Search

Background: Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF is a substantial and escalating unmet clinical need-and the lack of HFpEF-specific animal models represents a major preclinical barrier in advancing understanding of HFpEF. As established treatments for heart failure with reduced ejection fraction (HFrEF) have proven ineffective for HFpEF, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HFpEF, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology., Methods and Results: The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%-90% control) with marked diastolic dysfunction (increased E/E'). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca 2+ operational levels and markedly increased L-type Ca 2+ channel current. In HHR, prominent regions of reparative fibrosis in the left ventricle free wall adjacent to the interventricular septum were observed., Conclusions: Thus, the cardiomyocyte remodeling process in the etiology of this HFpEF model contrasts dramatically with the suppressed Ca 2+ cycling state that typifies heart failure with reduced ejection fraction. These findings may explain clinical observations, that treatments considered appropriate for heart failure with reduced ejection fraction are of little benefit for HFpEF-and suggest a basis for new therapeutic strategies., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants., Methods and Results: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2 -knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2 -knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis -eQTL for LCN2 expression., Conclusions: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

1. Throughout most of life, males have higher average blood pressures than females. This sexual dichotomy may be related to genetic factors including the X and Y sex chromosomes and genes that control sex steroids. Resultant physiological differences between men and women may also be relevant to the quantitative variation of blood pressure within the sexes. 2. The present overview collates our published and novel sex-related genetic data in relation to blood pressure from the Victorian Family Heart Study. These include a multipoint quantitative linkage analysis of the X chromosome and genetic association studies of single nucleotide polymorphisms (SNP) of the Y chromosome and genes encoding the androgen receptor (AR), oestrogen receptor alpha (ERalpha), 5alpha-reductase types I and II (SRD5A1 and SRD5A2) and aromatase (CYP19). 3. Systolic blood pressure (SBP) was linked (Z=3.3, genome-wide P < 0.05) to a region of the X chromosome that encompassed the AR gene and the Y chromosome was associated with diastolic blood pressure (DBP; P=0.03). In new analyses, we observed a possible association between a SNP in AR and DBP in 369 males (84.5 vs 82.1 mmHg for genotype A vs genotype B, respectively; P=0.06) and a significant association between haplotypes of the Y chromosome and AR SNP in males (P=0.01) with a difference of nearly 6 mmHg DBP between extreme groups. Associations were also observed for polymorphisms of SRD5A1 and ERalpha with DBP and SBP in males, respectively. 4. The findings indicate that genes related to sexual phenotypes may be relevant to the normal variation in blood pressure, even within the sexes. Further genetic and physiological analyses will be required to confirm these observations and to determine the mechanisms of action and the nature of any interactions.

1. The long-term reduction in blood pressure following ACE inhibitor treatment in young spontaneously hypertensive rats (SHR) appears to depend on both the kidney and bradykinin. 2. The aim of this experiment was to examine the effects of ACE inhibition and bradykinin on renal morphology and blood pressure in SHR. 3. Between 6 and 10 weeks of age male SHR received one of four treatments: water (n = 26), ramipril (1 mg/kg per day; n = 24), ramipril (1 mg/kg per day) plus Hoe 140 (0.5 mg/kg per day; n = 25) or Hoe 140 (0.5 mg/kg per day; n = 25). 4. Renal medullary and cortical volumes were determined stereologically at 10 and 20 weeks of age. 5. After 4 weeks of treatment, ramipril reduced the size of the renal medulla while Hoe 140 increased medullary volumes compared to control. Ten weeks after treatment was stopped the renal medulla of the ramipril group had returned to normal, however, there was a persistent increase in medullary volume of both Hoe 140 treated groups. 6. Our results imply that bradykinin may influence the size of the renal medulla which may have important effects on the development of hypertension in SHR.

1. Brief treatment with angiotensin-converting enzyme (ACE) inhibitors in young spontaneously hypertensive rats (SHR) causes a reduction in blood pressure that persists into maturity. The lifetime effects of such treatment have not been studied. 2. Nineteen male SHR were treated with either water (n = 9) or perindopril (3 mg/kg per day) (n = 10) by daily gavage between 6 and 10 weeks of age and systolic blood pressure and bodyweight were measured each month until all animals died in old age. 3. Following treatment the systolic blood pressure of SHR treated with perindopril remained consistently lower than control SHR until about 82 weeks of age. After this age the blood pressure of control SHR fell spontaneously so that smaller differences were observed between the two groups in the last 4 months of the study. 4. Rats that received perindopril lived on average 1 month longer than control rats, but this difference was not statistically significant. 5. Thus, brief ACE inhibition in early life in SHR ameliorated the hypertension throughout life.

