HEART FAILURE WITH PRESERVED EJECTION FRACTION In Search of New Therapies by President's Message

Written by M. Mohsen Ibrahim
Sunday, 17 July 2016

President's Message

In Search of New Therapies

Uncomplicated essential hypertension is usually described as asymptomatic disease. However, shortness of breath (SOB) is possibly the earliest and the commonest symptom. SOB is secondary to heart failure resulting from impaired LV diastolic function while EF is preserved. Hypertension is one of the most common causes of heart failure with preserved EF (HFpEF).

HFpEF is gaining increasing importance in the medical community. During the past three years the pathophysiology and diagnostic criteria were defined while there is a lot of ongoing research in pharmacologic therapy. The standard treatment of heart failure with reduced EF (HFrEF) with blockade of the RAAS (RASB) and BB was not helpful in patients with HFpEF. HFpEF was previously named diastolic heart failure to differentiate it from the more familial heart failure with reduced EF (HFrEF) or systolic heart failure.

Asymptomatic LV diastolic dysfunction is common in the general population, its prevalence is 28% in USA. HFpEF is generally a disease of the elderly more common in women with heterogeneity in its pathophysiology and is associated with multiple co-morbidities. Co-morbidities include overweight/ obesity, diabetes mellitus, COPD, salt sensitive hypertension, metabolic syndrome, renal dysfunction, depression, iron deficiency and sleep apnea.

Comorbidities in HFpEF result in a systemic proinflammatory state leading to coronary microvascular endothelial inflammation with subsequent reduction in nitric oxide (NO) bioavailability. NO produce its beneficial protective effect by activating its receptor in the cytoplasm which is the enzyme soluble quanylate cyclase (SGC). The substrate of SGC is the nucleotide guanosine triphosphate (GTP) which changes into the second messenger cyclic guanasine monophosphate (cGMP). cGMP activates ionic channels in sarcolemma and protein kinase (PKG) involved in many cellular activities. The lack of NO will decrease cGMP content with reduction in PKG activity. Decrease in PKG leads to hypertrophy, increased resting tension and interstitial fibrosis.


HFpEF is not a homogenous but is rather a hetergenous condition consisting of several pathophysiological subtypes including chronic volume overload, associated right heart failure and/or pulmonary hypertension and exercise-induced diastolic dysfunction.

Diagnosis of HFpEF

The following criteria should be satisfied before making a diagnosis of HFpEF.

1. Presence of symptoms and signs of heart failure such as SOB, orthopnea, exertional fatigue and cough, basal pulmonary rales, edema of lower limbs, raised JVP and gallop sound over the heart.

2. Left ventricular ejection fraction is more than 50%. Patients with LVEF between 40 and 49% have been recently classified as a separate group of mid-range EF (HFmrEF). Patients in this group- grey zone have a different prognosis and respond differently to therapy.

3. Evidence of cardiac myocyte injury: elevated cardiac troponin levels, BNP > 35 pg/ml or NT-proBNP > 125 pg/ml.

4. Manifestations of LV diastolic dysfunction with absence of LV dilatation. Increase in left atrial (LA) volume (LA volume index >34 ml/m2), impaired LA function, increase in LV mass index > 115 (gm/m2) in males and > 95 (gm/m2) in females. Tissue Doppler echocardiography – mitral annulus velocity (ẻ ) and measurement of mitral inflow velocities (E and A waves) can diagnose impaired LV diastolic function. An increased E/ ẻ ratio ≥ 13 and a reduced ẻ velocity with tissue Doppler sample volume at mitral annulus septal and lateral walls (average ẻ) < 9 cm/sec.

Treatment of HFpEF

Treatment should be individualized since the pathophysiology is heterogenous and a uniform approach does not work. There is lack of benefit of traditional heart failure therapies.

A. Correction of co-morbidities namely control of hypertension, diabetes mellitus, obesity, metabolic syndrome and treatment of anemia, CKD and sleep apnea.

B. Symptomatic treatment such as diuretics for pulmonary congestion and edema, beta adrenergic blockers for tachycardia and antiarrhythmic drugs when needed to control atrial fibrillation- which is common in HFpEF and to treat other arrhythmias.


C. Exercise training may be helpful in improving patients physical functioning and diastolic function.

New Pharmacologic Agents

Many of the new drugs are under investigation. Success of therapy of HFpEF in clinical trials was defined by (a) amelioration of symptoms, improvement in 6 min walking distance and NYHA functional class (b) regression of elevated BNP and NT-proBNP, (c) decrease in LA volume index and improvement in tissue Doppler E/'e ratio (d) decrease in rate of heart failure hospitalization and, improvement in mortality rate compared to placebo.

1. Nebivelol: this vasodilator beta adrenergic blockers was tested in two trials with different results: (a) SENIOR trial, in patients older than 70 years, there was a reduction in all cause mortality or cardiovascular hospitalization. Patients studied had wide range of EF, there was no definite conclusion in patients with EF ≥ 50%. (b) ELANDD trial: no effect on symptoms or exercise capacity, but there was a direct correlation between the decrease in peak heart rate and decrease in Q2 consumption.

2. Aldactone: tested in the following trials: (a) ALDO-DHF: effect of spironolactone on diastolic function and exercise capacity. The primary endpoint being improved diastolic function and exercise capacity. Some measures of diastolic function improved with reduction in LV mass and NT-proBNP, though maximal exercise capacity, clinical symptoms and quality of life were not changed. (b) TOPCAT trial: compares spironolactone vs placebo in a large multinational study of HFpEF. Spironolactone failed to demonstrate a significant improvement in the primary outcomes (CV mortality, aborted cardiac arrest). There was a significant 17% risk reduction in heart failure hospitalization. A major interacting factor was where patients were recruited and the criteria used for their entry.

3. Sildenafil: a phosphodiesterone-5 inhibitor. It improved LV diastolic function and reduced pulmonary pressure in patients with HFpEF and pulmonary hypertension. There were no effects on exercise capacity, clinical status or diastolic function

4. LCZ 696: a combination of angiotensin receptor blocker and neprilysin inhibitor in a complex molecule. An increase in intracellular cGMP through blockade of neprilysin improves relaxation and hypertrophy. Two studies PARAMOUNT and


PARAGON-HF showed some promising results. In PARAMOUNT, there was a reduction in left atrial size and NT-proBNP. In PARAGON-HF, there was an improvement in NYHN class.

5. Vericiguat: an oral soluble guanylate cyclase stimulator independent of NO. In SOCRATES- PRESERVED study it showed no benefit.

6. Isosorbid mononitrate showed no benefit on walking distance.

7. Ivabradine- a sino-atrial. If current blocker improved peak O2 consumption, exercise capacity and decreased exercises induced E/'e ratio. There were no adverse events in 7 day trial.

8. Other agents in the experimental stages are: 1. Advanced glycation end products cross-link breakers e.g. alagebrium chloride, 2. Calcium cycling modulators, 3. Micro-RNAs.


HFpEF is an established clinical entity, its heterogenous pathophysiology has been clarified and the diagnostic criteria are well-defined. Control of hypertension which is possibly the most important cause of HEpEF is the best available therapeutic approach. Results of pharmacologic therapy beyond treatment of symptoms are not satisfactory. Promising agents include mineraloreceptor antagonists, neprilysin inhibitors and ivabradine. Properly designed large-scale and long-term clinical trials are needed.

President of the Egyptian Hypertension Society

M. Mohsen Ibrahim, MD

Prof. of Cardiology- Cairo University

Last Updated Tuesday, 02 August 2016