Hypertension disrupts the neuroendocrine system. Neuroendocrine factors have long been considered the main contributors to the development of HHD [25]. Among them, the renin-angiotensin-aldosterone system (RAAS) and catecholamines play a crucial role in the progression of HHD.

The activation of the RAAS is a crucial component of the pathological changes caused by hypertension. Angiotensin II (Ang II) is an important driver of a series of changes in the heart during HHD [18]. Ang II, which binds to angiotensin II type I receptor (AT1R) on the surface of cardiac myocytes, activates the G$\alpha$${}_{\text{q}}$ protein and phospholipase C (PLC), leading to the production of diacylglycerol and inositol 1,4,5-trisphosphate (IP${}_3$). IP${}_3$ increases intracellular calcium levels, increasing myocardial contractility through the calcium-calmodulin kinase II pathway [18, 27]. Initially, Ang II stimulation enables the heart to cope with higher afterloads. However, chronic stimulation of Ang II through sustained G$\alpha$q activation leads to myocardial hypertrophy [28]. Moreover, overexpression of G$\alpha$q can induce apoptosis in cardiac myocytes, which may be associated with increased endonuclease activity due to elevated intracellular calcium levels [29]. Inhibitors of G$\alpha$${}_{\text{q}}$ overexpression block the development of pressure overload-induced cardiac hypertrophy [30]. Another study also demonstrated that negative regulation of G protein-coupled receptor-mediated signaling pathways attenuates Ang II-induced cardiomyocyte hypertrophy and cardiac remodeling due to pressure overload [31, 32]. Ang II can also generate reactive oxygen species (ROS) through coupling with G$\alpha$${}_{\text{q}}$, which may further promote HHD [33, 34]. Apart from its direct effects on cardiac myocytes, Ang II can stimulate cardiac fibroblasts to release various cytokines, such as transforming growth factor-beta 1 (TGF-$\beta$1) and interleukin-6, promoting local production of Ang II and AT1R expression [35, 36]. Furthermore, the activation of the RAAS also promotes cardiac fibrosis progression. However, current research does not show beneficial effects of RAAS inhibitor treatment in heart failure with preserved ejection fraction (HFpEF) patients [37]. This suggests that RAAS activation may not be the main mechanism underlying the progression to HFpEF in HHD patients [38].

Increased blood pressure activates the sympathetic nervous system, leading to the release of catecholamines. Catecholamines bind to $\beta$-adrenergic receptors in cardiac cells [39]. The heart primarily expresses two types of $\beta$-adrenergic receptors ($\beta$AR), $\beta$1AR and $\beta$2AR, with $\beta$1AR being the most abundant on the surface of myocardial cells and $\beta$2AR accounting for 20% of myocardial adrenergic receptors in normal physiological conditions [40]. Current research suggests that excessive activation of $\beta$1AR leads to myocardial cell apoptosis and other adverse effects, while $\beta$2AR mediates cardiac protection [41, 42]. $\beta$1AR activation stimulates adenylate cyclase via G$\alpha$${}_s$, leading to increased cyclic adenosine monophosphate (cAMP) levels, subsequent activation of protein kinase A, and ultimately, upregulation of contractile proteins and calcium ion levels in myocardial cells [40]. However, cAMP also activates exchange proteins activated by cAMP (EPAC) [43]. EPAC1 contributes to the pathological growth of myocardial cells and may promote the transition from myocardial hypertrophy to heart failure, while EPAC2 may be involved in the occurrence of arrhythmias [18].

However, prolonged exposure to elevated blood pressure results in desensitization of adrenergic receptors due to sustained catecholamine stimulation [40]. $\beta$-adrenergic receptor desensitization leads to reduced downstream signaling and impaired cardiac functional reserve. This change serves as an important mechanism underlying the development of heart failure. $\beta$-adrenergic receptor desensitization is primarily mediated by GPCR kinases (GRKs) [44]. GRKs belong to the serine/threonine kinase family and consist of seven members, with GRK2 and GRK5 being the main regulators of $\beta$-adrenergic receptor desensitization in the heart. Inhibition of GRK2 with paroxetine improves hypertension-induced cardiac hypertrophy, dysfunction, and fibrosis in mice [45]. Additionally, in hypertensive patients with depression, those treated with paroxetine exhibited less cardiac remodeling than patients receiving other antidepressant medications [45]. Furthermore, $\beta$-arrestins are also involved in $\beta$-adrenergic receptor desensitization [46].

