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Epidemiology of Asymptomatic Pre-heart Failure: a Systematic Review

Purpose of Review To quantify the prevalence of asymptomatic pre-heart failure (pre-HF), progression to more severe stages, and associated mortality. Recent Findings A systematic review was conducted between 01 January 2010 and 12 March 2020 (PROSPERO: CRD42020176141). Data of interest included prevalence, disease progression, and mortality rates. In total, 1030 sources were identified, of which, 12 reported on pre-HF (using the ACC/AHA definition for stage B HF) and were eligible. Prevalence estimates of pre-HF ranged from 11 to 42.7% (10 sources) with higher estimates found in the elderly, in patients with hypertension, and in men. Three studies reported on disease progression with follow-up ranging from 13 months to 7 years. The incidence of symptomatic HF (HF/advanced HF) ranged from 0.63 to 9.8%, and all-cause mortality from 1.6 to 5.4%. Summary Further research is required to investigate whether early detection and intervention can slow or stop the progression from asymptomatic to symptomatic HF. Supplementary Information The online version contains supplementary material available at 10.1007/s11897-022-00542-5.


Introduction
Heart failure (HF) is a major public health issue and a leading cause of global morbidity and mortality [1]. An estimated 64.34 million individuals currently live with HF worldwide, contributing to 9.91 million years lived with disability [2], with numbers expected to increase in the future. The worldwide economic burden associated with HF is estimated at US $346.17 billion a year [3].
HF is a progressive disease that is classified by the American College of Cardiology (ACC) and American Heart Association (AHA) into four stages, based on the presence of structural remodeling and symptoms as shown in Fig. 1 [4•, 5•]. Briefly, patients are categorized as at risk of HF (stage A), with structural heart disease (stage B), with structural heart disease and symptoms of HF (stage C), or with refractory HF requiring specialized interventions (stage D) in which once a patient moves to a higher stage, they cannot revert to a lower stage [4•]. The ACC/AHA guidelines were developed to help identify patients with asymptomatic HF and to complement the clinically widely used NYHA classification which focuses solely on symptomatic HF. More recently, a universal definition of HF was published [6•], whereby they proposed the following stages: at risk for HF (ACC/AHA stage A), pre-HF (stage B), HF (stage C), and advanced HF (stage D). The proposed stages follow the same structure as the ACC/AHA staging system and address some of the gaps, namely the use of biomarkers to identify patients with structural disease, and clearly defined definitions for HF (e.g., abnormal cardiac function), which are now both included in the definition of pre-HF. The inclusion of stages A and B into a definition of HF may help with early detection and prevention of the progress from asymptomatic to symptomatic HF.
Asymptomatic HF includes patients at risk for HF and patients with pre-HF [4•]. Current estimates of the number of patients with asymptomatic HF vary widely but the number is thought to be higher than the number of patients with symptomatic HF (i.e., patients with HF or advanced HF) [7][8][9]. Patients with asymptomatic HF are at high risk of HF (including patients with hypertension, diabetes, and coronary artery disease) and can present with structural or functional cardiac abnormalities including previous myocardial infarction, left ventricle (LV) remodeling (including LV hypertrophy and low ejection fraction [EF]), and asymptomatic valvular disease [4•]. Other structural changes include asymptomatic LV systolic dysfunction (ALVSD) and asymptomatic LV diastolic dysfunction (ALVDD) [5•]. Studies tend to focus on ALVSD [10] rather than ALVDD which remains poorly understood [11].
Patients with structure cardiac dysfunction but without a clinical symptom are usually not detected unless an imaging assessment such as echocardiography is performed. There is increasing evidence for the use of natriuretic peptide (NP) biomarkers, such as B-type NP (BNP) and N-terminal pro-BNP (NT-proBNP), to detect the presence or severity of HF with a high diagnostic accuracy [12][13][14][15][16]. However, factors such as age, sex, race, renal dysfunction, and body mass index (among other cardiac/non-cardiac conditions) can affect the clearance of NPs [17][18][19][20][21], in which case, different cut-off levels are needed for different patient populations. Nevertheless, the use of BNP as a biomarker in the diagnosis of HF has been included in HF guidelines, including in the diagnosis of asymptomatic HF [22][23][24][25][26] and pre-HF [6•].
Asymptomatic HF in the general population is often unidentified unless a screening program is implemented with echocardiography; therefore, information on the epidemiology of asymptomatic HF in the general population is scarce. This systematic review aims to report the prevalence of asymptomatic in different patient groups and to describe its progression to symptomatic stages of HF and the associated rate of mortality. There are a number of definitions of asymptomatic HF and these definitions include a wide group of patients including those with no structural changes or symptoms. The ACC/AHA guidelines are widely used and provide clear guidance for identification of structural changes using echocardiogram providing an objective and uniform/standard definition for studying patients with asymptomatic HF. Therefore, we narrowed the focus of this review to concentrate on those studies reporting data on ACC/AHA stage B HF to minimize the bias in reported prevalence caused by differences in the definitions.

