Heart Failure (HF) is an inability to provide adequate cardiac output to the body at rest, or with exertion, or do so only in the setting of elevated filling pressure [1]. HF has recently been classified into three subtypes based on Left ventricular ejection fraction: HF with reduced left ventricular ejection fraction (HFrEF) with EF ≤40%; HF with preserved left ventricular ejection fraction (HFpEF) with EF >50%, elevated BNP levels, and presence of structural heart disease and LV diastolic dysfunction; and HF with mildly-reduced left ventricular ejection fraction (HFmrEF) with EF 41% - 49%, elevated BNP levels, and presence of structural heart disease and diastolic dysfunction [2]. HFpEF is a result of comorbidities the patient can have that will result in this disease; the comorbidities include advanced age, diabetes, arterial hypertension, and obesity. These results in systemic inflammation and multiorgan involvement that affect the lung, myocardium, skeletal muscle, and kidney are leading to diverse HFpEF phenotypes wfth variable involvement of pulmonary hypertension, myocardial remodeling, deficient skeletal muscle oxygen extraction during exercise, and renal Na+ retention [3]. During an Echocardiography examination, the patient may have any abnormalities such as left atrial dilatation, regional wall abnormality, diastolic dysfunction, left ventricular hypertrophy, or LVEF ≥50% [4]. The outcomes of HFpEF are a little better than HFrEF but the outcomes of hospitalized patients with HFpEF are similar to those with HFrEF [5] [6]. In some studies, the QOL may be bad and in some studies, the outcomes may be worse in HFpEF [7]. No guideline recommendations for specific HFpEF treatment but if a patient is congested, a diuretic should be used [8]. The ACC/AHA/HFSA guidelines (class IIb) now recommend the use of aldosterone receptor antagonists for consideration inappropriately for the selected patients to reduce hospitalization in patients with HFpEF if either elevated BNP or HF admission within 1 year or eGFR ≥30 mL/min/1.73m² or serum potassium <5.0 mEq/L and creatinine 2.5 mg/dL [8] [9]. The DAPA-HF, EMPEROR Reduced, EMPEROR Preserved and DELIVER Study both trials revealed benefits in clinical outcomes with SGLT2 inhibitors in patients with HFrEF within 1 month in the DAPA-HF trial, a reduction in the primary outcome of a composite of worsening HF or cardiovascular death with Dapagliflozin was rapidly apparent, with a sustained significant benefit at 28 days [10]. EMPEROR Preserved, Empagliflozin demonstrated a significant benefit compared with placebo at 18 days [11].

The patient was a 76-year-old female who had been a diabetic for 11 years until the month before coming to our attention. Following previous diabetes and hypertension, Metformin 1000 mg twice daily and Bendroflumethiazide 5 mg, and Amlodipine 10 mg once daily therapies were ongoing. In October 2021, the patient was admitted to the emergency room with dyspnea on moderate exertion, and a cough but she also had the same complaint one year ago prior and was treated at other hospitals. The patient was diagnosed with severe community-acquired pneumonia and was hospitalized for 5 days. After 2 weeks, the patient was hospitalized again, with the same complaints plus lower limb edema, and she reported having no improvement since the first admission. On general examination, she was dyspneic, SPO₂ 75% but kept on 4 L/min nasal cannula and SPO₂ increased to 96%, obesity grade 1 (BMI 35.3 kg/m²), BP 150/76 mmHg. On clinical examination she had lower limb pitting edema (grade 3), gallop rhythm and a heart rate of 125 bpm, irregular-irregular rhythm, and fine crackles on the anterior chest. The electrocardiogram (ECG) examination showed evidence of Left ventricular concentric hypertrophy and left ventricular overload and atrial fibrillation. Echocardiography studies revealed the left ventricular end-diastolic dimension (LVEDD) was 61 mm (indicating dilation), with moderate wall thickness and minimal left ventricular wall dysfunction, and left ventricular ejection fraction (LVEF) was preserved at 58%. Minimal secondary mitral and tricuspid regurgitation was found, and the left atrium was normal. The inferior vena cava (IVC) diameter was 20 mm collapsing. She had elevated filling pressure with diastolic dysfunction grade III. Her diastology studies revealed E/A 2.7, E/e/16.2, LAVI 46 ml/m², DT (MS) 96, TAPSE (mm) 16, and estimated pulmonary arterial pressure was 43 mmHg. Chest radiography the cardiac silhouette was slightly enlarged, prevalently on the left ventricle, with cephalization and alveolar infiltrates suggestive of cardiogenic pulmonary edema. The values of blood examinations were (e.g., Hb1Ac 8.4% (4.0% - 6.0%), FBG 12.1 mmol/L (3.5 mmol/L - 5.5 mmol/L), K + 4.62 mEq/L (3.5 mEq/L - 5.1 mEq/L), creatinine 124.6 μmol/L (60 - 120 μmol/L), eGFR (CKD-EPI) 58.5 ml/min/1.73m² (>90 ml/min/1.73m²), FBP normal, CRP 5 mg/L (0 - 5 mg/L), ALT 35.3 U/L (7 - 55 U/L), AST 19 U/L (8 - 33 U/L), LDL-C 7.2 mmol/L (<3.4 mmol/L, Triglyceride 2.32 mmol/L (<1.7 mmol/L), NT-proBNP not done, coronary angiography not done also. The diagnosis of new-onset HF with preserved LV ejection fraction, NYHA class II was confirmed (H2FPEF Score 9 points) and the patient was treated and discharged, after 1 week of hospitalization, with the following therapeutic plan (amiodarone was given for a short time rhythm control for Atrial fibrillation):

