LVH is an early compensatory response to hemodynamic overload in chronic hypertension (29, 30). LVH can predispose to cardiovascular events in individuals with hypertension who have coronary artery calcifications but without symptoms (31) or in individuals with hypertension independent of treatment and other existing cardiovascular risk factors (32). In addition, malignant LVH characterized by elevated biomarkers of cardiac injury and hemodynamic stress such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and troponins is associated with severe adverse outcomes such as heart failure with reduced ejection fraction, left ventricular dysfunction and cardiovascular death (33). Thus, high-sensitive cardiac troponin T (hs-cTnT) and NT-proBNP levels can be used to identify patients who are more likely to develop adverse outcomes (34). It is also important to note that malignant LVH and related adverse events may be more pronounced in black persons compared to white persons (35). However, intensive therapy to lower blood pressure can prevent malignant LVH and reduce the risk for adverse events (36). The pathogenesis and severity of LVH is different by sex. For example, aortic characteristic impedance, systemic vascular resistance, augmentation index, and carotid-femoral pulse wave velocity and proximal aortic compliance are independently associated with relative wall thickness in women but not in men (37). LVH is therefore, more often and more pronounced in women compared to men (38, 39). LVH can be pathological and physiological in pattern (40, 41). The distinguishing pathological changes include increased extracellular connective tissue relative to myocytes without commensurate capillary growth, and myocardial fibrosis that often manifests as diastolic dysfunction (1, 30, 42). In Physiological LVH, extracellular matrix and micro-vessel increase is proportional to the myocyte hypertrophy without deleterious effects on left ventricular function (42). This physiological pattern is seen as a normal response to physical exercise (42).

The mechanisms by which chronic hypertension leads to LVH may involve gap junction lateralization and overexpression of the fatty acid transporter cluster of differentiation 36 (CD36), redox-sensitive Protein Kinase C (PKC), increased oxidative stress, increased matrix metalloproteinase-2 (MMP-2) activity, abnormal Ca²⁺ homeostasis, increased activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, apoptosis, and abnormal regulation of junctional proteins (7, 43). All these compensatory changes participate in an orchestrated manner to compensate for increased stress, metabolic and functional demand but are likely to also induce decompensated heart failure when the pathological insult is persistent (7, 44, 45). At cellular level, LVH is a consequence of an increase in cardiac myocyte size due to functional demand but chronic blood pressure elevations may lead to death of cardiomyocytes progressing to dilated cardiomyopathy, a feature described as a transition from compensated to decompensated heart failure and mediated by neurohormonal signaling (45). The whole mark and characteristic feature of LVH is an increase in cardiomyocyte with fibrotic changes including medial hypertrophy and perivascular fibrosis (1). The structural features of LVH can either take concentric or an eccentric pattern depending on volume load, genetic factors, specific alterations of the extracellular matrix, neurohormonal milieu, pressure load severity, duration, rapidity of onset, concomitant medical conditions such as cardiovascular disease, metabolic disease such as diabetes mellitus and demographic factors such as age, race/ethnicity, gender (1, 46). The ultimate consequence of LVH with continued hemodynamic stress is progression to heart failure with either a preserved or a reduced left ventricular ejection fraction (47, 48). There is evidence of LVH regression with use of different classes of antihypertensive medication, however, there is considerable variability in individual responses including sex differences (49) owing to variability of pathological changes per individual and a number of studies have reported failure to regress LVH even when blood pressure is controlled (49–54).

Several proteins, mediators and cellular responses such as angiotensin II, cardiac myosin-binding protein C, endothelin-1, S-thiolated protein, norepinephrine, Rho and Ras proteins, thiols, oxidative stress, heat shock proteins, Fractalkine/C-X3-C Motif Chemokine Ligand 1 (CX3CL1), leukotriene-A4 hydrolase, calcineurin, and some kinases have been implicated in LVH which is associated with chronic elevated blood pressure (42, 55–57). The enzymatic cleavage of angiotensinogen by renin converts angiotensinogen to Angiotensin I and then angiotensin converting enzyme (ACE) converts Angiotensin I to Angiotensin II (58, 59). Angiotensin II is the main effector molecule of the renin angiotensin aldosterone system (RAAS) that serves to control blood pressure (58). Angiotensin II increases blood pressure by inducing water and sodium reabsorption, inducing vasoconstriction and exerting proliferative, pro-inflammatory and pro-fibrotic activities by binding to angiotensin type 1 and 2 receptors (59, 60) (Figure 2).

