Introduction

Heart Failure is a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/ or elevated intracardiac pressures at rest or during stress[1]. It is a progressive disorder in which signs and symptoms of heart failure (HF) are apparent and it is progressive despite normal ejection fraction.

Definition of HFpEF is symptom and sign (signs may not be present in the early stages of HFpEF and in patients treated with diuretics) of heart failure with left ventricular ejection fraction (LVEF)>=50% classified as “heart failure with preserved ejection fraction” (HFpEF)1 and elevated level of natiuretics polypeptide i.e, BNP 35 pg/ml and/or NT-proBNP 125 pg/mL and atleast one additional criteria:

1. Relevant structural heart disease: Left ventricle hypertrophy and left atrial enlargement (LVH and or LAE) as a sign of increase filling pressure.
2. Diastolic dysfunction on transthoracic imaging.

A number of epidemiological studies conducted since the millennium have shown that around 50 % of heart failure patients have a normal ejection fraction [2,3]. The silent and progressive nature contributes to increase risk of death even with normal ejection fraction. HF symptoms reduce the quality of life, leading to repeated hospital admissions for symptom management although the survival after diagnosis has improved with time, mortality is high 50% over 5 years. HFpEF patients has multiple co- morbidities and prognosis is as ominous as systolic HF.

More than half of HFpEF patients with an LVEF >50% has reduced GLS. Strain rate should provide us opportunity to explore more about HFpEF and its events, so its relationship is explored more. GLS has been found to be an independent predictor of mortality in patients of heart failure not in atrial fibrillation. It was found to be superior to all other parameters of echocardiograhy[4]. Some small studies by Hasselberg et al show GLS has a good correlation with exercise capacity in heart failure patients with both reduced and preserved LV function[5]

1.Factors predisposing HFpEF

Risk Factors and Comorbidities (Fig: 1)

1. Aging
2. Female
3. Hypertension
4. Obesity
5. Diabetes Mellitus
6. Chronic Obstructive Pulmonary Disease
7. Chronic Renal Disease
8. Pulmonary hypertension
9. Anaemia
10. Sleep apnoea syndrome
11. Atrial Fibrillation
12. Cardiomyopathy hypertrophic/restrictive/ infiltrative,
13. Coronary Artery Disease
14. Constrictive Pericarditis
15. Valvular heart disease                                                                                                                       

Pathophysiology Diastolic properties

Diastole allows ventricle to fill adequately in rest and exercise without abnormal increase in LA pressure. Phases are isovolumic pressure decline and filling. Filling is divided into early rapid filling, diastasis and atrial systole. Early rapid is 70-80% of LV filling, this diminishes with age and various disease states. Early diastole is driven by myocardial relaxation, LV elastic recoil, LV diastolic stiffness, LA pressure, ventricular interaction, pericardial constraint, pulmonary vein, mitral valve orifice area.

Diastasis is when LA-LV pressure are equal it is <5% of diastolic filling, Atrial systole contributes 15- 25% of diastole without raising mean LA pressure. In HFpEF relaxation and recoil are abnormal at rest and doesn’t enhance during exercise, so filling is maintained by increase LA pressure. During systole potential energy is stored in elastic elements of cardiomyocytes and extracellular matrix. During relaxation potential energy is released as elastic element recoil and return to their original length and orientation, this causes LV pressure to fall rapidly during isovolumic relaxation[15]. This fall in pressure produces diastolic gradient in LA-LV apex, which accelerates blood flow from LA-LV apex diastolic intraventricular pressure gradient pulls blood rapidly, so it is a measure of LV suction. This process gets affected in HFpEF. Extracellular matrix (ECM) consists of fibrillar protein such as collagen types 1 and III, elastin, proteoglycan, basement membrane protein collagen IV, laminin, fibronectin, matrix metalloprotein (MMPs), tissue inhibitors of metalloproteins (TIMP), transforming growth factor b (TGFB), cytokines. This fibrillar collagen is increased in HFpEF75 (Fig: 6).