Natriuretic peptides (NPs) constitute a class of peptide hormones with blood pressure-regulating functions categorized into three types: atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) [47]. ANP and BNP are produced and secreted by the heart, while CNP is synthesized by vascular cells [48]. It has been demonstrated that NPs are closely associated with the development of LVH and HF resulting from hypertension [23]. Upon binding of ANP and BNP to natriuretic peptide receptor (NPR), the activation of guanylate cyclase ensues, leading to increased levels of cyclic guanosine monophosphate (cGMP) [47]. This activation initiates downstream processes, including the activation of protein kinase G (PKG) and cGMP-gated ion channels, ultimately reducing intracellular calcium ion levels [47]. This cascade also suppresses signals linked to cardiac hypertrophy. This series of events is thought to be a critical mechanism through which natriuretic peptides exert their anti-cardiac hypertrophy effects [49]. Furthermore, NPs have been found to mitigate the progression of cardiac fibrosis. Knockout mice lacking NPR exhibit a notable increase in myocardial fibrosis, which does not correlate with blood pressure levels [50]. Additionally, NPs can inhibit the proliferation of cardiac fibroblasts induced by Ang II. Current research suggests that the antifibrotic effects of NPs are also mediated through the cGMP-PKG pathway. ANP is susceptible to degradation by neprilysin. Recent studies indicate that inhibiting neprilysin can impede the activation and proliferation of cardiac fibroblasts, which is attributed to the restoration of PKG signaling within fibroblasts [51]. Furthermore, ANP has been shown to stimulate mitochondrial autophagy, enhance mitochondrial function, and lower intracellular oxidative stress levels [52]. Patients with hypertension exhibit elevated levels of NPs [47]. However, prolonged exposure to high levels of NPs can lead to desensitization of NPR [23]. This desensitization weakens the cardioprotective effects of NPs, thereby promoting the occurrence and development of HHD [53].

The heart’s unique function demands a substantial amount of energy. Physiologically, 95% of the heart’s adenosine triphosphate (ATP) is produced through oxidative phosphorylation in the mitochondria, while the remaining ATP is primarily derived from glycolysis [54]. Most ($>$60%) ATP is generated using fatty acids as metabolic substrates, with the rest coming from glucose, lactate, ketone bodies, and other sources [55, 56]. Cardiac contraction is powered by approximately 60% to 70% of the generated ATP [54]. Due to limited ATP reserves in cardiomyocytes, which can be depleted within seconds, any disruption in the energy production process significantly impacts cardiac function [54]. To cope with this characteristic, the myocardium is highly adaptable in its choice and shift of metabolic substrates, despite fatty acids being the primary substrates [57]. Studies indicate that cardiomyocytes rapidly shift to glucose metabolism when the workload increases [58].

Traditionally, it was believed that myocardial substrate preference would shift toward glucose during ventricular hypertrophy and heart failure [59]. However, recent research suggests that cardiac metabolism maintains a great deal of flexibility even in severe heart failure, allowing it to adjust substrate use to accommodate changes in arterial supply and workload [60]. Consequently, myocardial fatty acid uptake may remain unaffected [18]. However, fatty acid oxidation (FAO) is reduced in pathological ventricular myocardial hypertrophy [57]. The imbalance between fatty acid uptake and utilization leads to the accumulation of lipids such as triglycerides, ceramides, and diacylglycerols, which are synthesized from excess fatty acids within cardiomyocytes. While triglycerides are considered harmless, the lipotoxicity of ceramides and diacylglycerols can result in mitochondrial dysfunction and apoptosis [57, 61, 62]. Furthermore, an excess of intracellular fatty acids can promote the development of myocardial insulin resistance [63, 64].

Acetyl coenzyme A carboxylase is the rate-limiting enzyme for fatty acid synthesis, and animal studies have shown that knocking down the acetyl coenzyme A carboxylase 2 gene in cardiac tissues increases fatty acid oxidation, reduces glucose oxidation, and prevents ventricular hypertrophy caused by increased load [65, 66]. Similarly, overexpression of medium-chain acyl-coenzyme A dehydrogenase has been shown to reduce left ventricular hypertrophy caused by increased load [67]. Additionally, increasing dietary fatty acid intake in the context of heart failure reduces glucose oxidation and improves cardiac function [68].

