Hypertensive Cardiac Hypertrophy Research Articles

Abstract 203: Angiotensin II Induced ER Stress in the Heart is Attenuated by Exercise

Recent evidence indicates that endoplasmic reticulum (ER) stress plays an important pathophysiological role in a number of chronic diseases including cardiovascular disease. In this study, we demonstrate that ANGII-induced ER stress in the heart is attenuated by exercise. Methods: Male rats were implanted with telemetry probes and trained to do exercise. After collecting baseline blood pressure, hypertension was induced by implanting osmotic minipumps containing ANGII 200ng/kg/min for 42 days or saline. Rats were randomized into sedentary (SED) or exercise trained (ExT). BP and cardiac functions were measured by radiotelemetry and echocardiography. At the end of the study, heart tissues were analyzed for ER stress and hypertrophy markers by real time RT-PCR and Western blotting. Results: are tabulated. The protein expression pattern for Grp78 and CHOP were similar to mRNA. Conclusions: 1. ANGII infusion induces ER stress in the heart and contributes to cardiac hypertrophy. 2. EXT attenuates hypertensive response, cardiac hypertrophy and ER stress. 3. ER stress and ROS dependent mechanism contribute to ANGII induced cardiac hypertrophy and contribute to the development of hypertension.

Relationship of Cardiac Sympathetic Nerve Innervation and Excitability to Cardiac Hypertrophy in Very Elderly Male Hypertensive Patients

Our study aimed to disclose the relationship of cardiac sympathetic nerve innervation and excitability to myocardial hypertrophy in very old elderly male hypertensive patients with low serum testosterone level. A total of 80 elderly male hypertensive patients aged from 80 to 95 years were recruited. Heart rate variability is determined by 24 h dynamic electrocardiogram and heart rate variability analysis system. Cardiac function and left ventricular mass index were determined using color Doppler ultrasound. Standard deviation of all normal sinus R-R intervals over 24 h (SDNN) significantly decreased in hypertensive cardiac hypertrophy patients as compared with those without cardiac hypertrophy. SDANN and Standard deviation of the average normal sinus R-R intervals for all 5-min segment index, time-domain index reflecting sympathetic nerve tension, obviously decreased and LFnu and LFnu/HFnu, frequency-domain index representing sympathetic nerve excitability, significantly increased in hypertensive cardiac hypertrophy patients as compared with those without cardiac hypertrophy. Myocardial norepinephrine content significantly increased while tyrosine hydroxylase expression significantly lowered in hypertensive cardiac hypertrophy patients, and a negative correlation between myocardial tyrosine hydroxylase expression and myocardial norepinephrine content was present. Serum total testosterone level decreased in hypertensive cardiac hypertrophy patients and was an independent risk factor for the increase in myocardial norepinephrine content and decrease in tyrosine hydroxylase expression. These data confirm that cardiac sympathetic nerve hypoinnervation and relative increase in cardiac sympathetic nerve excitability are closely related to cardiac hypertrophy in very old hypertensive patients. A lower serum total testosterone level was the independent risk factor of cardiac sympathetic nerve hypoinnervation and relative increase in excitability in very old male hypertensive patients.

Profilin-1 promotes the development of hypertension-induced cardiac hypertrophy

Cardiac hypertrophy is a major cause of heart failure and sudden cardiac death among hypertensive individuals. The present study examined the effects of profilin-1 on hypertension-induced cardiac hypertrophy. We used adenovirus injection to knockdown or overexpress profilin-1 in spontaneous hypertensive rats (SHRs). As a control, blank adenovirus was injected into age-matched SHRs and Wistar-Kyoto rats (WKYs). SBP and cardiac mass index were measured. Cardiac tissues were stained with hematoxylin-eosin and sirius red, and cardiac ultrastructure was imaged using transmission electron microscopy. Actin filament was quantified by staining with TRIC-tagged phalloidin. Caveolin-3 abundance and endothelial nitric oxide synthase (eNOS) activity were measured using real-time quantitative PCR, Western blot or immunofluorescence staining. Endogenous profilin-1 was highly expressed in hypertrophic myocardium of SHRs compared with WKYs. Lowering profilin-1 expression in SHRs significantly attenuated hypertension-induced cardiac hypertrophy and fibrosis and displayed a significant preservation of myofibrils, sarcolemmal caveolae, abundance of caveolin-3 protein, activity of eNOS and production of nitric oxide (NO). In contrast, transgenic overexpression of profilin-1 in SHRs induced more serious cardiac hypertrophy and fibrosis with significant reduction of sarcolemmal caveolae, caveolin-3 protein, eNOS activity, and production of NO when compared with SHR controls. Profilin-1 promotes cardiac hypertrophy partly through interfering with the formation of sarcolemmal caveolae and attenuating the eNOS/NO pathway. These results demonstrate a crucial role for profilin-1 in hypertensive cardiac hypertrophy.

