Treatment Of Hypertensive Heart Disease Research Articles

Macrophage RAGE deficiency prevents myocardial fibrosis by repressing autophagy-mediated macrophage alternative activation.

Myocardial fibrosis (MF) is the characteristic pathological feature of various cardiovascular diseases that lead to heart failure (HF) or even fatal outcomes. Alternatively, activated macrophages are involved in the development of fibrosis and tissue remodeling. Although the receptor for advanced glycation end products (RAGE) is involved in MF, its potential role in regulating macrophage function in cardiac fibrosis has not been fully investigated. We aimed to determine the role of macrophage RAGE in transverse aortic constriction (TAC)-induced MF. In this study, we found that RAGE expression was markedly increased in the infiltrated alternatively activated macrophages within mice hearts after TAC. RAGE knockout mice showed less infiltration of alternatively activated macrophages and attenuated cardiac hypertrophy and fibrosis compared to the wild-type mice. Our data suggest that mice with macrophage-specific genetic deletion of RAGE were protected from interstitial fibrosis and cardiac dysfunction when subjected to pressure overload, which led to a decreased proportion of alternatively activated macrophages in heart tissues. Our invitro experiments demonstrated that RAGE deficiency inhibited the differentiation into alternatively activated macrophages by suppressing autophagy activation. In the co-culture system, invitro polarization of RAW264.7 macrophages toward an alternatively activated phenotype stimulated the expression of α-smooth muscle actin and collagen in cardiac fibroblasts. However, the knockdown of RAGE and inhibition of autophagy in macrophages showed reduced fibroblast-to-myofibroblast transition (FMT). Collectively, our results suggest that RAGE plays an important role in the recruitment and activation of alternatively activated macrophages by regulating autophagy, which contributes to MF. Thus, blockage of RAGE signaling may be an attractive therapeutic target for the treatment of hypertensive heart disease.

Biomimetic nanoparticles loaded lutein functionalized by macrophage membrane for targeted amelioration pressure overload-induced cardiac fibrosis

Lutein is a strong antioxidant with anti-inflammatory, anti-oxidative and cardioprotective effects and could be a promising candidate for the treatment of hypertensive heart disease (HHD), but is not clinically appealing because of its low oral bioavailability and main distribution in the eyes. To address this, a biomimetic drug delivery system-MMLNPs was established by coating macrophage membranes (MMs) onto lutein-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (LNPs). This study characterized the physical properties of biomimetic nanoparticles and examined the targeting capability, therapeutic effects and mechanism, and biosecurity of administering them for cardiac fibrosis therapy in the transverse aortic constriction (TAC) model and in vitro. Transmission electron microscope mapping and dynamic light scattering analysis proved that MMLNPs were spherical nanoparticles camouflaged by a layer of cell membrane and had negative zeta potential. Confocal laser scanning microscopy and flow cytometry analysis showed that MMs on the biomimetic nanoparticles hindered the phagocytosis of macrophages and facilitated the targeting of activated endothelial cells. Ex vivo fluorescence imaging experiments demonstrated the targeting of biomimetic nanoparticles to the injured heart. EdU assay indicated that MMLNPs have the same potential to inhibit angiotensin (Ang) II-induced cardiac fibroblast proliferation as free lutein. Furthermore, echocardiography showed that MMLNPs improved cardiac function and structure, and Masson staining and western blotting showed that MMLNPs ameliorated cardiac fibrosis. We found MMLNPs inhibited the interleukin (IL)-11/ERK signaling pathway which was up-regulated in the TAC model compared to the sham-operated mouse. Biochemical testing and hematoxylin and eosin staining proved that the long-term use of MMLNPs lacked biological toxicity. Collectively, MMLNPs might be a promising nanodrug delivery approach to attenuate pressure overload (PO)-induced cardiac fibrosis.

