Heart Failure With Preserved Ejection Fraction: Relevance of a Dedicated Dyspnoea Clinic

Jan Verwerft; Lucie Soens; Jokke Wynants; Marc Meysman; Siddharth Jogani; Danielle Plein; Sarah Stroobants; Lieven Herbots; Frederik H. Verbrugge

Disclosures

Eur Heart J. 2023;44(17):1544-1556.

Abstract and Introduction

Abstract

Background and Aims: Heart failure with preserved ejection fraction (HFpEF) is a syndrome with a heterogeneous presentation. This study provides an in-;depth description of haemodynamic and metabolic alterations revealed by systematic assessment through cardiopulmonary exercise testing combined with exercise echocardiography (CPETecho) within a dedicated dyspnoea clinic.

Methods and Results: Consecutive patients (n = 297), referred to a dedicated dyspnoea clinic using a standardized workup including CPETecho, with HFpEF diagnosed through a H₂FPEF score ≥6 or HFA-PEFF score ≥5, were evaluated. A median of four haemodynamic/metabolic alterations was uncovered per patient: impaired stroke volume reserve (73%), impaired chronotropic reserve (72%), exercise pulmonary hypertension (65%), and impaired diastolic reserve (64%) were the most frequent cardiac alterations. Impaired peripheral oxygen extraction and a ventilatory limitation were present in 40% and 39%, respectively. In 267 patients (90%), 575 further diagnostic examinations were recommended (median of two tests per patient). Cardiac magnetic resonance imaging, coronary or amyloidosis workup, ventilation–perfusion scanning, and pulmonology referral were each recommended in approximately one out of three patients. In 293 patients (99%), 929 cardiovascular drug optimizations were performed (median of 3 modifications per patient). In 110 patients (37%), 132 cardiovascular interventions were performed, with ablation as the most frequent procedure.

Conclusion: Holistic workup of HFpEF patients within a multidisciplinary, dedicated dyspnoea clinic, including systematic implementation of CPETecho reveals various haemodynamic/metabolic alterations, leading to further diagnostic testing and potential treatment changes in the majority of cases.

Structured Graphical Abstract

Key Question: Which haemodynamic and metabolic alterations are revealed when systematic assessment including cardiopulmonary exercise testing with echocardiography (CPETecho) is performed in patients with heart failure and preserved ejection fraction (HFpEF) within a multidisciplinary, dedicated dyspnoea clinic?

Key Finding: On average, four haemodynamic/metabolic alterations were present, with a median of two further diagnostic tests recommended. Medication prescriptions were changed in virtually all patients (median of three changes per patient), while cardiovascular interventions were performed in one third.

Take Home Message: Holistic work-up of HFpEF patients within a multidisciplinary, dedicated dyspnoea clinic, including systematic implementation of CPETecho reveals various hemodynamic and metabolic alterations, leading to further diagnostic testing and potential treatment changes in the majority of cases.

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Set-up of the different components of a dedicated dyspnoea clinic for heart failure with preserved ejection fraction. For patients with a confirmed diagnosis according to either the HFA-PEFF score, the H₂FPEF score, or both, downstream implications of testing are presented. CT, computed tomography; ECG, electrocardiogram.

Introduction

Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of all heart failure cases, with a growing incidence and prevalence because of an aging population and increasing frequency of risk factors such as obesity, diabetes, hypertension, and kidney disease.^[1] Despite the significant burden of HFpEF in terms of morbidity, mortality, and associated healthcare costs, current guidelines make few recommendations.^[2,3] These basically comprise the use of diuretics to alleviate signs and symptoms of congestion and the treatment of relevant comorbid conditions. Only recently, the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) became the first trial to show a significant reduction in the combined risk of cardiovascular mortality and heart failure hospitalizations with a dedicated pharmacological treatment for HFpEF.^[4] The most recent American guidelines acknowledge these results with a class IIa recommendation (level of evidence B) for sodium–glucose co-transporter 2 inhibitors (SGLT2i) in HFpEF.^[3] This apparent lack of therapeutic consequences for HFpEF compared with the wealth of possible treatments for patients with a reduced ejection fraction has contributed to a sense of indifference to making a correct and early diagnosis. The emergence of diagnostic HFpEF scores has definitely contributed to create awareness and allows a consistent diagnosis supported by a clear association with clinical outcomes.^[5–8]

In this study, patients meeting diagnostic criteria for HFpEF according to the H₂FPEF or HFA-PEFF score underwent a standardized workup with clinical evaluation, lab testing, spirometry, transthoracic echocardiography at rest, and cardiopulmonary exercise testing combined with exercise echocardiography (CPETecho) within a multidisciplinary, dedicated dyspnoea clinic. The aim was to describe haemodynamic and metabolic alterations revealed by this approach, with their downstream impact on further diagnostic testing and treatment changes.