Angiotensin II increases blood pressure and induces pathological features characteristic of hypertensive heart disease by activating angiotensin II receptors, regulating cardiac contractility, cardiac remodeling, growth, inflammation, apoptosis and impulse propagation (59, 61). Angiotensin II activates extracellular signal-regulated kinase (ERK)/ mitogen-activated protein kinases (MAPKs) pathways via G protein-coupled receptors (GPCRs) or growth factor-stimulated tyrosine kinase receptors leading to an increase in protein synthesis, extracellular matrix proteins and activation of endothelin-1 effects which result in induction of cardiac fibrosis (42). Heat shock proteins 90 (HSP90) mediate cardiac hypertrophy that is induced by angiotensin II through the stabilization of IкB kinase (IKK) complex (62). Activation of the Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) during hemodynamic stress, inflammation and reactive oxygen species (ROS) production in cardiac myocytes also contributes to cardiac hypertrophy in hypertensive heart disease (42).

Another mechanism associated with LVH is activation of calcineurin and calmodulin kinase II (CaMKII) due to enhanced sensitivity to calcium resulting in calcineurin binding to and dephosphorylating nuclear factor of activated T cells (NFAT)(42, 63). This step increases hypertrophic gene expression through mechanisms that are not yet clear (63). Intergrins have also been implicated in LVH mediated by RAAS and MAPKs pathways (42).

LVH progresses to heart failure when the compensatory mechanisms have failed to meet the functional and metabolic demands of the myocardium (64). Heart failure is a progressive clinical syndrome characterized by reduced ability of the heart to pump blood to meet the body's metabolic demand (65, 66). Symptoms include dyspnoea, fatigue, peripheral oedema or distended jugular veins (65, 66). The symptoms/signs are caused by abnormality in cardiac function and structure and the clinical syndrome is characterized by an increase in natriuretic peptide levels and pulmonary or systemic congestion (67). Heart failure can either be acute or chronic (68). The classification of heart failure is based on left ventricular ejection fraction (LVEF) and can present either with reduced ejection fraction (HFrEF)) or preserved ejection fraction (HFpEF) (65, 67). The clinical stages of heart failure based on United states (US) guidelines fall into four categories (67, 69) as shown in Table 1. The pathogenesis, risk factors and therapeutic response in heart failure is sex dependent. For example, women are more susceptible to traditional risk factors for heart failure and have more severe symptoms especially with higher left ventricular ejection fraction compared to men (70, 71). However, in terms of the adverse outcomes such as hospitalization and mortality, the prognosis regardless of the ejection fraction state, appears to be better for women than men (72). In general, specific data on sex differences in heart failure is still limited due to the fact that women are underrepresented in most studies (72). Also, while women may have more disease severity on some outcomes, this is not the case with other outcomes or symptoms such as plaque rupture which is more common in men (71, 73).

The transition from hypertrophy to heart failure in hypertensive heart disease is driven by several cellular mediators many of which are progressive changes already explained under LVH and these include oxidant stress, apoptosis, insufficient angiogenesis, mitochondria dysfunction, metabolic derangements and fetal gene program induction (74, 75). The underlying pathways and cellular mediators that are activated to mediate the pathology of heart failure in hypertensive heart disease include peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and PGC-1β (64), GPCRs, p38, ERK1/2, JNK, CAMKII, protein kinases (type C, G, and A), Growth factor-mediated stimulation of mechanistic target of rapamycin (mTOR) (74), epigenetic modulators (such as NFAT, MEF2) and transient receptor potentials (74, 76). Most of these pathways have been reviewed elsewhere (74). PGC-1α and PGC-1β both play a role in the maintenance of cardiac function during pressure overload such that in the progression to heart failure, a deficiency of PGC-1β is shown to accelerate the transition (64). The hormone ligands that mediate the activation of these pathways include angiotensin II, endothelin 1, α-adrenergic receptors and β- adrenergic receptors (74). At organ level, multiple cardiac, vascular, and non-cardiac abnormalities associated with hypertensive heart disease underly the pathophysiology of heart failure (77, 78). These include impaired structural and functional changes of the left ventricle, myocardial ischemia, autonomic deregulation, endothelial dysfunction and vascular stiffening (77, 79). The RAAS is an important contributor that plays a central role in the transition from LVH to heart failure in hypertensive heart disease and has been explained above.