Left Ventricular Twisting as Determinant of Diastolic Function: A Speckle Tracking Study in Patients with Cardiac Hypertrophy

Left ventricular hypertrophy (LVH) can develop in response to training with morphological changes in the heart and to pathological increase in afterload such as in essential hypertension. Deformation analysis using two-dimensional (2D) strain echocardiography can detect early systolic function abnormalities in patients with LVH. The aim of this study was to characterize left ventricular twisting (LVT) modifications, in professional athletes, compared with control subjects and with patients with hypertensive cardiopathy. Seventy-six patients were enrolled: 37 professional athletes with cardiac hypertrophy (group A), 22 patients with early hypertensive cardiopathy (group B) cross-matched for LV mass index, and 17 healthy controls (group C), with no evidence of cardiac hypertrophy. All patients had no concomitant cardiac disease. All patients were investigated at rest using transthoracic echocardiography. LVT was obtained with speckle tracking analysis, using dedicated software. LVT was reduced in group A compared to group B and C (group A: 8.0° ± 2.4°; group C: 10.3° ± 2.3°; group B: 16.0° ± 4.2°; P < 0.01). In overall population, LVT showed a significant correlation with transmitral flow pattern (r =-0.58, P < 0.01) and with age (r =-0.57, P < 0.01). LVT showed the best predictive value to diagnose diastolic dysfunction (AUC: 0.86, P < 0.0001). 2D strain can identify specific patterns of myocardial deformation in professional athletes, controls, and patients with early hypertensive cardiopathy. In our study LVT showed a parallel trend with modifications of diastolic function and could represent a promising tool to differentiate functional cardiac hypertrophy from hypertensive cardiac hypertrophy.

Additive beneficial effects of amlodipine and atorvastatin in reversing advanced cardiac hypertrophy in elderly spontaneously hypertensive rats

1. Additive beneficial effects on cardiovascular disease have been reported for amlodipine and atorvastatin. However, it is still unclear whether the combination of amlodipine and atorvastatin has additive beneficial effects on the regression of advanced cardiac hypertrophy in hypertension. In the present study, the effects of the drug combination on advanced cardiac hypertrophy were investigated in elderly spontaneously hypertensive rats (SHR). 2. Elderly SHR (36 weeks old) were randomly allocated into four groups of 12: (i) a vehicle-treated control group; (ii) an amlodipine (10 mg/kg per day)-treated group; (iii) an atorvastatin (10 mg/kg per day)-treated group; and (iv) a group treated with a combination of amlodipine and atorvastatin (both at 10 mg/kg per day). Drugs were administered by oral gavage every morning for a period of 12 weeks before hearts were harvested for analysis. 3. Combined administration of amlodipine and atorvastatin significantly suppressed cardiomyocyte hypertrophy, interstitial fibrosis and upregulation of hypertrophic and profibrotic genes, and also improved left ventricular diastolic dysfunction to a greater extent than did amlodipine monotherapy. Further beneficial effects of combination therapy on advanced cardiac hypertrophy were associated with a greater reduction of NADPH oxidase-mediated increases in cardiac reactive oxygen species (ROS), rather than decreased blood pressure and serum cholesterol levels. 4. To elucidate the underlying molecular mechanisms, we examined cardiovascular NADPH oxidase subunits and found that amlodipine clearly attenuated the expression of p47(phox) and p40(phox) and slightly but significantly reduced p22(phox) and Rac-1 levels in heart tissue. Combination treatment with amlodipine plus atorvastatin led to a further reduction in p22(phox), p47(phox) and Rac-1 protein levels compared with amlodipine alone. 5. In conclusion, combined amlodipine and atorvastatin treatment has a greater beneficial effect on advanced cardiac hypertrophy compared with amlodipine monotherapy. The benefits are likely to be related to the additive effects of the drugs on the suppression of NADPH oxidase-mediated ROS generation.