· Lisinopril 5 mg q.d, Amiodarone 800 mg b.d 2/52 then 400 mg b.d 2/52 Furosemide 40 mg po q.d, Metformin 1 gm b.d, Atorvastatin 40 mg q.d and Rivaroxaban 15 mg q.d

In November 2022, the patient presented for a follow-up visit in good condition, reporting some mild muscle pain after taking Atorvastatin. Dyspnea with moderate-intense exertion was present and easy fatigability and cough. The patient was clinically well compensated, with normal blood pressure and functional NYHA class II, normal FBG. ECG confirmed possible left ventricle hypertrophy and normal rhythm but the rate was not controlled; the therapeutic plan was updated as follows:

· Lisinopril 10 mg q.d, Metoprolol 50 mg q.d, Metformin 1 gm b.d, Atorvastatin 40 mg q.d, and Rivaroxaban 15 mg q.d

In December 2021, the patient presented at the programmed 1-month follow-up visit with improvement, albeit with asthenia and dyspnea with moderate exertion and moderate lower limb pitting edema. She reported frequent night coughs last two weeks and occasionally muscle pain. The patient was clinically compensated and maintained NYHA class II. Blood values were normal except for FBG. At ECG (sinus rhythm, heart rate 77 bpm), possible left ventricle hypertrophy with left ventricle overload was confirmed. Echocardiography examination showed an increase of concentric remodeling, LVEDD from 62.2 mm and LVEF was 55%, and regional wall moderate dysfunction, and her diastology revealed E/A 4.90, E/e/15, DT (ms) 102.00, LAVI (ml/m²) 86.00, TAPSE (mm) 22.00 and estimated pulmonary pressure (mmHg) 40.00, mild mitral regurgitation (EROA) 13.00 mm². These ECHO parameters qualified to be in stage 3 diastolic dysfunction. A dynamic ECG Holter examination was performed, showing an average heart rate of 89 bpm (min-max: 66 - 114 bpm), no ventricular couplet, no isolated ventricular ectopic (VE), and atrial fibrillation. The average arterial pressure was 140/80 mmHg with hypotensive peaks. Following these results, the diagnosis of HFpEF was still there and ameliorated by initiating Spironolactone and Dapagliflozin, by modifying the therapeutic plan as follows:

· Spironolactone 25 mg q.d;

· Dapagliflozin 10 mg q.d;

· Lisinopril 10 mg q.d;

· Metoprolol 50 mg q.d;

· Atorvastatin 40 mg q.d;

· Rivaroxaban 15 mg q.d.

A titration was planned for Lisinopril and spironolactone for two weeks. After the second step-up (from 20 mg to 40 mg) a lipothymia episode (as transient global cerebral hypoperfusion characterized by rapid onset, short duration, and complete spontaneous recovery) was reported, with arterial pressure of 70/51 mmHg; therefore the dosage of Lisinopril was reduced to 10 mg q.d, spironolactone was up titrated 50 mg q.d and potassium was monitored every after two weeks and all results were maintained at an average 4.32 mEq/L (min-max 3.72 - 4.9 mEq/L). There was no significant side effect reported after one-month follow-up but only mild recurrent urinary tract infection and some muscle pain due to statin.

In May 2022, the patient presented asymptomatic at the follow-up visit, with minimal dyspnea on intense exertion, and was ranked NYHA I. At the medical evaluation, the patient lost weight (10 kg), had an arterial pressure of 128/80 mmHg, and had good clinical compensation. HbA1c 6.2% and other Blood values were normal, LDL-C 3.8 mmol/L, Triglyceride 1.8 mmol/L. The ECG revealed sinus rhythm and heart rate at 86 bpm. At echocardiography, LVEF 60%, and normal morphological/functional parameters of both heart sides, diastolic dysfunction grade I. Treatment was modified by maintaining at Metoprolol 50 mg q.d. and reducing the dose of atorvastatin to 20 mg q.d, continuing with Rivaroxaban 15 mg for stroke prevention.