Efficacy of the combination of valsartan and hydrochlorothiazide in the treatment of hypertensive heart disease

Purpose: To investigate the effectiveness of the combination of valsartan and hydrochlorothiazide in managing hypertensive heart disease.Methods: From August 2020 to October 2022, the case data of 120 patients in Lu’an Hospital of Anhui Medical University, Lu’an, China were analyzed retrospectively. Based on the different treatment options, 54 patients with hypertensive heart disease who received valsartan alone (80 mg, once daily) for 3 months were placed in control group (CG), while 66 patients who received valsartan combined with Systolic blood pressure (SBP), therapeutic effect, diastolic blood pressure (DBP), and incidence of adverse effects were also recorded for CG and SG.Results: In the SG, there were significant reductions in SBP, DBP, LVMI and LVPWT compared to CG, while EF showed significant increase after treatment (p < 0.05). In both groups, SBP, DBP, LVMI and LVPWT decreased significantly after treatment compared to pre-treatment values, but EF however showed a significant increase (p < 0.05). In the SG, there was a significant increase (p < 0.05) in the total effective rate compared to CG and there was also a significant reduction (p < 0.05) in the total incidence of adverse effects compared to CG.Conclusion: Valsartan combined with hydrochlorothiazide is more effective in treating patients with hypertensive heart disease than valsartan monotherapy alone. However, the combination treatment should be subjected to further clinical trials prior to its introduction into clinical practice.

Quinapril treatment curtails decline of global longitudinal strain and mechanical function in hypertensive rats.

Left ventricular (LV) global longitudinal strain (GLS) has been proposed as an early imaging biomarker of cardiac mechanical dysfunction. To assess the impact of angiotensin-converting enzyme (ACE) inhibitor treatment of hypertensive heart disease on LV GLS and mechanical function. The spontaneously hypertensive rat (SHR) model of hypertensive heart disease (n = 38) was studied. A subset of SHRs received quinapril (TSHR, n = 16) from 3 months (mo). Wistar Kyoto rats (WKY, n = 13) were used as controls. Tagged cardiac MRI was performed using a 4.7 T Varian preclinical scanner. The SHRs had significantly lower LV ejection fraction (EF) than the WKYs at 3 mo (53.0 ± 1.7% vs. 69.6 ± 2.1%, P < 0.05), 14 mo (57.0 ± 2.5% vs. 74.4 ± 2.9%, P < 0.05) and 24 mo (50.1 ± 2.4% vs. 67.0 ± 2.0%, P < 0.01). At 24 mo, ACE inhibitor treatment was associated with significantly greater LV EF in TSHRs compared to untreated SHRs (64.2 ± 3.4% vs. 50.1 ± 2.4%, P < 0.01). Peak GLS magnitude was significantly lower in SHRs hearts compared with WKYs at 14 months (7.5% ± 0.4% vs. 9.9 ± 0.8%, P < 0.05). At 24 months, Peak GLS magnitude was significantly lower in SHRs compared with both WKYs (6.5 ± 0.4% vs. 9.7 ± 1.0%, P < 0.01) and TSHRs (6.5 ± 0.4% vs. 9.6 ± 0.6%, P < 0.05). ACE inhibitor treatment curtails the decline in global longitudinal strain in hypertensive rats, with the treatment group exhibiting significantly greater LV EF and GLS magnitude at 24 mo compared with untreated SHRs.

NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload.

Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, the regulatory mechanism of inflammation and its role in the stressed heart remain unclear. IL-1β (interleukin-1β) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that neural signals activate the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1β production to induce adaptive hypertrophy in the stressed heart. C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7 (P2X purinoceptor 7), and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of ATP, were used for analysis. Pressure overload was induced by transverse aortic constriction. Various animal models were used, including pharmacological treatment with apyrase, lipopolysaccharide, 2'(3')-O-(4-benzoylbenzoyl)-ATP, MCC950, anti-IL-1β antibodies, clonidine, pseudoephedrine, isoproterenol, and bisoprolol, left stellate ganglionectomy, and ablation of cardiac afferent nerves with capsaicin. Cardiac function and morphology, gene expression, myocardial IL-1β and caspase-1 activity, and extracellular ATP level were assessed. In vitro experiments were performed using primary cardiomyocytes and fibroblasts from rat neonates and human microvascular endothelial cell line. Cell surface area and proliferation were assessed. Genetic disruption of NLRP3 resulted in significant loss of IL-1β production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac nonimmune cells in myocardial IL-1β production and cardiac phenotype. Pharmacological depletion of extracellular ATP or genetic disruption of the P2X7 receptor suppressed myocardial NLRP3 inflammasome activity during pressure overload, indicating an important role of ATP/P2X7 axis in cardiac inflammation and hypertrophy. Extracellular ATP induced hypertrophic changes of cardiac cells in an NLRP3- and IL-1β-dependent manner in vitro. Manipulation of the sympathetic nervous system suggested sympathetic efferent nerves as the main source of extracellular ATP. Depletion of ATP release from sympathetic efferent nerves, ablation of cardiac afferent nerves, or a lipophilic β-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1β production, and adaptive cardiac hypertrophy during pressure overload. Cardiac inflammation and hypertrophy are regulated by heart-brain interaction. Controlling neural signals might be important for the treatment of hypertensive heart disease.