Copper Deficiency After Gastric Bypass Surgery

after adjusting by log-transformed age and BMI. Similarly, the quantitative trait diastolic arterial blood pressure was significantly associated with the variant (P < 0.023): homozygous CC: 74.2 ± 0.6, heterozygous CT: 76.2 ± 0.7 and homozygous TT: 78.1 ± 1.7 mm Hg. In summary, the findings of Lieb et al. can also be generalized to Argentinean population, as an example of replication in a different group of European descent. However, these results do not exclude other possible effects of the variants of the FAAH on metabolic syndrome–related phenotypes, for instance arterial blood pressure or plasma triglycerides. These data, which need to be confirmed in larger samples, may be of interest because the use of FAAH as a therapeutic target in hypertension is under evaluation not only because of the potential beneficial effect of endocannabinoid-related drugs on arterial blood pressure but also on the development of the hypertensive cardiac hypertrophy (2,3).

Genetic Variation in the FAAH Gene and Metabolic Syndrome–related Phenotypes

TO THE EDITOR: We read with great interest the article “Variants in the CNR1 and the FAAH Genes and Adiposity Traits in the Community” by Lieb et al. about a lack of association of common variants of the CNR1 and FAAH genes with surrogate measures of adiposity in a large community-based sample of individuals (1). The authors performed a comprehensive analysis of common variation across these two genes and observed no evidence for association of any variant with BMI, waist circumference, and visceral adipose tissue volume. In a smaller (n = 420) but well-characterized sample of adult men of self-reported European ancestry (aged 34.4 ± 0.4 years, mean ± s.e.), selected from a population-based study in Argentinean people, we explored the role of the C/T rs6703669-FAAH variant in the genetic susceptibility of metabolic syndrome–related phenotypes. The variant was selected as a tagSNP capturing common variation in the promoter region of the gene (pair-wise approach at r2 = 0.8, minor allele frequency >10%). Genotyping was performed by allele-specific PCR and genotypes were in Hardy–Weinberg equilibrium. In agreement with Lieb et al., we found no evidence of association between the variant and any of the obesity-related phenotypes: BMI as a continuous trait (logarithmically transformed) P = 0.9, waist circumference P = 0.25, obesity status as a discrete trait P = 0.24, and measurement of body fat content by bioelectrical impedance P = 0.4. Nevertheless, when we analyzed the serum lipid variables in relation to the rs6703669, a significant association was observed with plasma levels of triglycerides: homozygous CC 105.1 ± 5.9, heterozygous CT 131.3 ± 7.5 and homozygous TT 119.2 ± 15.5 mg/dl, P < 0.015, adjusted by log-transformed age and BMI. Accordingly, hypertriglyceridemia evaluated as a discrete trait (plasma triglycerides ≥150 mg/dl), also showed significant association with the variant (OR per T allele: 1.31, 95% CI 1.04–1.66, P < 0.022). Finally, we evaluated the possible association of the rs6703669 and other metabolic syndrome–related phenotypes and observed a significant association with arterial hypertension (dichotomized as a discrete trait): OR per T allele: 1.43, 95% CI 1.06–1.95, P = 0.01, after adjusting by log-transformed age and BMI. Similarly, the quantitative trait diastolic arterial blood pressure was significantly associated with the variant (P < 0.023): homozygous CC: 74.2 ± 0.6, heterozygous CT: 76.2 ± 0.7 and homozygous TT: 78.1 ± 1.7 mm Hg. In summary, the findings of Lieb et al. can also be generalized to Argentinean population, as an example of replication in a different group of European descent. However, these results do not exclude other possible effects of the variants of the FAAH on metabolic syndrome–related phenotypes, for instance arterial blood pressure or plasma triglycerides. These data, which need to be confirmed in larger samples, may be of interest because the use of FAAH as a therapeutic target in hypertension is under evaluation not only because of the potential beneficial effect of endocannabinoid-related drugs on arterial blood pressure but also on the development of the hypertensive cardiac hypertrophy (2,3). This study was partially supported by PICT 05-25920 (Agencia Nacional de Promoción Científica y Tecnológica). A.L.B., S.S., C.G., and C.J.P. belong to Consejo Nacional de Investigaciones Científicas y Técnicas. A.L.B. is recipient of a Health Ministry Fellowship (Beca Ramón Carrillo-Arturo Oñativia Ministerio de Salud y Ambiente de la Nación) Convocatoria 2008. The authors declared no conflict of interest.