Aging:

The prevalence of HFpEF increases with age in both sexes[152], it is due to increase comorbidity. LV Diastolic function directly influences some of the pathophysiological mechanisms behind HFpEF. Aging is also linked with an increase in arterial stiffness and a reduction in endothelium-dependent vasodilation[7, 8, 150]. Arterial LV systolic and LV diastolic stiffness increases with aging, there is increase in cardiomyocytes size, apoptosis, decrease in cardiomyocytes number, alter growth factor regulation, focal collagen deposition, blunted beta adrenergic responsiveness, increased transforming growth factor ß signaling reduced expression of elastases leading to interstitial fibrosis, mitochondria oxidative stress, genomic instability, excitation contraction coupling, altered calcium handling protein leading to altered calcium handling[154], LV stiffness which increases progressively with age, and this increase is more prominent in women[153].

Female:

Both epidemiological studies and randomized trials consistently showed that most HFpEF patients are women (50–84%)[155]. This sex bias can partly be attributed to the age distribution of the population at risk as women have a higher life expectancy. LV stiffness increases progressively with age, and this increase is more prominent in women.

Obesity, arterial hypertension, and diabetes mellitus are common in HFpEF patients and often coexist[156]. Arterial hypertension increases cardiac structural remodelling and functional changes which increases afterload on the LV, further increasing pro-hypertrophic signalingn in cardiomyocytes. It directly impaires ventricular-vascular coupling[15] and leads to arterial stiffness[161], increases LV systolic and LV diastolic stiffness[17], impaires relaxation. Proinflammatory and profibrotic signal leads to monocyte-macrophage mediated changes in ECM collagen homeostasis and myofilament phosphorylation of cardomyocytes causes increase myocardial fibrosis and titin phosphorylation which increases myocardial stiffness.

Diabetes mellitus:

Diabetes mellitus can contribute to the development of HFpEF through several pathways. It is associated with a systemic inflammatory state and increased oxidative stress, causing microvascular dysfunction and LV hypertrophy[158]. Diabetes accelerates atherosclerosis, leading to myocardial ischemia, progressively impairing renal function, contributing to volume overload. Diabetic heart has myocyte hypertrophy, intramyocardial microangiopathy and ECM fibrosis causing impaired endothelium function, endothelium dependant and independent vasodilatation, impaired LV relaxation, impaired passive LV diastolic stiffness and contractile dysfunction. Microalbuminuria is highly prevalent in HFpEF, being associated with LV remodeling, and is a prognostic marker for further disease development[181, 194, 195, 199, 323]. Elevated circulating and cellular levels of advance glycosylated end prduct (AGEs) have been measured in patients with CKD [192]. It increases with increase collagen accumulation and stiffness due to impaired renal clearance of AGEs together with their increased formation resulting from oxidative stress. AGE-induces crosslinking of ECM proteins increases myocardial stiffness[160] which is linked to development and progression of both HFpEF and HFrEF[190] and correlated positively with increased diastolic dysfunction in patients with diabetes mellitus type [133]. In the myocardium AGEs impair calcium handling in cardiomyocytes[329] which is mediated by carbonylation of SERCA2a, which impairs its activity[330], as well as by enhancing calcium leakage from the sarcoplasmic reticulum through the ryanodine receptor (RyR2), thereby promoting mitochondrial damage and oxidative stress[159]. Hence, reducing production and enhancing breakdown of AGEs could be a therapeutic option in HFpEF patients [183], particularly in patients with diabetes and CKD[17].

Obesity: Obesity is defined as a BMI ≥30 kg/m2. Patients with HF who have a BMI between 30 and 35 kg/m2 have lower mortality and hospitalization rates than those with a BMI in the normal range[66]. Obesity is a risk factor for HF [141]. The diagnosis of cardiac cachexia independently predicts a worse prognosis [65]. Morbidly obese (BMI 35–45 kg/m2) patients may have worse outcomes compared with patients within the normal weight range and those who are obese. In more advanced obesity weight loss may be considered to manage symptoms and exercise capacity [165]. Arising from a systemic inflammatory state and increased oxidative stress, they have impaired endothelial function [23]. It is a potent inductor of inflammatory signaling as visceral adipose tissue is infiltrated by macrophages, which continuously secrete inflammatory cytokines [63] leading to an increase plasma volume, correlating with LV end-diastolic pressure [119]. It increases metabolic and haemodynamic load on heart. Obesity influences LV geometry substantially more in women than in men- adipose mass is greater in women than men in any weight category and obese women have greater LV mass than obese men.

