New heart failure reclassification: are we left with more questions than answers?

KEYWORDS:

• Cardiovascular disease
• diastolic heart failure
• ejection fraction
• preserved ejection fraction
• reduced ejection fraction
• left ventricle
• systolic heart failure
• recovered ejection fraction

Cardiovascular diseases continue to be the leading cause of death, accounting for approximately 31% of all deaths worldwide with heart failure (HF) being a growing epidemic since 1997 [1,2]. Current estimates indicate that over 37.7 million people are afflicted with HF worldwide [3,4]. In the US alone, 5.8 million patients carry a diagnosis of HF and 875,000 additional new HF cases are expected each year [5].

The complexity of HF as a chronic long-term condition that continues to deteriorate and is associated with inordinate morbidity and mortality and whose intricate pathophysiology and ever-changing left ventricular (LV) cardiac mechanics are beginning to be comprehended; it has become apparent that the old concept of HF being simply viewed as ‘a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the LV to fill or eject blood’ is no longer applicable [6–8].

The introduction of the HF stage classification was an attempt to better understand the interaction existing between potential risk factors and underlying cardiac structural elements needed for the natural progression of LV dysfunction and symptom development to occur [9]. Not only this stage classification was useful to identify individuals along the natural continuum from those at risk of developing HF to those eventually reaching an advanced HF stage, but also provided physicians with treatment options depending on each individual stage while complementing the already useful New York Heart Association, primarily used to gauge symptom severity and functional limitation [10].

Unfortunately, these steps were not enough as the previously held concept of LV systolic versus diastolic HF continued to be a significant source of controversy and confusion, particularly when both of these mechanical abnormalities could coexist in any given HF patient [11,12].

This debate continued until the American College of Cardiology and the American Heart Association both agreed on making the much easier distinction between preserved (HFpEF) and reduced (HFrEF) not only based on left ventricular ejection fraction (LVEF) but also driven by a wealth of existing data clearly identifying two patient populations with different patient demographics, comorbid clinical profile, response to therapy, and overall prognosis [13].

However, it soon became apparent that a number of patients whose previous LVEF values have ranged >40%, >45%, >50%, and ≥55% did not necessarily fit this new reclassification scheme. Therefore, for the sake of convenience, these patients were further subgrouped. A HFpEF borderline subgroup identified patients with an LVEF between 41% and 49% and whose clinical profile, treatment patterns, and outcomes appeared to be similar to patients with HFpEF, while a HFpEF improved subgroup included patients not only previously diagnosed as HFrEF who now have LVEFs >40% but also are now considered to be clinically distinct from those with persistently preserved or reduced LVEF [13].

Even though this new reclassification is useful as it tries to ease patient identification, it still does not solve the main issue of impact on clinical outcomes, as novel HF therapies have not been up to par with the progression and natural evolution of the disease process and most contemporary HF trials have failed to improve outcomes above standard medical therapy [14,15]. This is certainly relevant among HFpEF as both diagnosis and management of this clinical entity not only has been always clinically challenging, but also therapeutic interventions to reduce symptoms and improve functional capacity as well as other patient-reported outcomes have not shown any significant clinical benefit.

An additional burden now being recognized is the overall impact of non-cardiac comorbidities among HF patients. Undoubtedly, as the general population continues to age, survival rates after myocardial infarction leading to LV remodeling continue to increase and a greater proportion of individuals are afflicted with obesity, diabetes, and poorly controlled hypertension and a greater number of HF cases will continue to emerge. This is particularly distressing as approximately 25% of Americans are known to have multiple chronic conditions, an estimate that increases significantly to up 75% in patients with 65 years of age and older [16]. Unfortunately, the clinical impact of chronic comorbid conditions though almost universal among HF patients, it is significantly more relevant in HFpEF patients when compared to their HFrEF counterparts [17].

Despite the dismal outlook, a recent publication from the European Society of Cardiology is somewhat encouraging. Though this publication intended to aid health professionals to make everyday decisions with regard to how to approach and manage HF by applying evidence-based data with the hope of eventually making HF a preventable and treatable disease [18], there would still be instances in which clinicians would have to make treatment decisions without the benefit of proven data or the support of a general consensus statement [18].

The incremental value of using angiotensin-converting enzyme inhibitors/aldosterone receptor blockers, β-blockers, mineralocorticoid antagonists, and the most recently introduced neprilysin inhibition for the treatment of HFrEF still contrasts to the disappointing results seen from most major HFpEF trials [19].

To complicate further matters, rapid advances in the treatment of chronic HF the American College of Cardiology (ACC)/American Heart Association (AHA), Heart Failure Society of America (HFSA), and European Society of Cardiology (ESC) have recently published new updated guidelines [18,20]. Though it will be impossible to cover in great detail all common and diverging points, suffices to mention that recommendations with regards to revascularization and implementation of disease management programs are for the most part congruent. However, while substantial disagreement is evident regarding recommendations for using different pharmacological agents, some significant discrepancies are also encountered when examining the role of cardiac resynchronization therapy and implantable cardioverter defibrillators.

At the end, we are unfortunately left with more questions than answers. Most importantly, why the need four HF guidelines,including three from North America, though ideally, a general consensus statement aimed at resolving most conflicts while explicitly stating which clinical trial(s) provide(s) the most robust evidence as well as showing improvement of the intended outcome variable, will be most useful. Surely, it is evident the field of HF is rapidly evolving, not only in terms of understanding its complex pathophysiology but also in implementation of new therapeutic options. Furthermore, poor representation of comorbidities and disease-specific area contributing to different HF phenotypes was not clearly addressed. Finally, a unifying consensus regarding measures of LV ejection fraction should be more clearly delineated, particularly when this variable has received so much emphasis as it is now being employed on the current reclassification and the utility of its intermediate values not fully appreciated.

Investigators are now urged to conceive prospective studies that incorporate this new HF reclassification so that we have a better understanding on how to apply diagnostic, management, and outcome data with regard to specific conditions such as hypertrophic cardiomyopathy, cardiac amyloidosis, cardiac sarcoidosis, myocarditis, peripartum cardiomyopathy, adults with congenital heart disease, survivors of cancer therapy, muscular dystrophies, right HF, and cardiorenal syndrome to mention a few.

As we all wait for these data, we certainly hope that as reclassification of HF continues to evolve, this will certainly have a positive overall impact on treatment options, device intervention, outcome assessment, and follow-up care of these HF patients.

Declaration of interest

The authors have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. Postgraduate Medicine peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

None reported.

Additional information

Funding

This manuscript was not funded.