The Mechanism Actions of Astragaloside IV Prevents the Progression of Hypertensive Heart Disease Based on Network Pharmacology and Experimental Pharmacology.

Astragaloside IV (AS-IV) has been used to treat cardiovascular disease. However, whether AS-IV exerts a protective effect against hypertensive heart disease has not been investigated. This study aimed to investigate the antihypertensive and cardioprotective effects of AS-IV on L-NAME-induced hypertensive rats via network pharmacology and experimental pharmacology. The network pharmacology and bioinformatics analyses were performed to obtain the potential targets of AS-IV and hypertensive heart disease. The rat hypertension model was established by administrated 50 mg/kg/day of L-NAME for 5 weeks. Meanwhile, hypertension rats were intragastrically administrated with vehicle or AS-IV or fosinopril for 5 weeks. Cardiovascular parameters (systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rates, and body weight), cardiac function parameters (LVEDd, LVEDs, and fractional shortening), cardiac marker enzymes (creatine kinase, CK-MB, and lactate dehydrogenase), cardiac hypertrophy markers (atrial natriuretic peptide and brain natriuretic peptide), endothelial function biomarkers (nitric oxide and eNOS), inflammation biomarkers (IL-6 and TNF-α) and oxidative stress biomarkers (SOD, MDA, and GSH) were measured and cardiac tissue histology performed. Network pharmacological analysis screened the top 20 key genes in the treatment of hypertensive heart disease treated with AS-IV. Besides, AS-IV exerted a beneficial effect on cardiovascular and cardiac function parameters. Moreover, AS-IV alleviated cardiac hypertrophy via down-regulating the expression of ANP and BNP and improved histopathology changes of cardiac tissue. AS-IV improved endothelial function via the up-regulation of eNOS expression, alleviated oxidative stress via increasing antioxidant enzymes activities, and inhibited cardiac inflammation via down-regulating IL-6 and TNF-α expression. Our findings suggested that AS-IV is a potential therapeutic drug to improve L-NAME-induced hypertensive heart disease partly mediated via modulation of eNOS and oxidative stress.

Treatment of Hypertensive Heart Disease by Targeting Smad3 Signaling in Mice

Transforming growth factor β (TGF-β)/Smad3 signaling plays a central role in chronic heart disease. Here, we report that targeting Smad3 with a Smad3 inhibitor SIS3 in an established mouse model of hypertension significantly improved cardiac dysfunctions by preserving the left ventricle (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS), while reducing the LV mass. In addition, SIS3 treatment also halted the progression of myocardial fibrosis by blocking α-smooth muscle actin-positive (α-SMA+) myofibroblasts and collagen matrix accumulation, and inhibited cardiac inflammation by suppressing interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP1), intercellular cell adhesion molecule-1 (ICAM1) expression, and infiltration of CD3+ T cells and F4/80+ macrophages. Interestingly, treatment with SIS3 did not alter levels of high blood pressure, revealing a blood pressure-independent cardioprotective effect of SIS3. Mechanistically, treatment with SIS3 not only directly inactivated TGF-β/Smad3 signaling but also protected cardiac Smad7 from Smurf2-mediated proteasomal ubiquitin degradation. Because Smad7 functions as an inhibitor for both TGF-β/Smad and nuclear factor κB (NF-κB) signaling, increased cardiac Smad7 could be another mechanism through which SIS3 treatment blocked Smad3-mediated myocardial fibrosis and NF-κB-driven cardiac inflammation. In conclusion, SIS3 is a therapeutic agent for hypertensive heart disease. Results from this study demonstrate that targeting Smad3 signaling with SIS3 may be a novel and effective therapy for chronic heart disease.