During HHD, early increased glucose utilization can compensate for the energy deficit caused by decreased fatty acid metabolism efficiency. However, as the pathology progresses, the overall metabolic efficiency decreases [18]. Recent studies indicate that myocardial glucose uptake capacity varies at different stages of progression. The glucose uptake rate rises in hearts with mild diastolic and systolic dysfunction but declines significantly in severe cardiac dysfunction [69]. Cardiomyocytes facilitate glucose entry through glucose transporter proteins (GLUT1 and GLUT4), with GLUT4 being the main isoform in adults and GLUT1 in fetuses [70]. Glucose transport via the GLUT1 pathway increases during the development of cardiac hypertrophy [71]. Overexpression of GLUT1 has been found to prevent heart failure due to increased load and attenuate mitochondrial dysfunction [72]. However, it can aggravate cardiac hypertrophy. Conversely, knocking down GLUT4 leads to more severe cardiac hypertrophy and contractile dysfunction [73]. Therefore, increased glucose levels in cardiomyocytes may attenuate cardiac hypertrophy development. Similar to fatty acids, despite increased glucose uptake and glycolysis, the oxidation rate remains unchanged [18]. This results in the accumulation of metabolic intermediates, including glucose-6-phosphate. The buildup of intermediates, in turn, may promote cell growth and protein synthesis, ultimately contributing to the progression of ventricular hypertrophy. This occurs through activating the mammalian target of rapamycin protein complex 1, enhancing the pentose phosphate pathway, and stimulating the hexosamine biosynthesis pathway [74, 75, 76].

Under physiological conditions, ketone bodies provide approximately 10% of the energy source for the myocardium [77]. In contrast, ketone body metabolism is elevated in patients with heart failure cachexia [57]. It has been shown that specific knockdown of succinyl coenzyme A:3 ketoacyl coenzyme A transferase in mouse cardiomyocytes promotes cardiac hypertrophy [78]. Thus, increased ketone body metabolism may be a metabolic adaptation to HHD.

Branched-chain amino acids provide less than 5% of the energy source for the myocardium under physiologic conditions [77]. In contrast, the levels of branched-chain amino acids are similarly increased in patients with HF. Excessive levels of branched-chain amino acids have been shown to inhibit $\alpha$-ketoglutarate and pyruvate dehydrogenase activity and promote contractile dysfunction [79, 80]. The mechanism by which they are elevated during pathological remodeling is unclear. However, branched-chain amino acids and their metabolites have been shown to activate mammalian rapamycin target proteins, which may lead to alterations in cardiomyocyte anabolism, proliferation, autophagy, and other processes [77].

Inflammation and immunity also play important roles in HHD [18, 81, 82]. Previous clinical trials targeting inflammation in LVH and HF drugs have yielded disappointing results [83]. However, the results of the CANTOS trial demonstrated that interleukin (IL)-1$\beta$ monoclonal antibody can reduce heart failure-related hospitalization and mortality in patients with previous myocardial infarction, demonstrating the potential of inflammation in HF treatment [84]. While the role of inflammation and immunity in HHD and heart failure has long been recognized, the understanding of this process has been limited by the knowledge of the immune environment in the heart and the available research methods. Recent advancements in fate mapping and single-cell analysis techniques have provided valuable opportunities for advancing cardiac immunology [85]. These tools have revealed the heterogeneity of the cardiac immune system, offering new insights into the roles of immunity and inflammation in HHD.

Macrophages, the most abundant immune cells in the heart, constitute 5–10% of the total cardiac cells [85, 86]. The heterogeneity of cardiac macrophages is being unveiled, with human heart macrophages categorized into at least three types based on transcriptomic and functional differences: self-renewing cardiac resident macrophages (TIMD4${}^{+}$LYVE1${}^{+}$FOLR2${}^{+}$CCR2${}^{-}$ macrophages, TIMD4${}^{-}$LYVE1${}^{-}$FOLR2${}^{-}$CCR2${}^{-}$ macrophages) and TIMD4${}^{-}$LYVE1${}^{-}$FOLR2${}^{-}$CCR2${}^{+}$ macrophages derived from circulating monocytes [87, 88]. Current research supports the notion that CCR2${}^{-}$ cardiac resident macrophages are involved in tissue repair and maintaining cardiac homeostasis [89, 90]. Under normal physiological conditions, these cells are the primary macrophage source in the adult mammalian heart. Conversely, CCR2${}^{+}$ macrophages derived from circulating monocytes increase in number in the postinjury heart and contribute to the inflammatory response during cardiac injury [89, 90].

