A 69-year-old woman was referred to by her local medical practitioner with worsening exertional dyspnea (NYHA III). She found difficulty mobilizing to her mailbox (120 m on a flat surface), as well as doing light housework and dressing. Her background history is relevant for long-standing hypertension (HTN), dyslipidemia, obesity, stage 3 renal impairment, and paroxysmal atrial fibrillation. Her medication profile is listed in Table 6-1. Physical examination revealed a well-looking woman with a blood pressure of 155/80 mm Hg on both arms, a heart rate of 72 in a regular rhythm, and respiratory rate of 20. Anthropomorphic measurements were a height of 162 cm and weight of 84 kg, with a calculated body mass index (BMI) of 32 kg/m². Precordial examination revealed the apex beat to be nondisplaced, with no palpable heaves or thrills. No murmurs were auscultated. The jugular venous pressure was estimated at 2 cm, and there was trace pedal edema. The remainder of the physical examination was normal. The electrocardiogram (ECG) confirmed sinus rhythm, with features of left ventricular hypertrophy (LVH) and left axis deviation. Chest radiography demonstrated clear lung fields and borderline cardiomegaly.

Laboratory profile demonstrated a mild anemia, with hemoglobin of 10.5 g/dL and a mean red cell volume of 92. Renal function was impaired with a urea of 22.4 mg/dL and creatinine of 1.02 mg/dL, leading to an estimated glomerular filtration rate (GFR) of 57.2 mL/min/1.73 m² via the MDRD equation, or 57.5 mL/min using the Cockcroft-Gault equation adjusted for the overweight patient. A resting N-terminal pro-brain natriuretic peptide (NT-proBNP) was mildly elevated at 385 pg/mL.

A transthoracic echocardiogram demonstrated moderate global concentric hypertrophy with normal systolic function, with an ejection fraction calculated via Simpson’s biplane method of 68%. The left atrium was mildly enlarged, with satisfactory valvular function and E/e’ ratio of 13. A recently performed stress echocardiogram was negative for inducible ischemia. Respiratory function tests revealed normal ventilatory function with no significant bronchodilator response. Exercise right heart catheterization was performed (Table 6-2), with evidence of a normal pulmonary capillary wedge pressure (PCWP) at rest, and a marked rise with exercise.

In summary, this 69-year-old woman presents with worsening NYHA III exertional dyspnea on a background of long-standing HTN.

There are a wide variety of differential diagnoses for exertional dyspnea, as highlighted in Figure 6-1. As the patient ages, the risk of both cardiac and noncardiac comorbidities contributing to dyspnea increases, and it is important to recognize that patients may have more than 1 cause for their dyspnea. Even for patients satisfying the diagnostic criteria of heart failure with preserved ejection fraction (HFpEF), multiple noncardiac contributions are often present.^1,2 In the present case, respiratory function tests and chest radiography were within normal limits, excluding major parenchymal or airway disease; however, computed tomography could be considered if clinical suspicion of respiratory disease was high. The normocytic anemia alone would not be expected to cause such a marked reduction in exercise capacity.

The cardiovascular differential diagnoses in the patient include ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy, and periods of paroxysmal atrial fibrillation with poor rate control or bradycardia.

Ischemic heart disease is common in patients with HFpEF, with over two-thirds of patients having angiographically proven coronary artery disease.^3,4 This patient did not complain of angina with exertion, although dyspnea can be taken as an angina equivalent, and importantly her stress echocardiogram was negative for ischemia. On further questioning, a coronary angiogram had been performed 2 years ago with no significant luminal pathology, making ischemia unlikely.

Restrictive cardiomyopathy can be a difficult diagnosis to make, often a diagnosis of exclusion, in patients with normal systolic function and severe diastolic dysfunction with elevated filling pressures, often with marked biatrial dilatation. The condition can either be familial or acquired, with the latter being caused by conditions such as amyloidosis, endomyocardial fibrosis, radiation, and chemotherapeutic agents. The patient described above had no clinical, laboratory, echocardiographic, or radiographic features consistent with any common etiology, and no relevant family history of heart failure (HF).

Despite the moderate concentric hypertrophy noted on this patient’s transthoracic echocardiogram, the pathological loading condition due to the history of long-standing HTN is the most likely etiology rather than a genetic hypertrophic cardiomyopathy. Cardiac magnetic resonance imaging can be useful to assess the scar pattern between these 2 etiologies, along with a relevant family history.

Poor control of the ventricular rate in atrial fibrillation can also lead to marked dyspnea, and underlying structural abnormalities such as atrial dilatation may predispose to its development. In this patient, the baseline ECG revealed sinus rhythm; however, ambulatory monitoring could be considered to exclude a paroxysmal arrhythmia.

In this case, in a hypertensive obese woman with no other significant contributing pathology, with exercise-induced dyspnea and marked pulmonary HTN, HFpEF is the most likely cause.

The cardinal symptom of HFpEF is exercise intolerance, together with classical symptoms and signs of HF as elucidated by history and physical examination. The Framingham criteria for HF, outlined in Figure 6-2, are the most widely used for the clinical diagnosis of HF across studies both for reduced and preserved ejection fraction.

Using phenomapping, a technique involving unsupervised machine learning to understand the intrinsic structure of data, investigators have recently identified 3 primary clinical phenotypes of HFpEF.⁵ Each of these groups demonstrates related comorbidities, pathophysiologies, and importantly, different clinical trajectories. The first group were younger patients, with lower levels of natriuretic peptides and better outcomes. The second had more significant comorbidities, including obesity, diabetes, and obstructive sleep apnea. These patients had the worst parameters of left ventricular (LV) relaxation. The third group, with the worst prognosis, were older, had poor renal function, and the most severe electrical and echocardiographic features of myocardial remodelling, including significant right ventricular (RV) dysfunction.

Although there is no single test for the diagnosis of HFpEF, the combination of clinical features of HF together with evidence for elevated filling pressures (in the setting of no other contributory pathology) must be demonstrated. Features of abnormal relaxation and elevated filling pressures can be suggested with abnormal echocardiographic parameters, such as an elevated E/e’, or elevated natriuretic peptides; however, invasive hemodynamic measurements are considered definite evidence of HFpEF.⁶ Considering the marked contribution of exercise to the developing symptomatology of this patient group, the addition of exercise to the evaluation is critical, particularly when the resting parameters fall within an indeterminate zone (Figure 6-3).⁷ The current ESC guidelines recommend a combination of clinical features, exclusion of a normal BNP, and echocardiographic features of functional impairment and structural remodelling.

MECHANISMS OF DISEASE

The reasons for exercise intolerance in HFpEF are multifactorial, and represent an interplay between impaired diastolic function together with peripheral mechanisms and comorbid conditions.

The physiologic parameters involved are highlighted by Houstis and Lewis via the Fick equation (Figure 6-4) demonstrating the variables involved in peak VO₂, a quantitative measure of exercise capacity. Patients with HFpEF demonstrate abnormalities in chronotropic competence and often have smaller stroke volumes; however, the VO₂ may also be limited by variables such as musculoskeletal discomfort or inadequate effort.⁸

Key mechanisms under investigation in HFpEF patients are outlined in Table 6-3.

To date, clinical trials in HFpEF (Table 6-4) have largely been disappointing reflecting variability in trial design,^9–13 heterogeneous population,⁵ relatively limited study duration (in comparison to the likely duration required for the development of HFpEF), and that the disease mechanisms are not yet fully understood.