Deliberating the Diagnostic Dilemma of Heart Failure with Preserved Ejection Fraction
In the past decade, a higher prevalence of heart failure with preserved ejection fraction (HFpEF) as compared to heart failure with reduced ejection fraction (HFrEF) is been noticed. The existing guidance and clinical trials fail to guide on how to define HFpEF due to variability in evidence. Redfield published a study titled “Deliberating the Diagnostic Dilemma of Heart Failure with Preserved Ejection Fraction” in the “American Heart Association” journal. A summary of the findings is given below:
Objective:
To improve the treatment approach for HFpEF by providing a complete understanding of disease pathophysiology.
To highlight current knowledge gaps for future research work.
To define the syndrome of HFpEF more precisely for improved patient selection, diagnosis, and future treatment approaches.
Method:
The findings were developed from the currently available evidence and scientific and medical knowledge. The selected articles were later distinguished depending on the usefulness/ efficacy of the procedure and methodology of clinical trials.
Findings:
It is essential to recognize the heterogeneity of clinical presentation in HFpEf as a diagnosis of this disease rely on the constellation of signs, symptoms, and other manifestation.
Understanding HFpEF Within the Context of Comorbidities:
Researches identified the presence of HFpEF with comorbidities. The 3 predominant phenotypes classified for HFpEF are: elderly/atrial fibrillation (older, high prevalence of atrial fibrillation); metabolic (obese, high prevalence of diabetes and hypertension), and lean diabetic (high prevalence of diabetes in the absence of obesity)
Understanding HFpEF Within the Context of Organ System Involvement:
There are multiple physiological abnormalities with cardiac and extracardiac system organs in patients with HFpEF. Due to the comorbidities and extracardiac abnormalities, noncardiovascular outcomes exceed cardiovascular disease endpoints. Therefore, HFpEF phenotype guided approaches to treatment are proposed because of the variation in clinical presentations.
Understanding HFpEF Within the Context of Natural History:
The information on signs and symptoms such as rest congestion, exercise-induced pulmonary congestion is essential to diagnose the clinical syndrome of HFpEF. Hence, the natural history of disease must be an important consideration.
Practical Approach to HFpEF Diagnosis:
Diagnostic tools: History
Nonhospitalized HFpEF: Dyspnea on exertion
Hospitalized HFpEF: Rest congestion
Criterion: Orthopnea
Diagnostic tools: Physical examination
Nonhospitalized HFpEF: May be normal
Hospitalized HFpEF: Diagnostic
Criterion: Jugular venous pressure, Rales, Peripheral oedema, Third heart sound
Diagnostic tools: Natriuretic peptides
Nonhospitalized HFpEF: Supportive
Hospitalized HFpEF: Supportive
Criterion: major European Society of Cardiology (ESC) criterion includes N-terminal pro-B-type natriuretic peptide >220 (660 in AF); minor ESC criterion includes >125 (375 in AF)
Comments: Natriuretic peptides are higher by 3- to 3.5-fold in atrial fibrillation (AF) than in sinus rhythm and might be falsely low in obese individuals with heart failure
Test characteristics: High negative predictive value for overall heart failure although the negative predictive value is less robust in HFpEF. Up to 20% with invasively proven HFpEF have low N-terminal pro-B-type natriuretic peptide (<125); >125 cut-point: sensitivity 77% specificity 53%
Diagnostic tools: Echocardiography
Nonhospitalized HFpEF: Supportive
Hospitalized HFpEF: Supportive
Criterion:
Diastolic function: Tissue Doppler of mitral septal and lateral e′ and E/e′ ratio
Comment- ESC criteria: septal e′<7 or lateral e′<10 (<75 y); septal e′<5 or lateral e′<7 (≥75 y); E/e′ ratio ≥15 (major), 9–14 (minor)
Test characteristic- Septal e′<7: sensitivity 46%, specificity 76%; E/e′ ratio >9: sensitivity 78%, specificity 59%. Systematic review: E/e′ correlated with invasive left ventricular (LV) filling pressures with summary r 0.62 in 9 studies.