Study Selection
Observational (non-interventional) studies (including cohort, case-control, and cross-sectional studies) that included patients with pre-HF (stage B HF, as defined by the ACC/AHA guidelines) and that reported on data of interest (incidence, prevalence, risk factors, disease progression, prognosis, hospitalization, mortality) were retained. The definition of pre-HF includes patients with structural heart disease but no current or prior symptoms of HF such as patients with previous myocardial infarction, LV remodeling including LV hypertrophy and low EF, or asymptomatic valvular disease [27]. Original studies published as full-text or abstracts in English were considered and reviews were retained for snowballing only. The following publications were excluded: expert opinions, editorials, letters to editors, non-clinical and experimental studies, phase I-III clinical trials, case reports, case series, and literature reviews/meta-analyses (data was not extracted but used for snowballing only). Search outputs were screened, based on titles and abstracts, independently by two independent assessors with conflicts resolved by a third assessor. References retained after screening were reviewed in depth in order to confirm eligibility. Reasons for excluding studies at this stage were documented (e.g., no epidemiologic data of interest, no data on patients with pre-HF). A PRISMA flow chart illustrates the study selection process in Fig. 2.

Data Extraction and Methodological Quality Assessment
Data extraction was performed independently by two reviewers using a standardized data extraction form that was piloted prior to the start of data extraction, using five relevant publications. Conflicts were resolved by a third senior assessor.
For each retained study, information extracted included the following: • General information The methodological quality of retained full-text publications was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools for original studies [28], with the tools being specific to each type of study design. Studies were judged to be at low risk of bias (good quality) if they met at least 7 of 9 items of the checklist for cohort studies, 8 out of 10 items of the checklist for case series (appropriate for non-comparative cohort studies), or 8 out of 11 items of the checklist for studies reporting prevalence estimates. The review was conducted using the methods proposed by the Cochrane group [29] and the Institute of Medicine of the National Academy of Medicine [30].

Study Selection and Study Characteristics
The selection of sources through the various phases of the search is summarized in a PRISMA flow chart (Fig. 2). A total of 1030 sources were identified through the literature search covered from 01 January 2010 to 12 March 2020.
After screening, there were 81 full-text publications retained for in-depth review to confirm eligibility. During the indepth review, 69 sources were further excluded, mainly because they did not report data on pre-HF (n = 35; 50.7%), or because they did not estimate the epidemiologic parameters of interest (n = 32; 46.4%). Pragmatic searches and snowballing yielded no additional sources. Data were thus extracted from 12 full-text articles.
From the 12 retained publications, there were 10 studies reporting prevalence [

Prevalence of Pre-heart Failure
The key characteristics of the ten studies that reported estimates of the prevalence of pre-HF are summarized in According to Table 2, the prevalence of pre-HF in the studies conducted in the general population increased with age. This is particularly apparent when comparing the studies conducted in the elderly population (prevalence, 59.1%; age, 56 to 84 years) [

Disease Progression in Patients with Pre-heart Failure
Data on the progression of HF from pre-HF to symptomatic HF (HF or advanced HF) in the literature is lacking. According to a large retrospective cohort study conducted in the USA, the incidence rate of new-onset symptomatic HF among patients with pre-HF (n = 1637) was estimated at 1.14 per 100 person-years in men and 0.63 per 100 person-years in women [38••]. In an Italian study that included patients with both at risk of HF or pre-HF (n = 337), 9.8% patients required hospitalization due to a transition from asymptomatic to new-onset (symptomatic) HF over a median follow-up of 22 months (interquartile range: 30-47 months) [41••]. In a prospective cohort study conducted in Japan, 1.1% of patients with pre-HF were admitted to the hospital for HF (HF or advanced HF) after a median follow-up of 12.7 months (

Mortality in Patients with Pre-heart Failure
Only three studies reported mortality rates in patients with pre-HF. In the US general population (all age groups included), the all-cause mortality rate of patients with pre-HF was estimated at 0.