Macrophages have been identified as key contributors to the development and progression of HHD [91]. Earlier animal experiments utilized the nonselective depletion of macrophages through clodronate liposome injection to investigate their role in HHD. One study demonstrated a deterioration in left ventricular ejection function in hypertensive rats following macrophage removal [92]. Conversely, another study found that macrophage depletion attenuated hypertension-induced left ventricular hypertrophy while improving cardiac fibrosis [93]. These studies suggest a potential heterogeneous role of macrophages in HHD. To further elucidate the distinctions among different macrophage sources, Liao et al. [94] employed a CCR2${}^{+}$ antagonist-based approach to specifically block circulating-derived monocyte infiltration in mouse hearts. The results revealed an initial increase in macrophage numbers in the heart after transverse aortic constriction (TAC), returning to baseline levels at 2 weeks, and a mild increase again in the late phase (4 weeks). These changes in macrophage numbers corresponded to alterations in cardiac function, with the heart exhibiting compensatory hypertrophy early after TAC, followed by progressive cardiac dysfunction and heart failure at 2–4 weeks. The increase in macrophages resulted from the proliferation of cardiac resident macrophages, which facilitated the initial adaptive changes in response to pressure overload, potentially by promoting vascular generation [94]. A recent study of a genetic fate-mapping approach and single-cell transcriptome analysis demonstrated the cardioprotective role of cardiac resident macrophages in HHD [95]. This study also identified insulin-like growth factor-1 (IGF-1) as a potentially significant pathway for resident macrophage-mediated cardioprotection. The subsequent increase in late cardiac macrophages originated from the infiltration of circulating monocytes. However, circulating-derived CCR2${}^{+}$ macrophages mediate inflammatory injury and contribute to the deterioration of cardiac function, while reducing their infiltration helps maintain cardiac function. These findings are supported by additional studies, highlighting the potential of targeting CCR2${}^{+}$ macrophages as an important intervention strategy in HHD [96].

The activation of macrophages during HHD involves various mechanisms. Recent studies have shown that Ang II can directly promote macrophage activation through a pathway independent of AT1R [97]. This process is facilitated by the pattern recognition receptor dectin-1 on the macrophage surface, and the knockdown of dectin-1 significantly reduces Ang II-mediated cardiac injury. Although direct studies in HHD are lacking, mechanical stress can directly activate macrophages. A study utilizing a mouse model of dilated cardiomyopathy demonstrated that tissue-resident macrophages can sense mechanical stretch via transient receptor potential vanilloid 4 (TRPV4), leading to increased macrophage production of IGF-1, which plays a critical role in cardiac vascular neogenesis [98]. Furthermore, other studies have indicated that mechanosensory ion channels on the macrophage surface, such as PIEZO1, can respond to changes in mechanical stress and initiate downstream proinflammatory pathways [99].

Lymphocytes likewise play an important role in the pathologic process of HHD. Studies have shown that CD4${}^{+}$ T cells promote the development of cardiac fibrosis due to pressure load [100]. In a mouse model of pressure overload, the development of cardiac fibrosis coincided with the infiltration of CD4${}^{+}$ T cells into the myocardium [101, 102]. The interaction between cardiac fibroblasts and T cells plays an important role in this process. A recent study demonstrated that cardiac fibroblasts induced by interferon-gamma (IFN-$\gamma$) can express major histocompatibility complex II (MHCII) and present antigens to CD4${}^{+}$ T cells [103]. At the same time, T cells can promote the transformation of fibroblasts to myofibroblasts, thereby facilitating the progression of fibrosis [101]. Meanwhile, the use of T cells expressing chimeric antigen receptor targeting fibroblast activation proteins significantly reduced cardiac fibrosis in the Ang II-induced hypertensive mouse model [104]. Other immune cells, such as dendritic cells, are also involved in the development of HHD [105].

The gut microbiota is crucial in maintaining host health, impacting various physiological functions, including blood pressure regulation [106]. Bacterial metabolites are instrumental in mediating this effect [107]. Moreover, the gut microbiota has emerged as a significant factor influencing hypertension-induced target-organ damage. A recent study demonstrated that germ-free mice exhibit more severe cardiac and renal injury following Ang II-induced hypertension than colonized mice [108]. This highlights the protective role of gut microbes in mitigating hypertension-induced organ damage. Dietary habits significantly influence physiological factors in the host, with the gut microbiota serving as a vital intermediary. Different dietary patterns impact gut microbial metabolites, which are crucial for their physiological functions [109]. For instance, the fermentation of dietary fiber by gut microbes produces short-chain fatty acids, known to lower blood pressure and reduce cardiac hypertrophy and fibrosis [110]. The gut microbiota also influences other host metabolites associated with hypertension and immune system modulation [106].

Elevated blood pressure can trigger the development of cardiac fibrosis, characterized by excessive collagen buildup in the spaces between cells and blood vessels [17]. In HHD, the distribution of fibrosis can vary at different stages of progression. In the early stages, fibrosis may be localized to the subendocardium or around blood vessels. As HHD advances, fibrosis can extend outward toward the subepicardium, leading to a more diffuse pattern [16, 111]. Fibrosis reduces the flexibility of the ventricles and serves as the underlying mechanism for hypertension-related HFpEF. The presence of higher levels of fibrosis may explain why pathological LVH is resistant to treatment, unlike physiological hypertrophy [23]. Recent studies have shed light on several factors contributing to cardiac fibrosis in hypertension, including the activation of the RAAS [112, 113], inflammation and immunity [114, 115], and mechanical strain [116].