Effect of Milrinone injection on hypertensive heart disease complicated with heart failure

Objective To observe and analyze the clinical effect of Milrinone injection in the treatment of hypertensive heart disease complicated with heart failure. Methods From February 2016 to January 2017, 80 patients with hypertensive heart disease complicated with heart failure in Cilin Hospital were selected and randomly divided into observation group and control group according to the digital table, with 40 cases in each group.The control group was given conventional therapy, including antihypertensive therapy and the treatment of heart failure and so on.The observation group was treated with Milrinone injection on the basis of the control group.The clinical manifestations of the two groups were compared and analyzed. Results The cardiac function indicators, B-type natriuretic peptide (BNP) and 6MWD in the observation group were better than those in the control group after treatment [observation group: HR (59.31±2.03) times/min, LVEF (55.98±5.31)%, LVEDd (54.37±0.83)mm, SBP (119.53±7.04)mmHg, DBP(67.31±2.94)mmHg, BNP (198.32±21.54)ng/L, 6MWD (332.61±52.70)m; control group: HR (67.63±2.95)min, LVEF (40.51±4.96)%, LVEDd (60.55±1.47)mm, SBP (128.47±8.35)mmHg, DBP (76.37±3.75)mmHg, BNP (227.43±25.96)ng/L, 6MWD (254.78±26.16)m], the differences were statistically significant (t=14.6943, 13.4651, 23.1532, 5.1769, 12.0250, 20.5215, 8.3663, all P<0.05). The incidence rate of adverse reactions of the observation group (7.5%) was lower than that of the control group (10.0%), the difference was not statistically significant (χ2=0.156, P<0.05). Conclusion Milrinone injection in the treatment of hypertensive heart disease has good effect, can obviously decrease BNP concentration, increase the patients' life quality, and with no obvious adverse conditions. Key words: Hypertension; Heart disease; Heart failure; Milrinone injection

Abstract 026: Gut Bacteria Metabolite Attenuates Ang II-induced Cardiac Damage

Increasing evidence suggests that the gut microbiota critically influence host health and immune homeostasis. Microbiome-host communication occurs via gut bacterial metabolites which are resorbed by the host and target various organs. Short-chain fatty acids (SCFA) are produced from bacterial fermentation, are highly abundant in the gut but can also be detected in the blood. Recently, the SCFA propionate has been shown to regulate T cell differentiation into effector and regulatory T cells in peripheral tissues. Since activation of the immune system is known to substantially contribute to hypertensive target organ damage and anti-inflammatory strategies have been shown to be beneficial in animal models, we hypothesized that treatment with propionate would be beneficial in angiotensin (AngII)-induced target organ damage. Male NMRI mice received AngII infusions for two weeks and propionate (P) or vehicle (C) in drinking water. To deplete endogenous SCFA production mice were fed a low-fibre diet. Body weight was similar among all groups. Propionate treatment significantly reduced albuminuria (C 1143 ± 193; P 302 ± 69 μg/d). Propionate significantly reduced cardiac hypertrophy as measured by heart-to-tibia ratio (C 10.1 ± 0.4; P 8.9 ± 0.4 mg/mm) and was confirmed by echocardiography. Propionate treatment significantly reduced interstitial (C 16.5 ± 0.8%; P 6.6 ± 0.2%) and perivascular cardiac fibrosis (C 1.5 ± 0.06; P 1.1 ± 0.03 μm/μm) as measured by fibronectin and collagen I immunofluorescence, respectively. In vivo cardiac electrophysiology studies showed a significantly reduced susceptibility to ventricular arrhythmias in propionate-treated mice (C 71 ± 14%; P 24 ± 16%), indicating the functional relevance of the improved cardiac morphology. Propionate reduced the expression of IL-17 in CD4+ T cells in spleen and lymph nodes as measured by flow cytometry. Our data indicate that propionate attenuates AngII-induced cardiac remodeling and reduces susceptibility to arrhythmias. The gut microbiome is a promising target for treatment of hypertensive heart disease.