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Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Haemodynamic and metabolic alterations associated with exercise intolerance or exertional dyspnoea
Haemodynamic/metabolic alteration	Exercise echocardiography findings	CPETecho findings	References
Cardiac limitations
Impaired CO reserve	[140×peak CO (L/min)]/predicted peak VO₂ (mL/min) < 0.8	CO/VO₂ slope <5 OR VT₁ < 40% of predicted VO₂ with exercise oscillatory ventilation	^14,15,21
Impaired chronotropic reserve	(peak HR–rest HR)/[(220–age)–rest HR] < 0.8 or <0.62 (negative chronotropic medication)		¹³
Impaired SV reserve	Peak SV <42 mL/m² ΔSV <20%	Lower than predicted O₂ pulse O₂ pulse plateau	^11,12,16
Impaired diastolic reserve	Exercise averaged E/e'>15 Exercise septal E/e'>14		^6,16,19
Pulmonary hypertension	mPAP/CO slope >3 mmHg/L/min with mPAP >30 mmHg	V _E/VCO₂ slope >36, suggestive of pulmonary vascular disease	^17,18
Ischaemia	Regional wall motion abnormalities Repolarization abnormalities	VO₂ plateau O₂ pulse decrease	¹⁴
LVOT obstruction	Systolic anterior mitral valve movement LVOT gradient >50 mmHg Systolic blood pressure rise <20 mmHg	VO₂ plateau O₂ pulse decrease	^14,16
Dynamic mitral valve regurgitation	ERO increase >10–13 mm² during exercise	VO₂ plateau O₂ pulse decrease	¹⁶
Impaired peripheral oxygen extraction		CO/VO₂ slope >7 Peak AVO₂diff/(Hb) < 0.8 V _E/VO₂ > 50	^14,20
Ventilatory limitation		V _E/MVV >0.7 with MVV = 40×FEV₁ VT₁ > 40% of predicted VO₂ with peak VO₂ < 0.85 and RER >1.10	^14,15
Ventilation–perfusion mismatch		V _E/VCO₂ slope >36 PETCO₂ < 33 mmHg at rest and <3 mmHg increase with exercise peak V _D/V _T >0.3	^14,17
Submaximal effort		RER <1.05 with V _E/VCO₂ < 30 and VO₂/Watts >8	¹⁴
Anxiety/hyperventilation		RER at rest >1.10 Rest RER >1.05 and PETCO₂ < 28 mmHg High V _E/VCO₂ slope with no other limitation	²²

AVO₂diff, arteriovenous oxygen difference; CO, cardiac output; CPETecho, cardiopulmonary exercise test with concomitant echocardiography; ERO, effective regurgitant orifice; FEV₁, maximal expiration volume in 1 s; Hb, haemoglobin; HR, heart rate; LVOT, left ventricular outflow tract; mPAP, mean pulmonary arterial pressure; MVV, maximal voluntary ventilation; PETCO₂, end-tidal CO₂ pressure; RER, respiratory exchange ratio; SV, stroke volume; V _D/V _T, dead space over tidal volume; VT₁, first ventilatory threshold; V _E, peak ventilation; VCO₂, CO₂ production; VO₂, oxygen consumption.