The production and maintenance of the cardiac collagen matrix primarily involve cardiac fibroblasts, which constitute 10–25% of all cardiac cells [86, 117]. These fibroblasts originate from both the endocardium and the epicardium [118]. When activated, fibroblasts can transform into myofibroblasts, which have an increased capacity to produce collagen and are key contributors to tissue fibrosis following cardiac injury [119]. The current studies support the significant role of proinflammatory cytokines and changes in the extracellular matrix composition in converting fibroblasts into myofibroblasts [116, 120, 121]. It should be noted that the role of fibroblasts from different origins in the development of cardiac fibrosis may not be consistent. Recent investigations indicate that endocardial-origin fibroblasts exhibit a preference for responding to cardiac injury caused by pressure overload compared to epicardial-origin fibroblasts [122]. The Wnt signaling pathway promotes the activation of endocardial-origin fibroblasts. Targeted removal of endocardial-origin fibroblasts attenuated pressure overload-induced cardiac fibrosis and improved cardiac function in one study. However, an earlier study suggested that fibroblasts from different origins play similar roles in cardiac hypertrophy resulting from TAC [123]. The reason for this discrepancy may be advances in genetic tracing techniques.

Myofibroblasts express $\alpha$-smooth muscle actin, which grants them contractile capabilities [124]. Therefore, during the early stages of the disease, myofibroblast production helps maintain cardiac function to some extent. However, these cells exhibit an enhanced ability to synthesize and secrete collagen, and the collagen produced is fortified through cross-linking, making them more resistant to degradation by matrix metalloproteinases [125]. Consequently, collagen production increases while degradation decreases, leading to collagen matrix accumulation and fibrosis formation. Furthermore, once formed, myofibroblasts can secrete TGF-$\beta$, triggering the activation of additional myofibroblasts and further fueling the progression of fibrosis [119].

The heart is an integrated system where various components, apart from the left ventricle (LV), play significant roles in the progression of HHD.

Enlargement of the left atrium (LA) is a recognized hallmark of HHD, and LA dysfunction is pivotal in facilitating the transition to HF while serving as a key marker for cardiovascular conditions, such as atrial fibrillation [126, 127, 128, 129]. The mechanisms behind LA involvement in HHD are multifaceted. Hypertension itself can induce atrial myocardial dysfunction and fibrosis. Indications of LA dilation and fibrosis markers are observed in spontaneously hypertensive rats at seven months of age [130]. Similar to the LV, aberrant activation of the RAAS and the adrenergic system in hypertension is instrumental in LA remodeling and fibrosis [131, 132]. The electrophysiologic function of the left atrium is similarly affected, with hypertension-induced changes in atrial myocytes potentially contributing to the development of atrial fibrillation due to alterations in calcium homeostasis [130, 133]. Meanwhile, unfavorable LV characteristics, including increased LV mass and impaired diastolic function, are associated with diminished LA function in HHD patients, potentially exacerbated by higher afterload [134]. In a mouse model with partial stenosis of the ascending aorta, the left atrium exhibited fibrosis, increased susceptibility to atrial fibrillation, and conduction abnormalities, among other changes [135]. Importantly, the neurohumoral functions related to the LA can also have a significant impact on HHD, as evidenced by a clinical trial demonstrating that left atrial appendage closure significantly reduced RAAS activity and lowered systemic blood pressure [136].

Systemic hypertension also impacts the right ventricle (RV), resulting in concentric RV remodeling and impaired RV diastolic function [137, 138]. Numerous clinical studies have linked adverse RV remodeling to an unfavorable prognosis [139, 140, 141]. Right heart involvement may be attributed to pulmonary hypertension secondary to left heart conditions [142]. Similar to the LV, the right heart undergoes a transition from compensation to decompensation as pulmonary artery pressure rises [143]. Right ventricle-pulmonary artery decoupling occurs when right ventricular contractility no longer matches the increased afterload. The precise mechanism by which left heart alterations lead to pulmonary hypertension remains unclear, with possible contributors including endothelial injury and neuroendocrine hormone metabolic disorders [142, 144].

ACEIs/ARBs are the most commonly used class of drugs for the treatment of HHD, with the effects of lowering blood pressure, reversing cardiac remodeling, and relieving myocardial fibrosis [216, 217]. ACEIs are more recommended than ARBs for the treatment of hypertension [179, 218]. However, in a recent network meta-analysis of randomized controlled trials comparing the effects of different antihypertensive drugs on reversing LVH, ARBs not only have a better effect on reversing LVH than $\beta$-blockers and calcium channel blockers but also have a better effect on reversing LVH than ACEIs. Similar advantages of ARBs have been observed in animal studies [219]. This may be because ARBs reduce oxidative stress and better inhibit collagen synthesis [220]. In addition, ARBs reduce cardiac damage by raising plasma Ang II levels and activating the ACE2-angiotensin (1-7) [Ang (1-7)]-Mas pathway [221].