Sinapic acid prevents hypertension and cardiovascular remodeling in pharmacological model of nitric oxide inhibited rats.

ObjectivesHypertensive heart disease is a constellation of abnormalities that includes cardiac fibrosis in response to elevated blood pressure, systolic and diastolic dysfunction. The present study was undertaken to examine the effect of sinapic acid on high blood pressure and cardiovascular remodeling.MethodsAn experimental hypertensive animal model was induced by L-NAME intake on rats. Sinapic acid (SA) was orally administered at a dose of 10, 20 and 40 mg/kg body weight (b.w.). Blood pressure was measured by tail cuff plethysmography system. Cardiac and vascular function was evaluated by Langendorff isolated heart system and organ bath studies, respectively. Fibrotic remodeling of heart and aorta was assessed by histopathologic analyses. Oxidative stress was measured by biochemical assays. mRNA and protein expressions were assessed by RT-qPCR and western blot, respectively. In order to confirm the protective role of SA on endothelial cells through its antioxidant property, we have utilized the in vitro model of H2O2-induced oxidative stress in EA.hy926 endothelial cells.ResultsRats with hypertension showed elevated blood pressure, declined myocardial performance associated with myocardial hypertrophy and fibrosis, diminished vascular response, nitric oxide (NO) metabolites level, elevated markers of oxidative stress (TBARS, LOOH), ACE activity, depleted antioxidant system (SOD, CAT, GPx, reduced GSH), aberrant expression of TGF-β, β-MHC, eNOS mRNAs and eNOS protein. Remarkably, SA attenuated high blood pressure, myocardial, vascular dysfunction, cardiac fibrosis, oxidative stress and ACE activity. Level of NO metabolites, antioxidant system, and altered gene expression were also repaired by SA treatment. Results of in vitro study showed that, SA protects endothelial cells from oxidative stress and enhance the production of NO in a concentration dependent manner.ConclusionsTaken together, these results suggest that SA may have beneficial role in the treatment of hypertensive heart disease by attenuating fibrosis and oxidative stress through its antioxidant potential.

Clinical analysis of 56 gestational hypertension patients with heart disease

Objective To investigate the early diagnosis and preventive measures for gestational hypertensive patients with heart disease.Methods Clinical data of 56 gestational hypertensive patients with heart disease were retrospectively analyzed.Results Aggressive treatment of maternal deaths occured in 1 case,2 cases of stillbirth,and the other 55 cases had good maternal prognosis.Conclusion Treatment of hypertensive heart disease in pregnancy should be based on the strong heart vasodilator,diuretic,caution magnesium sulfate.In the control of heart failure after 6-8h,shall terminate the pregnancy.Active treatment of the primary disease,to correct anemia and hypoproteinemia,early diagnosis of heart failure and strictly control expansion of indications can help to improve the prognosis of hypertensive heart disease in pregnancy. Key words: Gestational hypertension; Heart disease; Heart failure

Neuromodulation Device Therapy for Treatment of Hypertensive Heart Disease

Hypertensive heart disease (HHD) is the leading cause of mortality and morbidity in the United States. Despite the availability of medical therapy it remains a challenge to treat. Autonomic nervous system imbalance resulting in overactivity of the sympathetic nervous system and under activity of the parasympathetic nervous system is integral in the development of hypertension and ultimately the development of HHD. Emerging data suggest that neuromodulation device therapy for treatment of HHD is promising.