Interaction Among Heme Oxygenase, Nuclear Factor-κB, and Transcription Activating Factors in Cardiac Hypertrophy in Hypertension

Deoxycorticosterone acetate-induced hypertension is a volume overload and human primary aldosteronism model characterized by severe cardiac lesions attributed to elevated inflammation, oxidative stress, fibrosis, and hypertrophy. An important cytoprotective pathway that counteracts tissue insults is the heme oxygenase (HO) system. Although the HO-1 gene promoter contains consensus binding sites for proinflammatory/oxidative transcription factors like nuclear factor-kappaB, activating protein (AP)-1, and AP-2, the effects of HO inducers on these transcription factors in cardiac lesions of deoxycorticosterone acetate hypertension are not fully understood. Hemin therapy normalized systolic blood pressure and markedly reduced the left:right ventricular ratio, left ventricular wall thickness, and left ventricle:body weight ratio, whereas the HO blocker, chromium mesoporphyrin, exacerbated cardiac fibrosis/hypertrophy in deoxycorticosterone acetate-hypertensive rats. The cardioprotection by hemin was accompanied by increased HO-1, HO activity, cGMP, superoxide dismutase, catalase, the total antioxidant capacity alongside the reduction of 8-isoprostane, AP-1, AP-2, nuclear factor-kappaB, and c-Jun-NH(2)-terminal kinase, whereas chromium mesoporphyrin abolished the hemin effects. Furthermore, hemin therapy attenuated transforming growth factor-beta(1) and extracellular matrix proteins like fibronectin and collagen, with a corresponding reduction of histopathologic lesions, including longitudinal/cross-sectional muscle fiber thickness, scarring, muscular hypertrophy, coronary arteriolar thickening, and collagen deposition. The suppression of AP-1, AP-2, nuclear factor-kappaB, and c-Jun-NH(2)-terminal kinase proinflammatory/oxidative mediators in the left ventricle of hemin-treated animals is a novel observation that may account for cardioprotection in deoxycorticosterone acetate hypertension. By concomitantly upregulating HO activity and cGMP and potentiating the total antioxidant status, hemin therapy reduced hypertension, suppressed oxidative stress, and attenuated extracellular matrix and remodeling proteins, with a reduction of histopathologic lesions that characterize cardiac fibrosis, hypertrophy, and end-stage organ damage.

Atrial natriuretic peptide gene promoter polymorphism is associated with left ventricular hypertrophy in hypertension

Recent studies suggest that the ANP (atrial natriuretic peptide)/NPRA (type A natriuretic peptide receptor) system modulates ventricular remodelling and cardiac hypertrophy in hypertension in Western populations. In the present study, we tested for any association between two SNPs (single nucleotide polymorphisms) in the ANP gene (one in the promoter and one exonic) with cardiac hypertrophy. We tested the hypothesis in 2118 hypertensive patients, including 945 with LVH [LV (left ventricular) hypertrophy] and 1173 without LVH, as well as 816 healthy control subjects. All subjects were genotyped for the -A2843G and A188G polymorphisms. We found that the GG genotype at position -2843 conferred a 2.2-fold risk for LVH compared with the AA or AG genotypes, including septal wall thickness (11.8+/-1.4 mm for GG compared with 10.9+/-1.4 and 10.7+/-1.3 mm for AA and AG respectively; P<0.01), posterior wall thickness (11.8+/-2.8 mm for GG compared with 10.6+/-1.2 and 10.6+/-1.4 mm for AA and AG respectively; P<0.01), LV mass index (62.7+/-13.6 g/m(2.7) for GG compared with 57.9+/-8.6 and 57.8+/-8.4 g/m(2.7) for AA and AG respectively; P<0.05) and relative wall thickness (50.7+/-10.8% for GG compared with 44.3+/-7.3 and 43.5+/-6.8% for AA and AG respectively; P<0.05). Plasma levels of ANP were significantly lower in the hypertensive patients with LVH carrying the GG genotypes compared with those carrying the AA or AG genotypes (P<0.01). No association of GG genotype with echocardiographic variables and plasma ANP levels was identified in hypertensive patients without LVH and in control subjects (P>0.05). No significant association between the A188G genotype and echocardiographic variables was found in either hypertensive patients or controls (P>0.05). In conclusion, our findings indicate that the -A2843G polymorphism in the ANP gene promoter might be a genetic risk factor for the development of LVH in patients with hypertension.