Chronic Obstructive Pulmonary Disease: Poor lung function is a risk factor for congestive heart failure (CHF), low FEV1 is associated with incident Heart failure (HF) and increases risk of hospitalization due to HF. HFpEF is in 5% of patients with more in older patients and subclinical diastolic dysfunction is there in 75% of COPD. Coronary ischemia with atherosclerosis is associated with diastolic dysfunction (Fig: 1).

Myocardial perfusion is also impaired by the vasoconstrictor effects of angiotensin II. During prolonged exercise, vasoconstriction occurs within metabolically less active tissues, mediated by angiotensin II and endothelin-1. Such response is inhibited in metabolically active tissues by NO and prostanoids, resulting in an efficient distribution of blood[147]. In a state of systemic inflammation, locally decreased NO bioavailability in the coronary microvasculature results in disinhibition of angiotensin II-mediated vasoconstriction, resulting in reduced blood delivery to the heart.

Aldosterone has been shown to directly promote myocardial fibrosis, left ventricular hypertrophy, and coronary microvascular dysfunction, acting through endothelial and myocardial mineralocorticoid receptors, independently of angiotensin II[146].

Pulmonary hypertension: HFpEF patients have increase pulmonary artery systolic pressure >40 mmhg due to elevated LV filling resulting increase in pulmonary venous filling pressure, increases reactive pulmonary vasoconstriction which increases pulmonary vascular resistance which is augmented in exercise. In some increase pulmonary venous filling pressure causes pulmonary vascular remodelling causes irreversible pulmonary hypertension.

Anemia and Iron Deficiency: Iron deficiency is the most frequent cause of anemia in HF patients, predict mortality its role in erythropoiesis. Iron is also a key factor in mitochondrial metabolism, crucial for cells with a high energy consumption such as cardiac and skeletal myocytes. In HF, iron deficiency arises from nutritional defects, increased red cell destruction, hepatic congestion, inflammatory bone marrow dysfunction, and chronic kidney disease. Iron deficiency affects functional status exercise capacity, it directly affect microvascular function by inhibiting mitochondrial respiration, cardiomyocyte damage, eventually contributes to progression of HFpEF (Fig: 3), by limiting energy production, impairing energy-dependent Ca2+reuptake during diastole[118] and contributes to oxidative stress.It impairs oxygen-carrying capacity, and the severity of anemia predicts mortality, but the role of treatment is uncertain[35].

Coronary artery disease: In coronary artery disease (CAD) acute ischaemia contributes to diastolic dysfunction causes change in endothelium vascular function which contributes to HFpEF. CAD is common in patients with HFpEF[36]. In general, contemporary revascularization guidelines should be used in the care of patients with HFpEF and concomitant CAD. It might be reasonable to consider revascularization in patients for whom ischemia appears to contribute to HF symptoms, but whether these interventions improve outcomes is not entirely clear[112, 113].

Genetic Regulation: Cardiomyopathy hypertrophic/restrictive/ infiltrative. Little is known about potential genetic determinants of HFpEF. Some genetic cardiomyopathies do exhibit a phenotype with preserved ejection fraction like hypertrophic cardiomyopathy and hereditary transthyretin amyloidosis. It is difficult to discern genetic determinants of HFpEF from the influence of comorbidities.

Constrictive Pericarditis: The normal pericardium restrains ventricular ?lling, contributing to the elevation in intracardiac pressures that develop during conditions of increased venous return such as exercise. Patients with HFpEF characteristically develop marked increases in ?lling pressures with exercise or volume loading owing to diastolic dysfunction[6]. Further study to determine whether pericardial restraint contributes to the pathophysiology of HFpEF, whether surgical approaches to remove pericardial restraint might improve symptoms related to venous congestion[25].

Valvular heart disease: If a catheter-based therapy is being considered it may be particularly beneficial in patients with HF being considered for surgery, transcatheter aortic valve implantation or transcatheter mitral valve intervention.