The most common manifestation or complication of hypertensive heart disease is cardiac arrhythmias, and the most common among these is AFib (80). AFib is an irregular and very rapid heart rhythm associated with increased risk for blood clots in the heart, stroke, and heart failure (81–84). AFib can be detected on an electrocardiography (ECG) (Figure 3). During normal heart conduction, electrical signals from the sinoatrial node travel through the atria to the atrioventricular node, passes through the ventricles causing them to contract (Figures 3A,B). In AFib, the electrical signals conduct in a chaotic manner firing from multiple locations leading to faster and irregular heartbeats and characterized by lack of a P-wave and irregular QRS complexes on an ECG (85) (Figure 3C).

Although effective control of blood pressure prevents AFib, some antihypertensive drugs such as thiazide diuretics used to control blood pressure can contribute to AFib risk by inducing hypokalaemia and hypomagnesemia (80). The mechanisms associated with AFib are not yet clear but include modulation of L-type Ca²⁺ and K + currents and gap junction function, cardiac structural remodeling and autonomic remodeling which is characterized by altered sympathovagal activity and hyperinnervation (85). One explanation for the chaotic rhythms in AFib is that structural remodeling characterized by atrial fibrosis occurring in hypertensive heart disease is associated with reentry of a self-sustaining cardiac rhythm abnormality (86). Ectopic conduction activities originating from the pulmonary veins is one of the common triggers of AFib due to specific action potential properties of the pulmonary vein cardiomyocytes (86). Overall, the mechanisms of conduction arrhythmias associated with hypertensive heart disease are not yet clear. In addition, sex differences in the risk, pathogenesis and outcomes of AFib also exist but data is limited (87).

Coronary artery disease in hypertensive heart disease is accelerated by chronic elevation of blood pressure that induces endothelial dysfunction and exacerbates atherosclerotic processes (88). LVH exacerbates coronary artery disease by promoting myocardial ischemia mediated by a decreased coronary reserve and increased myocardial oxygen demand (88). Atherosclerosis remains the main cause of cardiovascular diseases and hypertensive heart disease accelerates complications of atherosclerotic diseases (89). Coronary arteries are considered the most susceptible blood vessels to atherosclerosis in the entire cardiovascular system due to their structurally higher curvature and torsion that plays a role in the localization of early coronary artery thickening (90) (Figure 4A). Blood pressure disturbances and irregularities and cardiac remodeling associated with hypertensive heart disease increase the risk of coronary artery disease and related complications such as myocardial infarction, angina, heart failure and AFib (88, 91, 92) (Figure 4B). The risk factors for coronary artery disease are similar with those associated with hypertension (93, 94). Sex differences in the burden, pathogenesis or severity of coronary artery disease do exist. For example incidental finding of coronary microvascular dysfunction is more common in women than men (95–98). In addition, coronary microvascular dysfunction occurs more in women than in men (99).

The mechanisms underlying the pathophysiology of coronary artery disease include fatty streak formation that activates macrophages to take up these lipids and deposit in the sub endothelium (100, 101). Immune cells including T cells are activated and recruited, secreting inflammatory cytokines in the process that results in the deposition of oxidized low-density lipoprotein (LDL) particles and collagen to form a stable subendothelial plaque that grows with time predisposing to vessel occlusion and atherothrombotic activity in chronic hypertension (101, 102) (Figure 4B). The immune system is intricately involved in atherosclerotic processes. Studies using apolipoprotein E–deficient mice have reported that when chronic inflammation does not resolve, tertiary lymphoid organs emerge in tissues and the adventitia of the aorta which become infiltrated with activated dendritic cells, B cells, and T cells of varying types (103, 104). These cells seem to target unknown antigens released from injured tissue and contribute to advanced atherosclerosis. The whole mark of disease progression is mediated by autoimmune B and T cells that become overly activated as a result of failure of anti-inflammatory effects to remove the continuous discharge of antigens from injured atherosclerotic tissue (104). Further, evidence of formation of neuroimmune cardiovascular interfaces characterized by expanded axon networks and activated artery-brain circuit activity in the adventitia is another proposed mechanism contributing to the progression of atherosclerosis in coronary artery disease (105). The whole process of atherosclerosis development has been described elsewhere (106). Shear stress associated with hypertensive heart disease and atherosclerotic changes leading to plaque progression and remodeling activates PKC epsilon, c-Jun N-terminal Kinase (JNK) MAP kinase, and p53 that worsen endothelial remodeling in the vasculature (107). High shear stress also activates matrix metalloproteinases (MMPs) resulting in thinning of artery wall and eccentric remodeling (107).