Interaction of BMP10 with Tcap may modulate the course of hypertensive cardiac hypertrophy

Elevated wall stress by hypertension induces an adaptive myocardial hypertrophy via releasing prohypertrophic hormones such as angiotensin II. In this study, we investigated the involvement of bone morphogenetic protein-10 (BMP10) in hypertension-induced cardiac hypertrophy. Expression of BMP10 was increased in the hypertrophied ventricles from hypertensive rats. BMP10 localized on cell surface and at stretch-sensing Z disc of cardiomyocytes, where BMP10 interacted with a protein called titin-cap (Tcap). A rare variant of the human BMP10 gene, Thr326Ile, was found to be associated with hypertensive dilated cardiomyopathy. The variant BMP10 demonstrated decreased binding to Tcap and increased extracellular secretion. Conditioned medium from cells transfected with wild-type or variant BMP10 induced hypertrophy in rat neonatal cardiomyocytes, except that medium from variant BMP10-carrying cells showed an enhanced effect reflecting the increased secretion. These observations suggested that hypertension induced expression of prohypertrophic BMP10, and the hypertrophic effect of BMP10 was modulated, at least in part, by its binding to Tcap at the Z disc.

Upregulation of intermedin and reduced neutral endopeptidase expression in hypertensive cardiac hypertrophy

Intermedin (IMD), a recently discovered vasodilator peptide, has potential to protect against ischemia–reperfusion injury and to attenuate ventricular remodeling in response to pressure overload. Its actions are mediated by the calcitonin receptor-like receptor in association with receptor activity modifying proteins (RAMPs 1–3). Using the spontaneously hypertensive rat (SHR) model at 20 weeks of age and the normotensive WKY control, the aim was to (i) verify oxidative stress and concentric hypertrophy and (ii) examine expression of IMD and receptor components and of neutral endopeptidase (NEP), probably an important mediator of IMD degradation.

Non-effect of p22-phox −930A/G polymorphism on end-organ damage in Brazilian hypertensive patients

The p22-phox subunit is an essential component of NAD(P)H oxidase enzymatic complex, which is considered the major source of oxidative stress products in the cardiovascular system. The -930G allele of p22-phox has been associated with higher promoter activity, increased NAD(P)H oxidase-mediated oxidative stress and hypertension. We recently reported that left ventricular hypertrophy is accompanied by increased myocardial p22-phox expression in aortic-banded rats, suggesting that this protein might be involved in hypertensive cardiac hypertrophy.

Strain Rate Imaging Differentiates Hypertensive Cardiac Hypertrophy from Physiologic Cardiac Hypertrophy (Athlete’s Heart)

This study sought to determine whether strain rate imaging could distinguish between individuals with hypertensive left ventricular hypertrophy (LVH) and those with strength-training athletic LVH. In all, 108 participants (30 hypertensive LVH, 30 strength-training LVH, 48 control) were enrolled. In addition to a baseline echocardiogram, strain, peak systolic strain rate (SR(S)), peak early diastolic strain rate (SR(E)), and peak late diastolic strain rate values were compared in the apical 4-chamber view. Athletes had no significant differences in strain, SR(S), SR(E), or peak late diastolic strain rate compared with control subjects (P = .11, .99, .85, and .09, respectively). Individuals with hypertensive LVH had significantly decreased strain, SR(S), and SR(E) (-16.8 +/- 3.2%, -0.99 +/- 0.15 s(-1), and 1.54 +/- 0.40 s(-1), respectively) compared with control subjects (-21.7 +/- 3.5%, -1.31 +/- 0.27 s(-1), and 2.35 +/- 0.57 s(-1), respectively; all P < .0001). Hypertensive LVH has significant longitudinal strain, SR(S), and SR(E) reductions versus control. The lack of these reductions in athletes suggests that strain rate imaging may have clinical use in discerning the physiologic LVH state.