The ACE2-angiotensin (1-7) [Ang (1-7)]-Mas pathway can antagonize the systematic biological effects of the RAAS and become a possible target for the treatment of myocardial fibrosis. An animal study revealed that pirfenidone inhibited the AT1R/p38 MAPK/RAS axis and activated the ACE2-angiotensin (1-7) [Ang (1-7)]-Mas pathway by activating liver X receptor alpha (LXR-$\alpha$), thereby improving the imbalance of the ACE/ACE2 ratio in rats with myocardial infarction and inhibiting myocardial remodeling and fibrosis [222]. A phase II clinical trial assessing the treatment of HFpEF patients with pirfenidone has shown effective reductions in myocardial fibrosis, but further trials are needed to verify this [223].

Angiotensin receptor/neprilysin inhibitors (ARNIs, such as sacubitril/valsartan) can antagonize both the natriuretic peptide system and RAAS, and they are recommended to be used to treat heart failure in preference to ACEIs/ARBs [224, 225]. Sacubitril/valsartan also effectively reduces blood pressure in hypertensive patients and has a high safety profile [226, 227]. The PARAMETER study revealed that ARNIs are more effective than ACEIs/ARBs in reducing dynamic central aortic and brachial artery pressures in elderly patients with high systolic blood pressure [228]. This suggested that ARNIs are superior to ACEIs/ARBs in controlling and preventing the progression of HHD. However, whether ARNIs can reverse hypertensive LVH is still being investigated (NCT03553810). Therefore, more research is needed to determine whether patients with HHD can use angiotensin receptor-neprilysin inhibitors (ARNIs) as an early alternative to ACEIs/ARBs. In HFrEF, sacubitril/valsartan outperformed ACEIs/ARBs in reducing the risk of cardiovascular death and improving LVH [229]. In HFpEF, a recent meta-analysis showed no significant difference in all-cause and cardiovascular mortality with RAAS antagonists in HFpEF patients, but ARNIs demonstrated superiority over ARB (odds ratio (OR): 0.80, 95% CI: 0.71–0.91) in reducing HFpEF-related hospitalizations [230]. Therefore, when patients with HHD progress to heart failure, ARNIs may be more effective than ACEIs/ARBs.

Mineralocorticoid receptor antagonists (MRAs) are a class of drugs that act on mineralocorticoid receptors by antagonizing aldosterone, which is used to treat heart failure and relieve cardiac remodeling and myocardial fibrosis [231]. In a randomized controlled study of 140 patients with type-2 diabetes, the eplerenone-treated group had a 3.7 g/m${}^2$ reduction in indexed left ventricular mass from baseline (95% CI: –6.7 to –0.7; p = 0.017) [232]. Compared with the control group, the concentration of plasma N terminal pro B type natriuretic peptide (NT-proBNP) and pro-collagen type I N-terminal propeptide decreased significantly, which suggested that it could reverse cardiac remodeling and prevent heart failure [232]. For HFrEF, MRA is often used in combination with other drugs, which are thought to reduce the risk of death better and reverse cardiac remodeling [233, 234]. For HFpEF, MRA does not reduce the risk of death [235, 236]. Therefore, the use of MRA is more beneficial when HHD progresses to HFrEF compared to when it progresses to HFpEF. The use of steroidal MRA (spironolactone, eplerenone) has been limited due to adverse effects (hyperkalemia, renal insufficiency, etc.) [237]. As a nonsteroidal MRA, finerenone is considered safer and can be used for treating diabetic nephropathy and heart failure [237, 238]. At natriuretic doses, finerenone was more effective than eplerenone in reducing cardiac hypertrophy and BNP and improving left ventricular systolic and diastolic function [239]. Finerenone may be an alternative to traditional MRA in the treatment of HHD.

In addition to drug therapy, RAAS antagonism has become the goal of many hypertension vaccines [240, 241, 242, 243]. In animal models, angiotensin I and II vaccines reduced blood pressure in hypertensive rats [240, 241]. However, in clinical trials, angiotensin I, while increasing angiotensin-1 antibody titers, did not reduce blood pressure in patients [242]. A randomized controlled trial evaluating the angiotensin-2 vaccine AGMG0201 revealed that AGMG0201 improved angiotensin-2 antibody titers and had a good safety profile but did not assess the effect of the vaccine on blood pressure in patients [243]. Another recent clinical trial found that zilebesiran, as a small interfering RNA (siRNA) drug, inhibits angiotensinogen synthesis in liver cells, and a single subcutaneous injection can reduce serum angiotensinogen and blood pressure levels and can be maintained for up to 24 weeks [244]. A new clinical trial of zilebesiran as an add-on treatment for patients with inadequately controlled hypertension is also underway (NCT05103332). Due to the lack of long-term antihypertensive drugs, compliance in patients with hypertension and HHD is often low. This often leads to unsatisfactory curative effects for HHD patients. Hypertension vaccines and siRNA drugs are expected to become effective long-term therapies to reduce blood pressure and compensate for the gap in hypertension treatment.