Although there are many proposed models of atherosclerosis based on animal studies and a few focused on humans, the challenge remains in translating our understanding to clinical practice (108).

Although excess dietary salt raises blood pressure, the effect of salt on blood pressure is variable in the population (127). While significantly elevating blood pressure in some individuals (salt sensitivity), excess salt has no effect on blood pressure in others (salt resistant) and there is a group of individuals (about 15%) whose blood pressure increases with low salt intake (inverse salt sensitivity) (127–129). Salt sensitivity of blood pressure (SSBP) results in part from genetic polymorphisms in genes regulating sodium handling and those not related to sodium handling such as the Protein Kinase CGMP-Dependent 1 (PRKG1), cytochrome b-245 alpha (CYBA) chain (also known as p22-phox), branched chain amino acid transaminase 1 (BCAT1), Solute Carrier Family 8 Member A1 (SLC8A1), SLC4A5, Angiotensin II Receptor Type 1 (AGTR1), Selectin E (SELE), cytochrome P450 family 4 subfamily A member 11 (CYP4A11), Neuronal precursor cell expressed developmentally down-regulated 4-like (NEDD4l) and Visinin Like 1 (VSNL1) (129–133). As explained above, RAAS activation leads to vasoconstriction, increased systemic vascular resistance (SVR) and elevation in blood pressure (134). In individuals with SSBP, RAAS is altered in that renin stimulation is reduced in salt depletion and the mechanisms are not adequate to suppress renin in high salt intake hence worsening the adverse effects of salt on blood pressure (135–138).

The handling of salt by the kidney and how salt contributes to water retention and elevated blood pressure is well known. The current dogma that sodium in the interstitial space equilibrates with plasma has been challenged in emerging studies that have now identified extrarenal handling of sodium that contributes to hypertension and sustenance of blood pressure in hypertensive heart disease (139, 140). It is now known that sodium can accumulate in tissues and skin without commensurate volume retention and activate innate and adaptive immunity leading to or sustaining hypertension (139, 141). Accumulation of salt in the skin is associated with autoimmune disease severity and heightening of inflammation in several diseases such as lipedema, diffuse cutaneous systemic sclerosis, multiple sclerosis, psoriasis and systemic lupus erythematosus (142–146). Several studies have demonstrated similar findings of increased sodium accumulation in the skin in hypertension using sodium magnetic resonance imaging (²³Na MRI) (147–150). For dietary sodium to reach the skin from the intestinal lumen, it is first absorbed across the apical membrane of enterocytes through sodium-hydrogen exchangers (NHE), sodium glucose cotransporter 1 (SGLT1), sodium-dependent phosphate transporter 2b (NaPi2b), glucose transporters (GLUT) and endothelial sodium channels (ENaC) and pumped across the basal membrane of the intestine into the interstitium by Na-K ATPases (151–154). From the insterstitium sodium diffuses into the intestinal capillaries for transport. In the vasculature, excess dietary salt diminishes the buffering capacity of the negatively charged glycocalyx lining the endothelium and the red blood cells leading to extravasation of sodium and accumulation of salt in the interstitial tissues (140, 155, 156). Accumulation of salt in the skin increases the density and hyperplasia of the lymph-capillary network and this effect is mediated by activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells (140). TonEBP binds to and activates the promoter of the gene encoding vascular endothelial growth factor-C (VEGF-C) resulting in VEGF-C secretion and trapping by macrophages, augmenting interstitial hypertonic volume retention, decreasing endothelial nitric oxide synthase expression and elevating blood pressure in response to excess dietary salt (140). In addition, the hypertonic milieu contributed by the accumulation of sodium in the skin that induces the expression of VEGF-C increases lymphangiogenesis as a compensatory mechanism to eliminate sodium from the skin but this process is usually disrupted in hypertension, exacerbating hypertensive heart disease (147, 148). Low salt diet has shown to improve dermal capillary density and blood pressure in hypertension (157).