Effect of Long-term Administration of a Prostacyclin Analogue (Beraprost Sodium) on Myocardial Fibrosis in Dahl Rats

Beraprost sodium (BPS) is an orally active prostacyclin analogue. The effects of BPS on the heart, including coronary circulation improvement, myocardial and vascular protection and anti-fibrosis effect on myocardium interstitium, have previously been demonstrated. However, the effects of BPS on hemodynamics, cardiac function and myocardial contractility in patients in the hypertrophic phase have not been clarified. Therefore, in the present study, the effects of BPS under long-term administration were investigated using the hypertension model of salt-sensitive Dahl rats. Six-week-old Dahl rats were divided into three groups, an 8% high salt diet group treated with BPS (BPS group), an untreated 8% high salt diet group (HHF group) and an untreated 0.3% low salt diet group (Control group), and observations were conducted until 17 weeks of age. In the BPS and HHF groups, the survival rates after 11 weeks of high salt diet intake were 87.5% and 47.1%, respectively (p<0.05). At 17 weeks of age, the atrial systolic peak velocity/early diastolic peak velocity and heart weight index of the BPS group decreased significantly compared with the HHF group (p<0.05). The HHF group exhibited significantly more severe myocardial fibrosis mainly in the endocardial layer of the left and right ventricles compared with the BPS and Control groups (p<0.05). In the present study, long-term BPS administration preserved diastolic function and prevented myocardial interstitial fibrosis in the non-compensatory phase. The results of the present study suggest that BPS is effective for treatment of hypertensive cardiac hypertrophy.

β2-Adrenergic receptor polymorphisms and treatment-induced regression of left ventricular hypertrophy in hypertension

Although blood pressure is considered the major determinant of left ventricular hypertrophy in hypertension, genetic variability is increasingly being considered among the factors influencing this complication. beta(2)-Adrenergic receptors (beta(2)ARs) are up-regulated in hypertension and largely polymorphic within the human population. Recently, we have shown that the Glu27 beta(2)AR variant is strongly associated with cardiac hypertrophy in hypertension. The objective of this study is to verify whether this polymorphism also affects hypertrophy regression in response to antihypertensive therapy. In a prospective follow-up study we screened 970 hypertensive patients of Caucasian descent for the Gly16Arg, Gln27Glu, and Thr164Ile beta(2)AR polymorphisms and left ventricular echocardiographic hypertrophy and assigned selected patients to enalapril or atenolol to assess left ventricular hypertrophy regression after 2-year follow-up. Results were stratified according to treatment and the Glu27Gln polymorphism of the beta(2)AR. In cells with stable overexpression of the Glu27 or Gln27 variant of beta(2)AR, we also explored the implications of this polymorphism on hypertrophy-related intracellular signal transduction. Among hypertensive patients, the Gly16 allele was found in 63% of patients and the Glu27 allele was found in 40.6%. Both polymorphisms were in linkage disequilibrium, as expected. Four hundred forty-one hypertrophic hypertensive patients completed the 2-year follow-up. At baseline, patients carrying at least 1 allele of the Glu27 variant presented with a larger cardiac size despite similar blood pressure levels (142.9 +/- 22.5 g/m(2) in Glu27 carriers versus 138.2 +/- 18.4 g/m(2) in Gln27 carriers, P < .02). Blood pressure normalization was achieved by both drugs. At follow-up, compared with the Gln27 patients, the Glu27 patients showed a larger reduction in hypertrophy when treated with enalapril (percent change in left ventricular mass, -6.3% +/- 7.7% in Glu27 carriers versus -2.18% +/- 7.9% in Gln27 carriers; P < .05) but not with atenolol therapy (-2.8% +/- 8.9% in Glu27 carriers versus -2.4% +/- 8.8% in Gln27 carriers, P = not significant). In in vitro studies the activation of p38 and extracellular signal-regulated kinase (ERK-) 1/2 (data not shown) and the activity of the atrial natriuretic factor (ANF) promoter after isoproterenol (INN, isoprenaline) stimulation were larger in Glu27 beta(2)AR overexpressing cells than in Gln27 beta(2)AR overexpressing cells (fold difference compared with unstimulated cells, 9.7 +/- 2.9 for Glu27 beta(2)AR versus 4.2 +/- 0.3 for Gln27 beta(2)AR; P < .05). The Glu27 variant of beta(2)AR enhances hypertension-induced left ventricular hypertrophy. In these patients angiotensin-converting enzyme inhibitors are more efficient than beta-blockers in reducing cardiac size.