Table 2. Diagnostic and therapeutic treatment recommendations in the dyspnoea clinic
Recommendations for further diagnostic examinations
Exclude coronary artery disease	• Regional wall motion abnormalities
	• Repolarization abnormalities
	• Positive diastolic stress test
CMR	• Suspected cardiomyopathy
	• High burden of ventricular ectopy
	• Unexplained conduction disorder
Bone scintigraphy + serum light chains + serum/urine immune fixation	• (Bilateral) carpal tunnel syndrome, spinal stenosis, biceps
	• Tendon rupture, polyneuropathy
	• Biventricular hypertrophy, especially when pericardial effusion and/or apical sparing pattern of global longitudinal strain are present
	• Low QRS voltage over left ventricular mass ratio
Ventilation–perfusion nuclear scan	(Exercise) pulmonary hypertension with disproportionate ventilation–perfusion mismatch (V _E/VCO₂ slope >36 or PETCO₂ < 33 mmHg at rest or <3 mmHg increase with exercise)
High-resolution chest computed tomography	Restrictive lung function with impaired oxygen diffusion capacity with desaturation >5% during exercise
Pulmonary referral	• Ventilatory limitation of exercise (cfr. definition in Table 1)
Pulmonary referral	• Peak V _D/V _T >0.3
Optimization of cardiovascular drugs
SGLT2 inhibitor	• Glycated haemoglobin level >7%
	• Estimated glomerular filtration rate 25–60 mL/min/1.73 m²
	• NT-;proBNP >300 ng/L in sinus rhythm or >900 ng/L in atrial fibrillation
MRA	N-;proBNP >360 ng/L²³
Increase loop diuretic	• Any clinical sign of volume overload (oedema, pleural effusion, ascites)
	• Elevated cardiac filling pressures at rest
	• Dynamic secondary atrioventricular valve regurgitation with exercise pulmonary hypertension
Stop or reduce negative chronotropic drug	Impaired chronotropic reserve [(peak HR–rest HR)/([220–age]–rest HR) < 0.62]
Improve hypertension control	• Systolic/diastolic blood pressure >130/80 mmHg at rest
Improve hypertension control	• Exercise systolic blood pressure rise ≥20 mmHg per 3.5 mL/kg/min rise in VO₂ ¹⁴
Improve dyslipidaemia control	• Low-;density lipoprotein cholesterol >115 mg/dL in primary prevention or >55 mg/dL in secondary prevention
Improve dyslipidaemia control	• Triglycerides >300 mg/dL
Anticoagulation	Atrial fibrillation or suspected thrombo-embolic pulmonary hypertension
Cardiovascular interventions
Rhythm control	• Atrial flutter ablation when present
	• Pulmonary vein isolation or rhythm control medication for paroxysmal atrial fibrillation
	• Atrial fibrillation ablation for persistent atrial fibrillation without extensive atrial remodelling
Ventricular ectopy ablation	Significant ventricular ectopy thought to contribute to exercise limitation
Pacing strategy	• Improve rate response in patients with a pacemaker and impaired chronotropic reserve
	• AAI pacemaker implantation when significantly impaired exercise capacity (peak VO₂ < 65% of predicted value) due to significantly impaired chronotropic reserve [(peak HR–rest HR)/([220–age]–rest HR) < 0.62] and CO reserve [(140×peak CO)/predicted peak VO₂ < 0.65]
	• Cardiac resynchronization therapy when emerging left bundle branch block and systolic function decline during exercise
	• Left bundle area pacing for first degree AV block and/or left bundle branch block with marked E–A fusion at rest or immediately during exercise when proven exercise pulmonary hypertension
	• Atrioventricular node ablation with left bundle area pacing for atrial fibrillation with CO limitation of exercise [(140×peak CO)/predicted peak VO₂ < 0.8] or uncontrolled HR
Valve intervention	Severe secondary mitral and/or tricuspid valve regurgitation at rest or during exercise after other therapeutic optimizations
Treatment of comorbid conditions
Intravenous iron therapy	• Transferrin saturation <20% and ferritin <300 μg/L
Intravenous iron therapy	• Ferritin <100 μg/L
Diabetes treatment	• Optimize diabetic control if glycated haemoglobin level ≥7%
Diabetes treatment	• Treat pre-;diabetes (glycated haemoglobin level ≥5.7%) with metformin if no contraindication²⁴
Obesity treatment	• Glucagon-;like peptide-;1 analogue when body mass index >30 kg/m²
Obesity treatment	• Consider bariatric surgery
Smoking cessation program	Any current smoker
Rehabilitation and exercise training
Consider in every patient, particularly when signs of impaired peripheral oxygen extraction (cfr. definition in Table 1)

CMR, cardiac magnetic resonance; CO, cardiac output; HR, heart rate; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal of pro-hormone B-type natriuretic peptide; PETCO₂, end-tidal CO₂ pressure; SGLT2, sodium-glucose linked transporter-2; V _D/V _T, dead space over tidal volume; V _E, peak ventilation; VCO₂, CO₂ production; VO₂, oxygen consumption.