1. Brief treatment with angiotensin-converting enzyme (ACE) inhibitors in young spontaneously hypertensive rats (SHR) causes a persistent reduction in blood pressure associated with a relatively selective reduction in renal vascular resistance. 2. To study the possible role of the kidney in this long-term hypotensive effect, we transplanted kidneys from untreated SHR into SHR that had been treated with perindopril (3 mg/kg per day) between 6 and 10 weeks of age and also transplanted kidneys from perindopril-pretreated SHR into untreated SHR. After transplantation, the remaining native kidney was removed so that only donor kidneys remained. 3. Untreated SHR that received kidneys from perindopril-pretreated SHR showed an initial fall in blood pressure followed by a rapid increase in pressure, weight loss and early death. 4. The transplantation of kidneys from control SHR into perindopril-pretreated SHR resulted in a rise in blood pressure that obviated the long-term reduction seen normally in these animals. 5. Kidneys from perindopril-pretreated SHR may be susceptible to the high blood pressure in untreated SHR. 6. The blood pressure increase in perindopril-pretreated SHR that accompanies substitution of the native kidneys by kidneys from untreated SHR further supports the hypothesis that the kidney is responsible for the long-term pressure effects following ACE inhibition in young SHR.

1. The aim of this study was to develop non-invasive echocardiographic methods of measuring left ventricular mass (LVM) in rats, and to determine their usefulness in detecting left ventricular hypertrophy. 2. After initial studies to identify the optimum transducer and to ascertain the resolution limits of echocardiography, the repeatability of LVM estimates was studied. The average difference between two independent estimates in 86 male rats (average LVM = 674.7 mg) was 5.4 mg, and the standard deviation of the difference was 107.6 mg. 3. To determine agreement between direct and indirect methods, LVM was measured in 38 male rats by echocardiography and compared with direct measurement of the left ventricular weight at sacrifice. The mean difference between the two methods was 9.14 +/- 56.6 mg. The limits of agreement were from -122.4 to +104.1 mg. 4. Echocardiography was then used to measure LVM in eight male spontaneously hypertensive rats and eight male normotensive Donryu rats at 9 weeks of age. The mean LVM of SHR was 768.2 mg +/- 152.6, which was significantly (2P less than 0.001) greater than the LVM of DRY (435.4 mg +/- 32.2). 5. We conclude that echocardiography provides a non-invasive, repeatable and relatively accurate estimate of LVM in rats. The method is a potentially useful tool for studying the development or regression of cardiac hypertrophy in longitudinal experiments.

Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats aged 4 and 16 weeks were given an acute oral dose of either Perindopril (3 mg/kg) or vehicle. Direct blood pressure (BP), glomerular filtration rate (GFR) and renal blood flow (RBF) were measured, and renal vascular resistance (RVR) calculated. GFR and RBF were lower in vehicle-treated SHR than WKY at 4 weeks of age, but were not different at 16 weeks. Acute Perindopril increased GFR and RBF and reduced RVR in both strains at both 4 and 16 weeks. Total body sodium, sodium intake and blood pressure were measured in SHR and WKY from 1 to 28 weeks of age. Rats of both strains were treated daily between 4 and 16 weeks of age with either Perindopril (3 mg/kg per day) or vehicle. Chronic Perindopril treatment prevented the development of hypertension in the SHR. From 16 to 28 weeks of age, after stopping Perindopril, BP rose slowly in SHR, but remained lower than vehicle-treated SHR. No changes in total body sodium occurred during Perindopril treatment. GFR and RBF were measured in SHR and WKY chronically treated with either Perindopril or vehicle, 3 days or 12 weeks after stopping treatment. In WKY, GFR and RBF were not different between Perindopril-treated and untreated rats at either measurement. In SHR, GFR and RBF remained significantly higher in rats previously treated with Perindopril at both ages. These findings suggest that renal haemodynamic abnormalities may be important in the initiation of hypertension in the SHR. These renal circulatory abnormalities and the hypertension of the SHR depend, at least in part, on intact converting enzyme activity, yet appear to be independent of abnormalities of total body sodium. At a later age, hypertension seems to develop independently of renal vascular abnormalities.

Treatment with the potent angiotensin converting enzyme inhibitor perindopril completely prevented any rise in blood pressure in the 2-kidney, 1-clip (2K1C) model of renal hypertension in rats. Withdrawal of this inhibitor was followed by a slow rise in blood pressure. In 2K1C rats treated with perindopril, pressor responses to angiotensin I fell during the treatment period, but returned to normal after the inhibitor was stopped. Pressor responses to angiotensin II (AII) increased during treatment with perindopril; this was presumably due to increased receptor sensitivity consequent on the falls in endogenous AII levels. Responses to AII fell to control levels after the inhibitor was stopped. It is concluded that an increased pressor sensitivity to AII is not the cause of the slowly developing hypertension in the 2K1C model of hypertension, and that the slow pressor response to AII must be due to other factors.

Total body sodium of male and female spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats was estimated weekly during the first 8 weeks of life by measuring exchangeable sodium (ENa). Blood pressure and sodium intake was measured from weeks 4 to 8. SHR had significantly higher blood pressure and sodium intake than WKY from 4 to 8 weeks of age. ENa was higher in SHR than WKY throughout the first 8 weeks of life. Relative sodium retention was observed in SHR during weeks 5 to 8 despite a significant rise in SHR blood pressure and fall in sodium intake. These findings suggest a change in the renal pressure/natriuresis relationship at this age in the SHR.