This patient presented with elevated filling pressure E/e/ and increased LAVI, increased LV remodeling, high BMI, hypertension, pulmonary hypertension, atrial fibrillation, and advanced age; all of these are reported to be diagnostic criteria for HFpEF in most of the studies [1] [2] [3]. Most HFpEF patients have comorbidities that induce systemic inflammation that affect the lung, myocardium, skeletal muscle, and kidney dysfunction leading to diverse HFpEF phenotypes with pulmonary hypertension, myocardial remodeling, and renal sodium retention [4]. This patient presented with elevated filling pressure and pulmonary hypertension as a result of the effect occurring in the lung, and myocardium in HFpEF [5]. Although this patient has good outcomes after being treated with MRA and SGLT2 inhibitor in general, the outcomes in HFpEF are a little better when not hospitalized than outcomes in HFrEF but the outcomes in hospitalization patients are similar for patients with HFpEF and patient for patients with HFrEF [6]. The overall burden of HFpEF is heavy and in some studies, QOL was impaired in HFpEF, and in some studies, QOL may be even worse in HFpEF [7]. This patient had many comorbidities that could lead to death and in most studies, the proportion of death due to Non-CV causes is higher in HFpEF than in HFrEF, and although both have functional capacity are significantly reduced, so we speculate the use of MRA (spironolactone) and SGLT2I (dapagliflozin) prevented death in this patient [8] [9] [10]. This patient presented with congestion and responded well to diuretics, which contributed to the good outcome of this patient, and in most of the studies, and they have recommended the use of diuretics in patients with HFpEF with congestion [9] [10]. All the comorbidities in this patient have managed accordingly, which could have contributed to the good outcome; the pressure was aggressively managed although a number of studies including I-PRESERVE, PEP-CHF, and TOPCAT showed that lowering BP did not necessarily improve HF outcomes [11] [12] [13]. Cross-sectionally more than 40% with HFpEF have Atrial Fibrillation (AF) and above 67% will have AF in the future; the presence of AF is associated with worsening outcomes [14]. In this patient, there was paroxysmal atrial fibrillation, the rhythm was controlled and stroke prevention which improved the outcome, although the impact of rhythm in HFpEF has not been adequately studied [14] [15]. The heart rate in this patient was maintained above 60 bpm because the patient with HFpEF frequently has chronotropic incompetence, where stroke volume or diastolic volume reserves may not be presented; high heart rate may be beneficial in this patient that resulted in a good outcome [6]. When compared with placebo both in EMPEROR Preserved and DELIVERY trials, the SGLT2i the Empagliflozin, and Dapagliflozin both reduced death and worsening heart failure in HFpEF [12]. This is the reason why our patient had a good treatment outcome. The decrease in HF severity, the patient’s clinical condition, and the dose reduction of other drugs for the polytherapy optimization, echocardiographic parameters, and the break of a long series of hospitalizations were achieved in only 6 months.

In conclusion, the real-life case series reported here demonstrates that Dapagliflozin and spironolactone therapy were beneficial for improved outcomes in hard-to-reach rural African population patients with HFpEF. The MRA and SGLT2 inhibitors given together to HFpEF patients in the African population play a crucial role in optimizing treatment and in reducing the need for surgical interventions or international referrals, preventing CV death and hospitalization events in HFpEF patients with different characteristics and comorbidities similar to other race in the real world. A big observational study is recommended in Africa to determine the benefit of SGL2 inhibitors (Dapagliflozin) and MRA (Spironolactone) in HFpEF patients.

We extend our sincere gratitude to all the members of the staff within the cardiology department and the Heart and Lung clinic at St. Francis Referral Hospital.

Since it was a case report, ethical clearance was waived, and the data were all fully anonymized before being accessed. The study followed the principles of the Declaration of Helsinki [WHO, 2001].

First authors: DMR contributed to conceptualization, data curation, formal analysis, writing original draft, investigation, visualization, and writing a review, supervision, BK investigation, writing a review, and editing, EM, writing review and editing, ABM visualization, review, and editing. All authors read and approved the final manuscript.

The authors declare no conflict of interest to declare.

Raphael, D.M., Mogella, A.H., Mtalemwa, E.E. and Kabuka, B. (2022) Dapagliflozin and Spironolactone Improved Clinical Symptoms and CV Outcomes in Patient with HF Preserved Ejection Fraction (HFpEF) in Hard-to-Reach Rural African Population: A Case Series. Case Reports in Clinical Medicine, 11, 465-473. https://doi.org/10.4236/crcm.2022.1111064