Abbreviations

Background

Electrical and mechanical dyssynchrony are common in patients with HF and depressed (inferior to 40%) EF. However, as many as 50% of patients with chronic HF have what is now called HFPEF. Patients with signs and symptoms of HFPEF (EF ≥ 50%), but not those with restrictive, DHF, will be studied in the KaRen multicentre study, looking at prognosis and electrical and mechanical dyssynchrony (using electrocardiography and echocardiography performed according to a stringent protocol and reviewed in a dedicated core laboratory) . Recent small studies suggest that LV dyssynchrony might exist in patients with HFPEF .

Electrical and mechanical dyssynchrony in HF with depressed EF are known to be harmful , but we do not have such information regarding HFPEF. Further studies are therefore necessary. But we also need to use a precise definition of HFPEF, which is not merely a diagnosis made on the basis of the presence of symptoms and preserved EF . We need to ensure that the diagnosis (elevated filling pressure) is in accordance with the guidelines . In line with these principles, KaRen is an ongoing registry looking at the prevalence and prognostic impact of dyssynchrony in HFPEF .

We designed KaRen as a prospective, multicentre, international, observational study to characterize HFPEF and determine whether electrical or mechanical dyssynchrony affects prognosis. We are looking at HF-related and non-cardiovascular hospitalizations over a follow-up time of 18 months.

Elements of heart failure with preserved ejection fraction

CHF affects about 2% of the western population, with prevalence increasing sharply from 1% in those aged 50 years to 10% in those aged over 75 years . It is the most common cause of hospitalization in patients aged over 65 years . CHF is defined as a syndrome characterized by an impaired ability of the heart to fill with and/or eject blood, resulting in a classical constellation of signs and symptoms .

HFPEF is being recognized increasingly as a pathophysiological entity . The proportion of patients with HFPEF is about 50% in studies of the general HF population . These patients were previously classified as having DHF or HFPEF. However, DHF has its own definition and may not be strictly identical to HFPEF . HFPEF can be defined as follows:

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  an EF superior or equal to 45%, superior or equal to 50%, or superior or equal to 55% ;

  
  
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  the presence of clinical signs and symptoms of HF, according to the Framingham criteria ;

  
  
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  objective signs of congestion or elevated filling pressure (natriuretic peptides, invasive haemodynamics, echocardiography) in the absence of acute ischaemia, severe valvular disease or other severe medical condition that explains the congestion.

As the specificity of signs and symptoms of congestion in elderly patients is debatable, the clinical evaluation is being corroborated systematically by the level of brain natriuretic peptide or N-terminal prohormone brain natriuretic peptide in the KaRen study . Furthermore, echocardiography should be performed before inclusion, which should be able to verify the diagnosis .

The prognosis of HFPEF in epidemiological surveys is nearly as poor as that of SHF, but in therapeutic clinical trials of HFPEF (PEP-CHF, CHARM-Preserved and I-PRESERVE), the prognosis was much better than in clinical trials of SHF patients . In I-PRESERVE, during a mean follow-up of 49.5 months, the primary outcome (death from any cause or hospitalization for a cardiovascular cause [HF, myocardial infarction, unstable angina, arrhythmia or stroke]) occurred in 36.5% of patients . According to a recent meta-analysis, mortality was 40.6% in the reduced LV EF group vs 32.1% in the HFPEF group after an average follow-up of 47 months . The great discrepancy between registries and clinical trials might be due in part to the fact that patients were categorized as HFPEF patients essentially on the basis of signs and symptoms of HF and a preserved EF; some “HF-like syndromes” might therefore have been included. We thus need to consider objective criteria, to distinguish “true” HFPEF from “HFPEF-like syndromes”, where comorbidities might explain symptoms that are not associated with any elevation in LV filling pressures. Furthermore, the clinical trials excluded older patients and/or those with significant comorbidities. In epidemiological surveys, information on cause of death is not available and may well have been non-cardiovascular.

Recently, Henkel et al. published complementary results. They found that HFPEF patients have less cardiovascular disease before death and are less likely to experience cardiovascular death than those with reduced EF, and that the proportion of cardiovascular deaths declined over time . Such observations have also been reported by Tribouilloy et al. . These recent data highlight the fact that the high mortality rates observed in HFPEF and SHF may have different causes. In SHF, the main reason is HF (pump dysfunction and sudden death), whereas in HFPEF, the causes are mixed and are explained, at least in part, by comorbidities . Nevertheless, we have to keep in mind that patients included in these studies may not have actually had HFPEF. Indeed, in CHARMES, the echocardiographic sub-study of the CHARM-Preserved study, a third of patients did not have any diastolic dysfunction . In addition, in clinical practice, we have observed that the elderly patients in whom we diagnose HFPEF are hospitalized repeatedly for congestion (that is cardiovascular in origin most of the time) before dying. Under these circumstances, they need diuretics and blood pressure control . Hence, we certainly have to improve their treatment to decrease their cardiovascular morbidity .