Cardiac Specific Gene Delivery of a Dual GC-A and GC-B Agonist, CD-NP, Mediates Anti-Hypertrophic Actions in a Model of Hypertensive Heart Disease beyond GC-A Activation Alone Via BNP

Introduction: Hypertensive heart disease (HHD) is characterized by altered myocardial structure and function, which is leading cause of heart failure and death. CD-NP is a newly developed dual guanylyl cyclase (GC)-A and GC-B agonist that is currently in clinical trials in post acute heart failure as a chronically delivered peptide. CD-NP has direct anti-hypertrophic and anti-fibrotic actions independent of blood pressure lowering. Hypothesis: We hypothesized that cardiac overexpression of CD-NP would result in a superior anti-remodeling effect than a single GC-A agonist, BNP.Methods: Here we defined the chronic effects of cardiac overexpression of CDNP we using adeno-associated vector serotype 9 (AAV9) in spontaneously hypertensive rats (SHR). We further compared the cardiac action of CD-NP to those of the single GC-A agonist, BNP. Results: The main findings of the study are illustrated on figure 1. A single intravenous injection of AAV9 induced sustained overexpression of CD-NP and BNP in the heart of SHR as verified by ELISA. The CNP ELISA assay also detected modest, but significantly elevated levels of circulating CD-NP in plasma. More importantly, compared to chronic overexpression of BNP, that has previously shown to induce significant reduction of cardiac weight, CD-NP had greater anti-hypertrophic actions 5 weeks post injection (p!0.05). Importantly, the anti-hypertrophic effects of CD-NP occurred with no changes in BP, suggesting a direct cardiac effect of this autacoid. Conclusion: Our studies demonstrate successful sustained cardiac CD-NP overexpression through a single systemic gene delivery approach. Of note, this novel peptide that combines the anti-hypertrophic and anti-fibrotic actions of both GC-A and GC-B activation, resulted in a significant reduction of cardiac mass, which was independent of BP lowering action and greater than that of the single CG-A agonist, BNP. These studies underscore that gene delivery of CD-NP can be useful in the treatment of HHD.

Traditional and Novel Markers of Renal Function and Outcomes in Outpatients with Heart Failure: The Atlanta Cardiomyopathy Consortium (TACC)

Introduction: Hypertensive heart disease (HHD) is characterized by altered myocardial structure and function, which is leading cause of heart failure and death. CD-NP is a newly developed dual guanylyl cyclase (GC)-A and GC-B agonist that is currently in clinical trials in post acute heart failure as a chronically delivered peptide. CD-NP has direct anti-hypertrophic and anti-fibrotic actions independent of blood pressure lowering. Hypothesis: We hypothesized that cardiac overexpression of CD-NP would result in a superior anti-remodeling effect than a single GC-A agonist, BNP.Methods: Here we defined the chronic effects of cardiac overexpression of CDNP we using adeno-associated vector serotype 9 (AAV9) in spontaneously hypertensive rats (SHR). We further compared the cardiac action of CD-NP to those of the single GC-A agonist, BNP. Results: The main findings of the study are illustrated on figure 1. A single intravenous injection of AAV9 induced sustained overexpression of CD-NP and BNP in the heart of SHR as verified by ELISA. The CNP ELISA assay also detected modest, but significantly elevated levels of circulating CD-NP in plasma. More importantly, compared to chronic overexpression of BNP, that has previously shown to induce significant reduction of cardiac weight, CD-NP had greater anti-hypertrophic actions 5 weeks post injection (p!0.05). Importantly, the anti-hypertrophic effects of CD-NP occurred with no changes in BP, suggesting a direct cardiac effect of this autacoid. Conclusion: Our studies demonstrate successful sustained cardiac CD-NP overexpression through a single systemic gene delivery approach. Of note, this novel peptide that combines the anti-hypertrophic and anti-fibrotic actions of both GC-A and GC-B activation, resulted in a significant reduction of cardiac mass, which was independent of BP lowering action and greater than that of the single CG-A agonist, BNP. These studies underscore that gene delivery of CD-NP can be useful in the treatment of HHD.