1.Cardiomyocyte contractile function:

The (giant) elastic sarcomeric protein titin is the dominant regulator of myocardial passive tension, and cardiomyocyte-derived stiffness (Fig: 5). 80% of left ventricular passive stiffness may be explained by titin, especially when sarcomere lengths are still within physiological boundaries, while in overstretched sarcomeres the contribution of the extracellular matrix becomes more dominant[35]. Titin regulates cardiomyocyte stiffness at the transcriptional and post-translational levels. At the transcriptional level, titin shifts from its compliant isoform N2BA toward its stiff isoform N2B have been postulated to contribute to diastolic dysfunction in HFpEF. Post-translational modi?cation of the titin N2B segment by protein kinase A (PKA)- and G (PKG) mediated phosphorylation has been shown to change cardiomyocyte passive tension (fig: 7). In cardiomyocytes, the giant protein titin operates as a bidirectional spring and gives stability to the other myofilaments. Titin determines the sarcomeric viscoelasticity, where as actin and myosin mainly contribute to force generation[32, 33, 34]. Mechanical energy stored in the sarcomeric protein titin during contraction contributes to recoil during relaxation, resting cardiomyocyte tension in diastole is a determinant of contractile force during systole. The relationship between “systolic” and “diastolic” function at the cellular level is expected to be highly interdependent. Titin-dependent stiffness is increased in patients with arterial hypertension and HFpEF, supporting its mechanistic role. Prominent features of myocardial remodeling in heart failure with HFpEF are high cardiomyocyte resting tension (Fpassive) and cardiomyocyte hypertrophy.Titin is able to modulate cardiomyocyte-based F passive by means of isoform switching, phosphorylation and oxidative modifications. Phosphorylation and oxidative modifications occur much faster. For HFpEF, the relative hypophosphorylation of PKG-dependent titin sites, offers potential therapeutic targets. This increases passive stiffness (Fpassive) upon stretch correlates with LV end- diastolic pressures and LV diastolic stiffness caused by changes in both ECM fibrillar collagen and cardiomyocyte titin. They also had increased titin dependent stiffness in association with significant changes in the phosphorylation state of titin, with decreased phosphorylation of a PKA/PKG site in the N2B element and increased phosphorylation of one of the PKC sites in the PEVK element[35]. Sites within the N2B element are phosphorylated by PKA and PKG, which decreases passive force. Sites within the PEVK element are phosphorylated by PKCα which increases passive force, hyperphosphorylation of the PKC/ calcium/calmodulin-dependent protein kinase II (CaMKII) site in the PEVK segment S4185(S469) of the N2B element is associated with increased myocardial stiffness in HFpEF patients[51].

The current study showed hypophosphorylation of PKG/PKA sites on titin in HFpEF patients, consistent with the reduction in passive tension detected when cardiomyocytes from HFpEF patients are treated with PKA/PKG. The finding that both changes in collagen and titin may play a pivotal role in the development of HFpEF[35].

One of the mechanisms necessary for relaxation to occur is the sarcoplasmic reticulum calcium ATP- ase (SERCA) pump, which removes calcium from the cytosol. Decreased levels or activity of SERCA can decrease the removal of calcium from the cytosol, which impairs relaxation of the ventricles. Several factors can affect the SERCA pump[16] like Ischemia, pathological LVH secondary to hypertension and aortic stenosis. There is a naturally occurring SERCA inhibitory protein called phosphlamban and increased levels of this protein impair relaxation.Diastolic intracellular calcium handling is a major determinant of LV relaxation. Dephosphorylated phospholamban (PLN) is an inhibitor of sarcoplasmic/endoplasmic reticulum Ca(2+)ATPase 2a (SERCA2a), but PKA-catalyzed (or CaMKII) phosphorylation of PLN results in the dissociation of PLN from SERCA2a, thus activating this Ca2+ pump and augmenting SERCA2a activity. In failing hearts, Ca2+ reuptake into the sarcoplasmic reticulum by the SERCA pump is delayed. Cardiomyocyte Ca2+ accumulation in the absence of concomitant enhancement of SERCA activity leads to elevated diastolic Ca2+, Ca 2+ transients with preserved or enhanced amplitude, and slower Ca2+ reuptake kinetics with impaired relaxation and promote remodeling. The inability of SERCA to expeditiously resequester Ca2+ becomes particularly explain the chronotropic intolerance of the myocardium and reduced exercise.  

Generation of cAMP, which stimulates PKA activity. cGMP is generated from activation of sGC by NO. cGMP stimulates PKG activity. Both PKA and PKG induce lusitropic effects, and lower cardiomyocyte stiffness through phosphorylation of the titin N2B segment. Sites within the PEVK element are phosphorylated by PKCα[76].