A group by Laffer et al. investigated hemodynamic changes in individuals with SSBP and found that compared to salt resistant individuals, individuals with SSBP had higher total peripheral resistance after salt loading which did not change after salt depletion and further, they also gained weight during salt loading but lost more weight during salt depletion that reflected failure to correct fluid retention (158). This study suggests that individuals with SSBP are unable to maintain and modulate a proper hemodynamic balance that reflects a dysfunction in the storage of salt in the interstitial compartment probably due to vascular dysfunction (156, 159).

Resident macrophages and dendritic cells in the interstitium of the skin are activated in the presence of excess dietary salt and via increased activity of the ROS producing reduced nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, the ROS oxidize arachidonic acid leading to formation of Isolevuglandins (IsoLGs) (160, 161). IsoLGs adduct to lysine residues and alter intracellular protein structure and function and the resulting IsoLG-protein adducts act as neoantigens presented to and activating T cells (160). The activated T cells produce interferon-gamma (IFN-γ), interleukin 17A (IL-17A) and tumor necrosis factor-alpha (TNF-α) which causes vascular damage and lead to hypertension (160, 162). The activated macrophages and dendritic cells produce inflammatory cytokines IL-1β, IL-6 and IL-23 which induce T cell proliferation and production of inflammatory cytokines implicated in hypertension (160) (Figure 5). It has been demonstrated in many studies that T cells infiltrate the kidney causing vascular injury via inflammatory cytokines and increased oxidative stress and contributing to salt sensitive hypertension (163–165).

Several cellular pathways have been implicated in salt sensitive hypertension. The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is an oligomeric complex containing the NOD-like receptor NLRP3, the adaptor Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1 implicated in salt sensitive hypertension (166). The inflammasome is activated when NF-κB upregulates the inflammasome components and pro-IL-1β leading to the assembly of components to form the NLRP3 inflammasome signaling complex (134, 166) (Figure 5). Activation of the NLRP3 inflammasome leads to the release of pro-inflammatory cytokines IL-1β and IL-18 via pyroptosis that involves the cleavage of gasdermin D and development of pores in the membrane of cells through which the cytokines and other cellular contents are released (134, 166). It has been demonstrated that the NLRP3 inflammasome can be activated in high salt environments in an ENaC-dependent manner leading to IsoLG-protein adduct formation in dendritic cells and macrophages and antigen presentation to activate cells of the adaptive immune system and leading to hypertension as explained above (167).

In high salt diets, small guanosine triphosphatases (GTP)ases Rho and Rac kinases are activated and lead to activation of sympathetic nerve outflow that results in blood pressure elevation (168). In vascular smooth muscles, Rho kinases facilitate vasoconstriction though GPCRs and Wnt pathways, and in vascular endothelium, Rho/Rho kinase inhibits nitric oxide (NO) leading to increased vascular resistance and vascular tone and salt sensitive hypertension (168).

A study by Chu et al., in 329 subjects looked at growth factors that are produced in relation to the activation of the phosphoinositide 3-kinase/ Ak strain transforming (PI3K-Akt) pathway, which is activated through serine and/or threonine phosphorylation of a range of downstream substrates (169). They found that individuals with SSBP had elevated levels of several growth factors compared to salt resistant group (169). The signal transduction PI3K-Akt Pathway regulates metabolism, proliferation, cell survival, growth and angiogenesis (170). The PI3K-Akt Pathway activation has been implicated to contribute to the progression of atherosclerotic plaque formation and pathological changes in the vasculature leading to hypertension and cardiovascular disorders in many studies (171–175). Several other cellular pathways associated with salt sensitive hypertension such as the WNK signaling pathway (176), Kelch-like 3/Cullin 3 ubiquitin ligase complex (177), brain Gαi2-proteins of GPCR (178, 179) in the central nervous system, MAPK/extracellular signal regulated kinase [ERK] mediated by angiotensin II in vascular smooth muscles (180), and redox signaling (181) have been well elucidated.