The ESC/ESH (European Society of Cardiology/European Society of Hypertension) guidelines for hypertension include beta-blockers as first-line antihypertensive agents, while the ACC/AHA (American College of Cardiology/American Heart Association) guidelines do not [179, 218]. Beta-blockers should be preferred for heart rate control in patients with myocardial infarction [245]. There is a lack of recommendations for the use of beta-blockers in hypertensive LVH without coronary heart disease, possibly due to the limited effect in reversing LVH [246, 247]. However, beta-blockers are superior to other antihypertensive medications in alleviating myocardial ischemia and preventing tachyarrhythmia in hypertensive LVH [246, 247]. Thus, beta-blockers possibly offer irreplaceable advantages in the treatment of HHD. In hypertensive heart failure, beta-blockers can effectively improve patients’ ejection fraction [248]. Moreover, a meta-analysis revealed that beta-blockers may reduce the risk of cardiovascular death in HFpEF patients, but the evidence is limited [235]. Therefore, trials of beta-blockers in the treatment of each stage of HHD are insufficient.

Cardiometabolic abnormalities are an important risk factor for hypertension and cardiovascular diseases, and patients with metabolic syndrome have a higher risk of HHD [249]. Improving metabolic abnormalities in HHD patients is a new therapeutic target. SGLT2 may be an important target for the treatment of cardiovascular diseases by improving metabolism. In a randomized controlled clinical trial, 124 hypertension patients with type-2 diabetes were randomly given 25 mg empagliflozin quaque die (QD) or a placebo for 12 weeks. The 24 h mean ambulatory blood pressure decreased significantly in patients treated with empagliflozin [250]. Another meta-analysis also demonstrated that SGLT2 inhibitors reduced ambulatory blood pressure but also revealed that the antihypertensive effect of SGLT2 inhibitors was more pronounced during the day than at night and was independent of the dose used [251]. SGLT2 inhibitors are beneficial in patients with LVH. In a randomized controlled trial, a group with type-2 diabetes and LVH using dapagliflozin had a significant decrease in left ventricular mass compared with a control group (95% CI: –5.13 to –0.51 g; p = 0.018), effectively reversing left ventricular remodeling [22]. Another randomized controlled trial of the effects of empagliflozin on left ventricular mass in patients with type-2 diabetes and coronary artery disease reported similar results [252]. In hypertensive heart failure rats, empagliflozin can modify cardiac relaxation and contraction functions and alleviate myocardial fibrosis [253]. In other clinical studies, SGLT2 inhibitors have benefits for both HFrEF and HFpEF, mainly reducing the risk of cardiovascular death and hospitalization for heart failure and improving the quality of life of patients with heart failure [254, 255, 256]. More clinical trials of SGLT2 inhibitors in patients with heart failure are also being conducted (NCT05737186). However, there is still a lack of clinical studies on the therapeutic effects of SGLT-2 inhibitors in patients limited to hypertensive heart failure.

Probiotics and prebiotics have beneficial effects on patients with HHD through multiple channels. Treatment with Bifidobacterium breve can reduce blood pressure and damage to related target organs in deoxycorticosterone acetate-salt rats [257]. By feeding Lactobacillus fermentum to male Wistar rats on a high-fat diet, systolic blood pressure (SBP) can be effectively reduced, and cardiometabolic abnormalities associated with hypersympathetic function can be inhibited [258]. The role of probiotics and prebiotics in treating hypertension has been further confirmed in clinical trials. In a meta-analysis of 14 studies involving 846 people with high blood pressure, the use of probiotics reduced SBP by 2.05 mmHg (95% CI: 3.87–0.24; p = 0.03) and diastolic blood pressure (DBP) by 1.26 mmHg (95% CI: 2.51–0.004; p = 0.047) [259]. The intake of multiple probiotics and probiotic intake for more than 11 weeks may have a greater antihypertensive effect [260]. A meta-analysis that explored the effect of prebiotics on blood pressure came to a similar conclusion that the intake of prebiotic beta-glucan fiber was effective in reducing blood pressure [261]. In addition to blood pressure control, probiotics and prebiotics can improve myocardial lesions. The probiotic Lactobacillus rhamnosus GR-1 reduced left ventricular hypertrophy and improved the ejection fraction in rats after myocardial infarction [262]. A high-fiber diet improves gut microbiota and supplements with acetate to lower blood pressure and improve LVH due to myocardial fibrosis and hypertension [263]. In addition, probiotics and prebiotics are also associated with benefits in lipid regulation and obesity treatment [264, 265]. Trials are underway to explore more different combinations of probiotics to treat hypertension [266]. As an important method to improve intestinal flora disorders, fecal microbial transplantation is being explored for more indications [267]. Trials of fecal microbiota transplantation for the treatment of hypertension are also in progress (NCT04406129, NCT05608447) [268].