Table 3. Baseline characteristics of the study population ( n = 297)
Demographics
Age (years)	73 ± 9
Women, n (%)	189 (64)
Vitals and anthropometrics
Systolic blood pressure (mmHg)	146 ± 23
Diastolic blood pressure (mmHg)	79 ± 14
Heart rate at rest (bpm)	69 ± 13
Height (cm)	165 ± 9
Weight (kg)	76 ± 15
Body mass index (kg/m²)	27.9 ± 5.3
Ideal body weight (kg)^a	61 ± 11
Excess body weight (kg)^a	15 ± 15
Fat-free mass (kg)^b	49 ± 8
Fat mass (kg)^b	27 ± 11
Cardiovascular risk factors
History of hypertension, n (%)	216 (73)
Diabetes mellitus, n (%)	47 (16)
Glycated haemoglobin (n = 221; %)	5.9 ± 0.7
Low-density lipoprotein cholesterol (n = 280; mg/dL)	89 ± 36
Obesity defined as a body mass index ≥30 kg/m², n (%)	94 (32)
Current smoker, n (%)	29 (10)
Cardiovascular history
Any history of atrial fibrillation, n (%)	148 (50)
Ischaemic heart disease, n (%)	80 (27)
Peripheral artery or cerebrovascular disease, n (%)	26 (9)
History of valve intervention, n (%)	51 (17)
Cardiac pacemaker, n (%)	35 (12)
NT-proBNP (n = 204; ng/L)	400 (230–741)
Comorbid conditions
Estimated glomerular filtration rate (n = 292; mL/min/1.73 m²)^c	65 ± 21
Renal replacement therapy, n (%)	2 (0.7)
Haemoglobin (n = 293; g/dL)	13.2 ± 1.6
Anaemia according to World Health Organization definition, n (%)	76 (26)
Ferritin (n = 263; ng/mL)	140 (62–220)
Transferrin saturation (n = 219; %)	25 ± 14
Iron deficiency (n = 263), n (%)	118 (45)
Medication use
Sodium–glucose co-transporter-2 inhibitor, n (%)	2 (0.7)
Mineralocorticoid receptor antagonist, n (%)	86 (29)
Renin–angiotensin blocker, n (%)	152 (51)
Beta-blocker, n (%)	197 (66)
Loop diuretics, n (%)	78 (26)
Thiazide diuretics, n (%)	64 (22)
Statin, n (%)	166 (56)
Other lipid-lowering drugs, n (%)	26 (9)
Metformin, n (%)	23 (8)
Glucagon-;like peptide-;1 agonist, n (%)	1 (0.3)
Insulins, n (%)	12 (4)
Other diabetic drugs, n (%)	10 (3)
Oral anticoagulants, n (%)	126 (42)
Antiplatelet drugs, n (%)	110 (37)
Amiodarone, n (%)	48 (16)
Class I antiarrhythmic drugs, n (%)	21 (7)
Verapamil/diltiazem, n (%)	6 (2)
Dihydropyridine calcium channel blockers	69 (23)
Digoxin, n (%)	3 (1)

Numbers indicate mean ± standard deviation in case of a normal distribution or median (interquartile range) otherwise for continuous variables and absolute numbers (percentage of the population) for discrete variables NT-proBNP, N-terminal of pro-hormone B-type natriuretic peptide.
^aIdeal body weight (kg) was calculated as 48 + 1.1 [height (cm)–150] in men or 45 + 0.9 [height (cm)–150] in women. Excess body weight was calculated as actual body weight minus ideal body weight.
^bFat-free mass was calculated as 5.1 [height (m)]^1.14 [body weight (kg)]^0.41 in men or 5.34 [height (m)]^1.47 [body weight (kg)]^0.33 in women. Fat mass was calculated as actual body weight minus fat-free mass.
^cCalculated according to the Chronic Kidney Disease Epidemiology Collaboration formula.

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Heart Failure With Preserved Ejection Fraction: Relevance of a Dedicated Dyspnoea Clinic

Abstract and Introduction

Abstract

Introduction

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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