Both Estrogen Receptor Subtypes, α and β, Attenuate Cardiovascular Remodeling in Aldosterone Salt–Treated Rats

Experimental and population-based studies indicate that female gender and estrogens protect the cardiovascular system against aldosterone-induced injury. Understanding the function of estrogens in heart disease requires more precise information on the role of both estrogen receptor (ER) subtypes, ERalpha and ERbeta. Therefore, we determined whether selective activation of ERalpha or of ERbeta would confer redundant, specific, or opposing effects on cardiovascular remodeling in aldosterone salt-treated rats. The ERalpha agonist 16alpha-LE2, the ERbeta agonist 8beta-VE2, and the nonselective estrogen receptor agonist 17beta-estradiol lowered elevated blood pressure, cardiac mass, and cardiac myocyte cross-sectional areas, as well as increased perivascular collagen accumulation and vascular osteopontin expression in ovariectomized rats receiving chronic aldosterone infusion plus a high-salt diet for 8 weeks. Uterus atrophy was prevented by 16alpha-LE2 and 17beta-estradiol but not by 8beta-VE2. Cardiac proteome analyses by 2D gel electrophoresis, mass spectrometry, and peptide sequencing identified specific subsets of proteins involved in cardiac contractility, energy metabolism, cellular stress response and extracellular matrix formation that were regulated in opposite directions by aldosterone salt treatment and by different estrogen receptor agonists. We conclude that activation of either ERalpha or ERbeta protects the cardiovascular system against the detrimental effects of aldosterone salt treatment and confers redundant, as well as specific, effects on cardiac protein expression. Nonfeminizing ERbeta agonists such as 8beta-VE2 have a therapeutic potential in the treatment of hypertensive heart disease.

Amlodipine Better Than Lisinopril?

The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) compared in >30 000 high-risk hypertensive patients the effects on coronary heart disease of 3 treatment strategies: (1) based on the diuretic chlorthalidone, (2) the calcium-channel blocker (CCB) amlodipine, and (3) the angiotensin converting-enzyme (ACE) inhibitor lisinopril, respectively.1 Sponsored by the National Heart, Lung, and Blood Institute, ALLHAT stands out because no differences occurred in the incidence of the primary end point that consisted of the combination of fatal coronary heart disease and acute myocardial infarction.1 Not surprisingly, the attention of the ALLHAT consortium shifted to secondary end points, such as stroke, or to loosely defined2 components of secondary end points, such as heart failure. At the end of the line, the ALLHAT investigators based their main conclusions on events that, at the initiation of the trial, they regarded as “soft data that will at best confirm or supplement the primary endpoint.”3 More importantly, what was not identical in the 3 treatment groups was the on-treatment blood pressure despite vigorous attempts to titrate and combine the study medications to achieve a blood pressure of <140 mm Hg systolic and 90 mm Hg diastolic.1 These salient features of ALLHAT should be kept in mind whenever one attempts to interpret the findings of this landmark trial. In this issue of Hypertension , Leenen et al4 published a post hoc analysis, in which they made a direct comparison of cardiovascular and other outcomes among the 18 102 ALLHAT participants randomly assigned to amlodipine or lisinopril. In line with previous reports,1 the incidence of the primary coronary end point and total and cardiovascular mortality were similar in both groups. However, the patients randomly assigned to lisinopril experienced higher risks of stroke, combined cardiovascular disease, gastrointestinal bleeding, …

New directions in the assessment and treatment of hypertensive heart disease

This article will review briefly the emerging new concepts in the diagnosis and treatment of myocardial fibrosis in patients with hypertensive heart disease. Although hypertensive heart disease is characterized clinically by development of left-ventricular hypertrophy in the absence of a cause other than arterial hypertension, changes in the composition of myocardial tissue also develop in arterial hypertension leading to structural remodeling of the myocardium (e.g. fibrosis). Recent available data on the determination of serum concentrations of collagen-derived serum peptides and quantitative analysis of echoreflectivity to address the presence of fibrosis in the myocardium of hypertensive patients are promising. In addition, preliminary data suggest that the goal of reducing myocardial fibrosis is achievable in patients with hypertensive heart disease using specific antihypertensive agents (e.g. those interfering with angiotensin II). The time has come to revisit the current management of hypertensive heart disease simply focused on detecting left-ventricular hypertrophy and controlling blood pressure to reduce left-ventricular mass. It is necessary to develop new approaches aimed at assessing and repairing alterations of myocardial structure and protect myocardial function and, in so doing, to reduce in a more-effective manner adverse risk associated with hypertensive heart disease.