Trials indicate that combining SERCA2a activation and Na+/K+-ATPase (NKA) inhibition may increase contractility and facilitate active relaxation, improving systolic as well as diastolic heart function, both of which would be bene?cial effects in the treatment of chronic HF.

Diastolic dysfunction cannot be observed by echocardiography at rest in one-third of patients with HFpEF as many patients with HFpEF in the early stages did not present an increase in LV ?lling pressure at rest. These patients usually have normal plasma levels of B natriuretic peptide (BNP), which leads clinicians to make a false diagnosis of no HF. Natriuretic peptides are released and produced in response to increased myocardial wall tension. HFpEF is characterized by hypertrophic hearts with a small LV cavity. Diastolic dysfunction in HFpEF does not appear to impair net LV ?lling.

Diastolic dysfunction cannot be observed by echocardiography at rest in one-third of patients with HFpEF as many patients with HFpEF in the early stages did not present an increase in LV ?lling pressure at rest. These patients usually have normal plasma levels of B natriuretic peptide (BNP), which leads clinicians to make a false diagnosis of no HF. Natriuretic peptides are released and produced in response to increased myocardial wall tension. HFpEF is characterized by hypertrophic hearts with a small LV cavity. Diastolic dysfunction in HFpEF does not appear to impair net LV ?lling, but this level of ?lling is at the expense of increased LA pressure which can lead to dyspnea, secondary pulmonary hypertension, and atrial remodeling, make patients prone to right ventricular (RV) dysfunction and atrial ?brillation.Abnormalities in patients with HFpEF are related to diastolic dysfunction and may present with impairments in relaxation, increases in chamber stiffness, or both. Increased cardiomyocyte stiffness and cardiomyocyte hypertrophy follows diastolic dysfunction and sets the chain reaction of pathologic maladaptation leading to overt HFpEF. Cardiomyocyte hypertrophy is an almost universal finding in human HFpEF. Comorbidities induce a systemic proin?ammatory state with elevated plasma levels of interleukin (IL)-6, tumor necrosis factor (TNF)-a, soluble ST2 (sST2), and pentraxin [3].Coronary microvascular endothelial cells reactively produce reactive oxygen species (ROS), vascular cell adhesion molecule (VCAM), and E-selectin. Production of ROS leads to formation of peroxynitrite (ONOO) and reduced nitric oxide (NO) bioavailability, both of which lower soluble guanylate cyclase (sGC) activity in adjacent cardiomyocytes.

1. Normal Endothelial Function: The endothelium is the inner most layer of the blood vessels, present from the smallest capillary to the aorta. They are a protective layer between the blood and extravascular tissues, endothelial cells and are dynamic, highly interactive cells that regulate vascular function and homeostasis[161]. The healthy endothelium prevents platelet aggregation and leukocyte adhesion, inhibits smooth muscle proliferation, and regulates vascular tone through release of vasoactive substances. These processes are largely mediated by nitric oxide (NO), the main endothelial effector molecule.NO has the unique property of being a gaseous signaling molecule, able to diffuse quickly into neighboring cells causing endothelium- dependent vasorelaxation which increases blood flow and the accompanying shear stress. NO activates soluble guanylyl cyclase (sGC) and its second messenger cyclic guanosine monophosphate (cGMP), produces relaxation of the vascular smooth muscles and widening of the blood vessel[161].

Cardiomyocyte hypertrophy is an almost universal finding in HFpEF. It is additionally induced by molecular pathways, NO-mediated mechanisms, by increased stretch on cardiomyocytes through intrinsic mechanotransduction mechanisms. Cardiac biopsies from HFpEF patients show increased extracellular fibrosis. Extracellular fibrosis is physiologically more important than cardiomyocyte stiffness in HFpEF, as LV end-diastolic pressure is only correlated to collagen-based stiffness, not to titin-based stiffness (Fig: 8). Cardiac fibroblasts play a prominent role in the development of extracellular fibrosis. In HFpEF, fibroblasts are presumed to convert to myofibroblasts because of exposure to transforming growth factor-β as a result of monocyte/macrophage myocardial infiltration16. Circulating inflammatory cytokines induce expression of endothelial adhesion molecules such as vascular cell adhesion molecule and E-selectin (Fig: 10). Secretion of inflammatory mediators.