Tricuspid regurgitation (TR) jet velocity
Comment- ESC criteria: TR velocity > 2.8 m/s or pulmonary artery systolic pressure >35 mmHg
Test characteristic- Pulmonary artery systolic pressure >35: sensitivity 46%, specificity 86%
Left atrial enlargement
Comment- ESC criteria advocate for separate cut points in sinus vs atrial fibrillation: Major: left atrial volume index >34 (sinus), >40 (AF); minor: left atrial volume index 29–34 (sinus), 34–40 (AF)
Test characteristic- Left atrial volume index >30 sensitivity 70%, specificity 71%
LV hypertrophy
Comment- ESC criteria emphasize concentric remodelling: Major: LV motility injury ≥149 (men), ≥122 (women) and relative wall thickness >0.42; minor: LV motility injury ≥115 (men), ≥95 (women) or relative wall thickness >0.42 or wall thickness ≥12 mm
Test characteristic- Can be normal. LV hypertrophy sensitivity 26% specificity 88%
Diagnostic tools: Invasive hemodynamics
Nonhospitalized HFpEF: May be normal
Hospitalized HFpEF: Confirmatory/ diagnostic
Criterion: Pulmonary capillary wedge pressure or LV end-diastolic pressure
Comments: High filling pressure defined as LV end-diastolic pressure ≥16 or pulmonary capillary wedge pressure ≥15 mm Hg
Test characteristics: Diagnostic
Diagnostic tools: Echocardiographic stress test
Nonhospitalized HFpEF: Suggestive
Criterion: Exercise measures of diastolic function and TR velocity
Comments: Ideally semi-supine bicycle test with imaging during exercise; however, universal protocols are lacking. Limited published data. TR velocity measurable in only ≈50% of individuals with HFpEF3
Test characteristics: Addition of exercise average E/e′>14 or septal E/e′>15 to ESC algorithm improved sensitivity (90% from 60% for ESC alone) with similar specificity (71% from 75%), but higher false-positive rate to 29%
Diagnostic tools: Noninvasive cardiopulmonary exercise testing
Nonhospitalized HFpEF: Suggestive
Criterion: Surrogate markers of cardiac functional limitation: peak Vo2, Ve/Vco2 slope
Comments: Mean peak Vo2 in HFpEF is decreased relative to normal values; whereas, in intermediate-range, shares overlap with noncardiac dyspnea.
Test characteristics: Peak Vo2 <14 discriminates HFpEF from noncardiac dyspnea with sensitivity 91%, specificity 51%
Diagnostic tools: Invasive cardiopulmonary exercise testing (right heart catheterization)
Nonhospitalized HFpEF: Confirmatory/ diagnostic
Criterion: Exercise measures of pulmonary capillary wedge pressure
Comments: Universal protocols are lacking. Can use single cut point of peak pulmonary capillary wedge pressure ≥25 mmHg37,42 vs change in pulmonary capillary wedge pressure indexed to change in flow (cardiac output)
Test characteristics: Diagnostic
HFpEF Diagnostic Algorithms:
Following two are the recent diagnostic algorithms proposed to guide HFpEF diagnosis:
1) As per the H2 FPEF score developed by Reddy et al, it incorporates 6 clinical and echocardiographic criteria. The obtained score helps in the discriminative diagnosis of HFpEF. There are emerging researches to evaluate the applicability of the H2FPEF score. The Alberta Heart Failure Etiology and Analysis Research Team sample suggest that an HFPEF score of >2 had a sensitivity of 89% to 90% to detect clinically adjudicated HFpEF and an H2 FPEF score <6 had a specificity of 82% to rule out HFpEF.
2) To add in HFpEF diagnosis, the European Society of Cardiology recently proposed a stepwise algorithm. This stepwise approach includes (A) pretest assessment based on HFpEF-predisposing and comorbid factors, (B) a score based on echocardiographic and natriuretic peptide levels separating patients into those with high scores (definite HFpEF), low (unlikely HFpEF), or intermediate scores (diagnostic uncertainty), with (C) further evaluation in those with diagnostic uncertainty, including functional testing with an exercise stress echocardiogram or invasive hemodynamic measurements at rest or with exercise. A high HFA-PEFF score (5–6 points) was found to diagnose HFpEF with high specificity (93%), on the other hand, a low HFA-PEFF score (0–1 point) ruled out HFpEF with a sensitivity of 99%. A large proportion of patients (36%) fell in the intermediate category.
Future Perspective:
As HFpEF is a clinical syndrome with a multitude of contributing risk factors, causes, and phenotypic manifestations there still exist a knowledge gap and future researches are required in the following focus area:
1) Animal models that recapitulate human HFpEF: for a better diagnostic approach, future research should support preclinical models to better understand disease pathogenesis, diverse disease manifestations, and natural history, in parallel with human studies.
2) Human studies that direct toward (a) careful phenotyping to untangle disease heterogeneity; (b) determinants of HFpEF disease progression and clinical trajectories; (c) the potential role of biomarkers (circulating, urinary, imaging) to distinguish HFpEF from noncardiac causes of dyspnea or comorbidities including novel methods such as exercise-induced pulmonary B lines; (d) the potential role of hemodynamic and activity monitors in the diagnosis of HFpEF or its pretest probability; (e) prospective validation of any proposed diagnostic algorithm opposing to gold standard invasive hemodynamic assessment in diverse populations, with focusing on diagnostic accuracy in patients who have HFpEF with only exercise-induced hemodynamic abnormalities.
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