Impaired Chronotropic and Vasodilator Reserves Limit Exercise Capacity in Patients With Heart Failure and a Preserved Ejection Fraction

Nearly half of patients with heart failure have a preserved ejection fraction (HFpEF). Symptoms of exercise intolerance and dyspnea are most often attributed to diastolic dysfunction; however, impaired systolic and/or arterial vasodilator reserve under stress could also play an important role. Patients with HFpEF (n=17) and control subjects without heart failure (n=19) generally matched for age, gender, hypertension, diabetes mellitus, obesity, and the presence of left ventricular hypertrophy underwent maximal-effort upright cycle ergometry with radionuclide ventriculography to determine rest and exercise cardiovascular function. Resting cardiovascular function was similar between the 2 groups. Both had limited exercise capacity, but this was more profoundly reduced in HFpEF patients (exercise duration 180+/-71 versus 455+/-184 seconds; peak oxygen consumption 9.0+/-3.4 versus 14.4+/-3.4 mL x kg(-1) x min(-1); both P<0.001). At matched low-level workload, HFpEF subjects displayed approximately 40% less of an increase in heart rate and cardiac output and less systemic vasodilation (all P<0.05) despite a similar rise in end-diastolic volume, stroke volume, and contractility. Heart rate recovery after exercise was also significantly delayed in HFpEF patients. Exercise capacity correlated with the change in cardiac output, heart rate, and vascular resistance but not end-diastolic volume or stroke volume. Lung blood volume and plasma norepinephrine levels rose similarly with exercise in both groups. HFpEF patients have reduced chronotropic, vasodilator, and cardiac output reserve during exercise compared with matched subjects with hypertensive cardiac hypertrophy. These limitations cannot be ascribed to diastolic abnormalities per se and may provide novel therapeutic targets for interventions to improve exercise capacity in this disorder.

Differential protein expression in hypertrophic heart with and without hypertension in spontaneously hypertensive rats

Although cardiac hypertrophy in hypertension has been well recognized, the molecular mechanisms for the development of hypertrophy are still largely unknown. In this study, the protein expression profiles of left ventricular myocardia in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at different ages were analyzed using 2-DE in combination with MALDI-TOF/TOF MS/MS. The results showed that 20 proteins were modulated in the hypertrophic myocardium. Out of these modulated proteins, 13 proteins presented significant changes in SHR at an early stage prior to the development of sustained hypertension, while the changes of the other 7 protein expressions occurred only at a late stage in SHR when the blood pressure was significantly elevated, and were largely reversible by treatment with rennin-angiotensin-aldosterone system inhibitors losartan or enalapril. These data demonstrate that the changes in energy metabolism in the hypertrophied heart favor an increase in glycolysis and a decrease in oxidation of fatty acid and glucose, which occur at an early stage in SHR without hypertension. Our results also provide evidence to support the hypothesis that oxidative stress plays an important role in the development of hypertensive cardiac hypertrophy.

β-Blockade in heart failure: adding SENIORS to the mixThe opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