Discussion
This systematic review of 12 studies provides a synthesis of the existing evidence on the prevalence of pre-HF. While it is noted that multiple asymptomatic heart failure definitions exist, this study focused on publications using the ACC/ AHA stage B HF definition to minimize the bias caused by different definitions, and as the ACC/AHA definition is most widely used [6•], this study can be applied directly to this large and under-studied patient group [27]. When comparing the prevalence of pre-HF to the prevalence of symptomatic HF using the same guidelines and in similar populations, the prevalence of pre-HF was five to ten times higher than that of symptomatic HF. In the USA, prevalence estimates of pre-HF ranged from 12.5 to 24.2% [38••, 39••] while the prevalence of symptomatic HF has been estimated at 2.2% by the American Heart Association [43]. As the latter association estimates that 6.5 million American individuals currently live with symptomatic HF, the number of patients with pre-HF may reach 50 million individuals in the USA, therefore underlining the importance of this condition in terms of public health [44]. This extrapolation also clearly highlights the fact that pre-HF patients are under-represented in clinical research. The lack of identification, but high prevalence, also means that there is an increasing global disease burden of undiagnosed asymptomatic HF patients, many of whom will progress to symptomatic disease requiring urgent intervention [27].
Identifying patients with pre-HF is relatively difficult as patients are unlikely to seek medical attention in the absence  [27,45]. However, screening the general population would lead to the occurrence of false positive and false negative findings, which may cause "harm" (be it physical or psychological) to healthy individuals. Also, screening would invariably lead to a significant increase in new referrals to specialist services (for assessment and/or diagnosis) and this would create a major burden on many, already oversubscribed, healthcare systems. Despite these challenges, the need to diagnose heart failure sooner is unequivocally needed [46,47]. Data on the mortality associated with pre-HF are scarce in the literature. However, it has been well documented that patients with symptomatic HF are at increased risk of premature death compared to healthy individuals. The 1-year mortality rate following diagnosis of symptomatic HF in the Framingham study ranged from 26 to 35% over the period 1950-1999 [48]. As HF is a progressive disease, the vast majority of patients with pre-HF patients will ultimately develop symptomatic HF. Thus, early identification of these patients and implementation of targeted interventions aiming to reduce the risk of progression from asymptomatic pre-HF to symptomatic HF may help prevent premature death attributed to symptomatic HF. Current guidelines recommend early identification of patients at risk for developing HF in order to prevent progression to clinical stages of HF [49][50][51]. In practice, this approach translates to the universal use of low-cost interventions such as medication (such as angiotensin-converting enzyme inhibitors or beta blockers) and lifestyle adaptation [33••]. This approach would provide benefit for various stakeholders, including patients and healthcare systems. Lifestyle changes could include improved education on HF, smoking/alcohol/illicit drug cessation, improved diet, salt restriction, weight loss, reduced fluid intake, and exercise [52]. These interventions could not only reduce premature death attributed to HF but they could have a significant impact on the patients' quality of life by limiting the worsening of outcomes such as arrhythmia, thromboembolism, and pulmonary congestion [53]. However, despite this common-sense approach to actively manage the risk of progression in asymptomatic pre-HF patients, this approach is rarely adopted, due to limitations in identifying these patients, concerns over adverse drug reactions (in people who perceive themselves as being "healthy"), and the lack of awareness of disease progression from asymptomatic to symptomatic disease [27]. This is a great area of educational unmet need [46].
Most of the studies identified (n = 9; 75%) relied on echocardiography performed by trained sonographers to ascertain HF diagnosis, which is the gold standard technique for diagnosing HF according to guidelines from the American Society of Echocardiography and the European Association of Cardiovascular Imaging [54]. Acquisition of images and interpretation of echocardiograms largely depend on the skills of the professional performing the assessment and could therefore explain the variability in the estimates obtained in the various studies. Indeed, several large population-based studies have identified that the degree of variability in measurements can vary by as much as 20% due to subjectivity and inter-operative variability [55]. In five (41.7%) studies, diagnosis validated by an expert panel decreased the chance of misclassification of HF stage due to assessor variability.
To adhere to the protocol submitted to PROSPERO, this review did not include publications after March 2020. It is possible that a more recent search may observe differing results. The generalizability of the findings presented here may be limited considering that nine (75%) communitybased studies were conducted in specific population subgroups defined either by age or ethnicity, and two studies had a very small sample size (n < 70). The impact of publication bias was minimized by the conduct of literature searches using two complementary electronic bibliographical databases and with pragmatic searches using search engines for gray literature. The assessment of the methodological quality of included studies represents a major strength of this study as it was shown to vary between observational studies.

Conclusions
In conclusion, results from the systematic review suggest that pre-HF is a prevalent condition and most likely only a fraction of patients are diagnosed in clinical practice due to their asymptomatic condition. Higher prevalence estimates were found in elderly patients, in men, and in those with pre-existing conditions such as hypertension. Progression from pre-HF to higher symptomatic stages (HF or advanced HF) is associated with an increased mortality. Hence, early detection of patients with pre-HF and implementation of targeted interventions may reduce the burden of disease by reducing the incidence of associated complications and premature mortality.