Patients with LVH benefit remarkably from intensive blood pressure lowering (<120 mmHg) to prevent complications (36). In clinical trials, several therapies have been reported to reduce LVH and its complications. Use of the neprilysin inhibitor sacubitril used for treatment of heart failure and the angiotensin receptor blocker valsartan was associated with reduced left ventricular mass index when compared to the angiotensin receptor blocker (ARB) Olmesartan, in participants with hypertension (204). Another clinical trial reported that combination of the ARB telmisartan and simvastatin did not only significantly reduce blood pressure but was able to reverse LVH and improve left ventricular systolic function (205). Similar findings were reported for a triple fixed dose combination of perindopril/indapamide/amlodipine (angiotensin-converting enzyme inhibitor (ACEI)/diuretic/calcium channel blocker (CCB)) in patients with essential hypertension followed for 14 months (206). Another interesting finding is from a clinical trial by Lal et al. where they used allopurinol, a xanthine oxidase inhibitor commonly used to reduce plasma uric acid in patients with gout, to determine its efficacy in reducing LVH (207). High dose allopurinol was more effective in reducing left ventricular mass and LVH when compared to febuxostatin (207) but caution must be exercised in using allopurinol in normouricemic individuals with controlled blood pressure as it can increase oxidative stress (208). In general, it appears that significant reversal of LVH is greater when both RAAS and sympathetic nervous system (SNS) inhibitors are used compared to drugs that just target blood pressure reduction (209). Other drugs as well as natural compounds or interventions used in combination have also been reported in clinical trials to ameliorate progression of LVH, examples include a nutraceutical combination of berberine, red yeast rice extract and policosanol (210), azelnidipine (211), losartan (212), low-dose eplerenone (213), metformin in patients with coronary artery disease without diabetes (214), diets low in fat and carbohydrate and regular consumption of green tea (215, 216).

Several clinical trials have reported beneficial therapies in the management of AFib. A few are discussed below.

When AFib is controlled, patients remain at risk for cardiovascular events, however, early rhythm control achieved by using antiarrhythmic drugs or atrial fibrillation ablation was effective in treating AFib and reducing the risk for cardiovascular events (217). In clinical practice, patients are first prescribed drugs such as beta blockers or a CCB in patients with asymptomatic AFib but a few clinical trials found that cryoballoon ablation was more effective compared to drug therapy as initial therapy for AFib (218, 219). Thus, rhythm control may be beneficial in both asymptomatic and symptomatic AFib (220). Further, radiofrequency ablation may delay or prevent paroxysmal AFib from progressing into persistent AFib (221). Despite its beneficial effect, caution should be exercised, as catheter ablation may also increase left atrial stiffness and worsen post-ablation diastolic function (222). Additional interventions for the management of AFib and its complications have been reported in other clinical trials elsewhere (223–227).

Patients with coronary artery disease also benefit from several interventional strategies including dietary interventions (228, 229), rivaroxaban monotherapy and other drugs (230–232), and physical exercise (233, 234). Further, lifestyle modifications have also been reported to be beneficial (235).

To alleviate heart failure and reduce its complications, several interventions are available (236). For example, in a clinical trial by Hieda et al. they found that physical exercise training for one year reversed left ventricular myocardial stiffness in patients with stage B heart failure with preserved ejection fraction that is characterized by LVH and N-terminal pro-B-type natriuretic peptide or high-sensitivity troponin (237). Therapeutic interventions for patients with heart failure also exist. Empagliflozin, dapagliflozin and spironolactone improves and ameliorates adverse outcomes of heart failure with persevered ejection fraction (238–240). In addition, individualized nutritional support as well as treatment with vericiguat for hospitalized patients with heart failure is also beneficial in reducing the risk for death and morbidity (241–243). Further, in patients with acute decompensated heart failure, usage of levosimendan in combination with Shenfu injection was effective in improving hemodynamics and enhance myocardial contractility (244). In severe heart failure where therapy is limited, use of omecamtiv mecarbil therapy is reported to have beneficial effects in reducing adverse outcomes (245). Management of heart failure is discussed in detail in the US and European guidelines.