This editorial refers to ‘Effects of nebivolol in elderly heart failure patients with or without systolic left ventricular dysfunction: results of the SENIORS echocardiographic substudy’ † by S. Ghio et al., on page 562 In early 2005, results of the SENIORS trial, a Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure was published. 1,2 A total of 2128 patients over the age of 70 were randomized to receive either nebivolol or placebo for a mean follow-up time of 21 months. Nebivolol is a third generation highly selective b1-adrenergic receptor inhibitor with vasodilator properties mediated through nitric oxide release. Treatment with this agent decreased all-cause mortality or cardiovascular hospitalization (P ¼ 0.04). Although previous studies using b-blockers (bisoprolol, carvedilol, or metroprolol) demonstrated a decreased relative risk of death in heart failure, 3 they enrolled younger patients (excluding patients .80 years of age) and focused on those with low left ventricular ejection fraction (LVEF). Thus, these studies may not be representative of patients seen in the general population, who may be older and have a higher prevalence of preserved systolic function. By demonstrating the morbidity and mortality benefits of b-blockade in elderly patients with heart failure, regardless of whether the LVEF was low, the SENIORS trial expands our understanding of this therapy. Ghio et al. 4 present results of an echocardiographic substudy performed on 104 of the original 2128 patients, reporting the impact of nebivolol on LV structure and function in patients stratified on the basis of LVEF, using 35% as a cut-point. In this subgroup, 59% of the patients had LVEF .35%, a considerably higher percentage than that was present in the overall study (35%). In the low LVEF group, nebivolol led to a decrease in LV end-systolic volume and an improved LVEF, changes indicative of reverse remodelling. In the group with preserved LV systolic function, nebivolol did not alter the LV size or function. The authors conclude that nebivolol reduces LV size and improves LVEF in patients with LVEF � 35% but this mechanism does not explain the improved morbidity and mortality in those patients with primarily diastolic dysfunction. The results of this study provoke a number of interesting questions. First, why should there be a unique remodelling response of patients with low LVEF? Is it fair to argue that, because patients with preserved LVEF did not have cardiac dilatation, reverse remodelling would not entail reductions in LV end-diastolic volume? Indeed, is there a reason to suspect that a patient who began the study with a normal LV end-diastolic volume should end it with anything else? It is worth noting that although ongoing debate attempts to clarify just what diastolic heart failure is, a considerable fraction of such patients have hypertensive cardiac hypertrophy and in such patients, reverse remodelling may simply represent hypertrophy regression. Whether this was the case in the current study is unknown because data on LV thickness or mass were not presented. On the other hand, if there is a large population of patients with diastolic heart failure in the absence of cardiac hypertrophy, how would reverse remodelling be recognized? It may be safe to conclude that this process uniquely impacts patients with low LVEF. Given the fact that reverse remodelling can be quantified (by means of cardiac size and function) in patients with low LVEF, important questions remain regarding its causes. Clearly, a subset of patients with dilated cardiomyopathy will respond to b-blocker therapy or to mechanical unloading of the heart with LV assist devices by demonstrating

Different Effects on Inhibition of Cardiac Hypertrophy in Spontaneously Hypertensive Rats by Monotherapy and Combination Therapy of Adrenergic Receptor Antagonists and/or the Angiotensin II Type 1 Receptor Blocker under Comparable Blood Pressure Reduction

To confirm that alpha1, beta adrenoceptor antagonists and angiotensin II type 1 receptor blockers (ARBs) have different abilities to attenuate progressive cardiac hypertrophy despite their comparable lowering of blood pressure, we compared the effect of these agents alone or in combination on hypertensive cardiac hypertrophy. Eight-week-old spontaneously hypertensive rats (SHR) were divided into 7 groups. Single administration of doxazosin, atenolol, or losartan, or half-dose combinations of these drugs were given orally for 6 weeks. The control group did not receive any drugs. The heart weight-to-body weight ratio (HW/BW), left ventricular mass index (LVMI), plasma brain natriuretic peptide (BNP) and left ventricular BNP mRNA expression were measured after 6-week administration. Blood pressure did not differ among the drug-treated groups, all of which showed lower blood pressure than the control group. The HW/BW and LVMI of the drug-treated groups, except the doxazosin group, were lower than in the control group. Moreover, the LVMI values of the groups receiving losartan were significantly lower than those in the groups without losartan (p < 0.05). Plasma BNP of the drug-treated groups was lower than that in the control group (p < 0.05). The left ventricular BNP mRNA expression of the drug-treated groups, except the doxazosin group, was lower than that in the control group. The atenolol group showed a higher level of BNP mRNA than the groups receiving losartan monotherapy or combination therapies (p < 0.05). In conclusion, the ARB had the strongest attenuating effect on the development of hypertensive cardiac hypertrophy, and the alpha1 and beta adrenergic receptor blockers were more effective in combination than as monotherapies in SHR.

Abstracts

Abstracts