Early recognition and treatment of hypertensive heart disease

Hypertension leads to left ventricular hypertrophy, diastolic dysfunction, and eventually clinical heart failure (hypertensive heart disease). There is an important need for physicians to recognize this entity, understand its pathophysiology, and become fluent in treatment options available. This review of recent basic science and clinical data serves to accomplish this task. In the past year, a number of exciting concepts have come to the forefront. First, data on the use of brain natriuretic peptide as a screening biomarker has shown promise in patients with symptoms of heart failure. For the earliest detection of structural changes, serum propeptide of procollagen type I, a marker of the deposition of type I collagen in the cardiac interstitium provides a noninvasive way to quantify myocardial fibrosis. Treatment options in the past few years have focused heavily on the anti-fibrotic effects of inhibitors of the renin-angiotensin-aldosterone system, perhaps supplanting beta blockers as first-line agents to regress left ventricular hypertrophy. The concept of aldosterone escape is discussed, highlighting the importance of aldosterone inhibitors in these patients. Lastly, we provide a comprehensive review of all antihypertensive classes and their effects on hypertensive heart disease. The incidence of hypertensive heart disease is increasing. Earlier detection may be possible with newly studied serum biomarkers. All anti-hypertensive treatments have shown improvement in regressing left ventricular hypertrophy, but inhibitors of the renin-angiotensin-aldosterone system possess the most potent anti-fibrotic effects. It is increasingly important for clinicians to identify and manage hypertensive heart disease to prevent increased morbidity and mortality.

Hypertensive Heart Disease

Left ventricular hypertrophy (LVH) and diastolic dysfunction (CHF-D) are the early manifestations of cardiovascular target organ damage in patients with arterial hypertension and signify hypertensive heart disease. Identification of hypertensive heart disease is critical, as these individuals are more prone to congestive heart failure, arrhythmias, myocardial infarction and sudden cardiac death. Regression of left ventricular (LV) mass with antihypertensive therapy decreases the risk of future cardiovascular events. The goal of antihypertensive therapy is to both lower blood pressure (BP) and interrupt BP-independent pathophysiologic processes that promote LVH and CHF-D. The purpose of this review is to summarize current and emerging approaches to the pathophysiology and treatment of hypertensive heart disease.

Intramyocardial Injection of Fibroblast Growth Factor-2 Plus Heparin Suppresses Cardiac Failure Progression in Rats With Hypertensive Heart Disease

A reduction of coronary flow reserve has been reported in patients with hypertensive heart disease (HHD), which suggests that myocardial ischemia may contribute to the progression to cardiac failure in HHD. Therefore, we evaluated whether fibroblast growth factor (FGF)-2 and/or heparin, which induce angiogenesis, may affect cardiac function in the setting of HHD. We used Dahl salt sensitive (DS) rats as an HHD model. Direct intramyocardial injection of 100 microg of FGF-2 plus 1.28 microg of heparin (n = 6), 100 microg of FGF-2 (n = 6), 1.28 microg of heparin (n = 6) or saline (n = 6) were performed in 9-week-old rats. Echocardiography was performed to evaluate cardiac function at 9, 11, and 13 weeks of age. Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations were measured at 8 and 13 weeks of age. DS rats were killed 4 weeks after myocardial injection (at 13 weeks of age), and myocardial capillary density was assessed by von Willebrand factor staining. Injection of FGF-2 plus heparin significantly decreased left ventricular end-diastolic diameter (P < 0.0001) and left ventricular end-systolic diameter (P < 0.0001), significantly improved the reduction of left ventricular fractional shortening (P = 0.0005), significantly decreased plasma ANP (P < 0.0001) and BNP (P = 0.016) concentrations, and significantly increased myocardial capillary density (P = 0.0002) compared with injection of saline. These findings indicate that intramyocardial injection of FGF-2 plus heparin suppresses the progression of cardiac failure in DS rats. FGF-2 plus heparin administration may be a new therapeutic strategy for the treatment of HHD.