Lifestyle management is essential for the treatment of hypertension and HHD. The lifestyle benefits for HHD patients mainly include reasonable diet control, moderate physical exercise, prevention of obesity, and moderate alcohol consumption or abstinence [179, 218].

Reasonable diet control is beneficial to patients with hypertension and heart disease. First, sodium intake is considered to have a causal relationship with hypertension, and reasonable sodium intake can effectively prevent and control hypertension [269, 270]. In addition, an appropriate increase in potassium-containing foods can also help control blood pressure [271]. The Dietary Approaches to Stop Hypertension (DASH) diet is considered a dietary strategy for hypertension independent of sodium intake [272]. A meta-analysis of 30 randomized controlled studies (5545 participants) found that the DASH diet reduced SBP by 3.2 mmHg (95% CI: –4.2 to –2.3; p 0.001) and DBP by 2.5 mmHg (95% CI: –3.5 to –1.5; p 0.001), regardless of whether participants had high blood pressure [273]. In addition, the Mediterranean diet can also reduce blood pressure and the risk of heart failure, but there is still insufficient research evidence [274, 275]. Long-term adherence to other dietary strategies, such as the Paleolithic diet (PD) or a Nordic Nutrition Recommendation (NNR) diet, is thought to improve left ventricular remodeling and may also benefit HHD [276].

Proper aerobic exercise can also be beneficial for people with high blood pressure. In a randomized controlled study on the effects of aerobic exercise on patients with refractory hypertension, 24-hour ambulatory blood pressure and office systolic blood pressure in patients with refractory hypertension who engaged in aerobic exercise decreased significantly compared with the control group [277]. Another meta-analysis highlighted that aerobic exercise reduced ambulatory blood pressure only in hypertensive patients taking antihypertensive medications [278]. Exercise is also beneficial for left ventricular hypertrophy in HHD patients. An animal experiment found that the metalloproteinase 2 of rats with losartan combined with physical exercise decreased significantly compared with that of sedentary spontaneously hypertensive rats using losartan. The reduction in cardiomyocyte diameter was observed only in rats with high doses of losartan (10 mg/kg) combined with physical exercise [279]. Another meta-analysis showed that physical exercise combined with antihypertensive medication significantly reduced left ventricular mass (95% CI: –21.63 to –1.81 g), and although there was a downward trend in left ventricular mass index and an upward trend in ejection fraction, the difference was not statistically significant [184].

MicroRNAs (miRNAs) are a class of endogenous noncoding small RNAs that mainly play a regulatory role in mRNA translation and degradation [280]. Many miRNAs participate in hypertension and HHD development [281, 282, 283]. The method of using microRNA to treat diseases is introducing miRNA-mimic or anti-miRNA oligonucleotide inhibitors [283]. A study has shown that recombinant adeno-associated virus delivery of endogenous and exogenous miRNA-21 into spontaneous hypertensive rats can reduce blood pressure and reverse cardiac hypertrophy. This is related to miRNA-21’s ability to promote mitochondrial translation to produce mitochondrial DNA (mtDNA)-encoded cytochrome b [284]. Another study effectively improved cardiac remodeling and cardiac function in rats with hypertension-induced heart failure by subcutaneous delivery of microRNA-208A inhibitors [285]. However, there is currently a lack of clinical trials on miRNAs for hypertension and HHD, so the efficacy and safety of miRNA therapy remain uncertain.

When HHD advances to severe heart failure, medication therapy alone is insufficient. Cardiac resynchronization therapy (CRT) is an effective surgical treatment to improve the prognosis and quality of life of patients with heart failure [286, 287, 288]. In recent years, cardiac contractility modulation (CCM) has emerged as a new surgical modality for the treatment of heart failure and has become a significant option for individuals who are ineligible for or do not respond well to CRT. A prospective study identified the safety and efficacy of CCM for HFpEF [289]. This discovery could offer new hope for HHD patients progressing to HFpEF, as they lack effective therapeutic drugs. In addition, patients with HHD usually have a higher risk of ventricular arrhythmia, especially in the presence of LVH and heart failure [290]. Implantable cardioverter defibrillators (ICDs) can effectively treat ventricular arrhythmias and significantly reduce the risk of death in heart failure patients [291, 292]. Therefore, for hypertensive heart failure patients who meet the indications, ICD therapy is necessary.