had permanent AF — evaluated for exertional dyspnea from 2000 to 2015 at the Mayo Clinic; an elevated rest or exercise pulmonary-capillary wedge pressure (PCWP) was part of the HFpEF definition. A further 146 patients undergoing the same evaluations were followed as controls; they were required to have normal ejection fractions and PCWPs and to be without a history of AF.

Ten-year survival declined with increasing AF burden, from 94% in controls, to 73% in those with HFpEF but no AF, to 62% for HFpEF and paroxysmal AF, to 38% for patients with HFpEF and permanent AF (P < .001).

Of those with paroxysmal AF, 52% progressed to permanent AF over the 10 years of follow-up. The greater the AF burden, the more likely was the risk of worsening AF severity. Progression was also significantly associated with impaired LA reservoir strain, lower LA compliance, and more pronounced elevation in baseline PCWP, the report notes.

Markers of congestion indicated greater severity in patients with permanent AF compared with other AF groups. They included more cardiomegaly and pulmonary edema, higher natriuretic peptide levels and LA volumes, and lower hemoglobin levels. 

Biventricular systolic function fell with increasing AF burden, accompanied by reduced left ventricular ejection fraction (LVEF) and global longitudinal strain.

However, cardiomegaly in patients with HFpEF and permanent AF stemmed entirely from atrial dilation; biventricular volumes did not change. Indeed, atrial dilation became more severe with increasing AF burden, such that LA volumes in patients with HFpEF and permanent AF were four times greater than those of controls, the group reports.

Such features were signs of ventricular interdependence, a hallmark of the proposed LA myopathy HFpEF phenotype. The interdependence is secondary to atrial dilation, which diminishes the space between the heart and pericardium. The resulting pericardial restraint causes the ventricles to compete with each other for space, raising right- and left-sided filling pressures and contributing to increased PCWP and pulmonary artery pressures, Borlaug explained.

"The blood vessels in the pulmonary vasculature remodel. Pulmonary vascular resistance goes up. There's more pulmonary hypertension. And that's when the right heart failure gets bad."

Relief of pericardial restraint by pericardiotomy is under study as a potential therapy specifically for patients with the LA-myopathy HFpEF phenotype, Borlaug said. Animal models suggest that the surgical technique can lead to decreased ventricular stiffness and filling pressures.

Patients with the proposed LA-myopathy HFpEF phenotype "are a group that could potentially respond to this."

The current study, the editorial contends, "extends and redefines existing knowledge on AF pathophysiology in HFpEF, and confirms that the heterogeneity of this heart failure category is multidimensional. The current study adds to a growing body of evidence reinforcing the need for individualized treatment in this clinical condition."

Borlaug discloses support from the National Institutes of Health. Reddy, the other coauthors, and Kosmala have disclosed no relevant financial relationships.

J Am Coll Cardiol. Published September 1, 2020. Report, Editorial


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