Variable phenotype in murine transverse aortic constriction

BackgroundIn mice, transverse aortic constriction (TAC) is variably characterized as a model of pressure overload-induced hypertrophy (left ventricular [LV] hypertrophy, or LVH) or heart failure (HF). While commonly used, variability in the TAC model is poorly defined. The objectives of this study were to characterize the variability in the TAC model and to define a simple, noninvasive method of prospectively identifying mice with HF versus compensated LVH after TAC.MethodsEight-week-old male C57BL/6J mice underwent TAC or sham and then echocardiography at 3 weeks post-TAC. A group of sham and TAC mice were euthanized after the 3-week echocardiogram, while the remainder underwent repeat echocardiography and were euthanized at 9 weeks post-TAC. The presence of TAC was assessed with two-dimensional echocardiography, anatomic aortic m-mode and color flow, and pulsed-wave Doppler examination of the transverse aorta (TA) and by LV systolic pressure (LVP). Trans-TAC pressure gradient was assessed invasively in a subset of mice. HF was defined as lung/body weight>upper limit in sham-operated mice.ResultsAs compared with sham, TAC mice had higher TA velocity, LVP and LV weight, and lower ejection fraction (EF) at 3 or 9 weeks post-TAC. Only a subset of TAC mice (28%) developed HF. As compared with compensated LVH, HF mice were characterized by similar TA velocity and higher percent TA stenosis, but lower LVP, higher LV weight, larger LV cavity, lower EF and stress-corrected midwall fiber shortening, and more fibrosis. Both EF and LV mass measured by echocardiography at 3 weeks post-TAC were predictive of the presence of HF at 3 or 9 weeks post-TAC.ConclusionsIn wild-type mice, TAC produces a variable cardiac phenotype. Marked abnormalities in LV mass and EF at echocardiography 3 weeks post-TAC identify mice with HF at autopsy. These data are relevant to appropriate design and interpretation of murine studies.     

The cardiac endothelin system in established pressure overload left ventricular hypertrophy

In normal hearts, endothelin-1 (ET-1) has been shown to initiate myocyte growth and to modulate cardiac function. However, regulation of the various components of the system and the functional effects of ET-1 in established left ventricular hypertrophy (LVH) are less clear. We thus studied ET-1, ET(A) receptor, and endothelin converting enzyme (ECE-1) mRNA regulation as well as the effects of ET-1 on coronary resistance, LV contractility and relaxation in hypertrophied rat hearts. Cardiac pressure overload, secondary to banding of the ascending aorta, resulted in a transient increase of cardiac ET-1 and ET(A) receptor mRNAs that reached a maximum at 2 days (+75% and +40%, respectively, P<0.05, each). ET-1 mRNA levels reached a second peak at 84 days of pressure overload (+60%, P<0.05), at the later time point in conjunction with elevated ECE-1 mRNA levels (+20%, P<0.05). The functional implications of ET-1 were examined in a study of isolated perfused hearts. Both hearts with established LVH and sham control hearts responded to ET-1 perfusion (10(-1)] to 10(-9) M) with an increase of coronary perfusion pressure (CPP; +85+/-15 and +75+/-8 mm Hg; P<0.001 each) and a slight decrease of LV systolic pressure (LVP; -12+/-9 and -9+/-7 mm Hg; P = NS). In contrast, ET-1 increased LV end-diastolic pressure (LVEDP) only in LVH hearts (+22+/-7 mm Hg, P<0.05 versus baseline and +20+/-7 mm Hg, P<0.05 versus sham). Direct stimulation of protein kinase C mimicked the effects of ET-1, whereas inhibition of this kinase or the Na+ -H+ exchanger blunted the effects of ET-1 on CPP, LVP, and LVEDP. Interestingly, coadministration of the vasodilator and the nitric oxide (NO) donor nitroglycerin not only prevented the increase of CPP and LVEDP, but also uncovered a slight positive inotropic effect of ET-1 in LVH hearts. Thus, the cardiac expression of ET-1, ET(A), and ECE-1 mRNAs displays a distinct pattern during early and advanced cardiac pressure overload. Furthermore, ET-1 mediates a slight depression of systolic, and a profound depression of diastolic, functional parameters in hearts with established LVH, effects that appear to be secondary to ET-1-related coronary vasoconstriction. The data suggest a functional role of the endothelin system in hearts with established pressure overload hypertrophy.     

Left Ventricular Morphology of the Giraffe Heart Examined by Stereological Methods

The giraffe heart has a relative mass similar to other mammals, but generates twice the blood pressure to overcome the gravitational challenge of perfusing the cerebral circulation. To provide insight as to how the giraffe left ventricle (LV) is structurally adapted to tackle such a high afterload, we performed a quantitative structural study of the LV myocardium in young and adult giraffe hearts. Tissue samples were collected from young and adult giraffe LV. Design‐based stereology was used to obtain unbiased estimates of numbers and sizes of cardiomyocytes, nuclei and capillaries. The numerical density of myocyte nuclei was 120 × 10³ mm^?3 in the adult and 504 × 10³ mm^?3 in the young LV. The total number (N) of myocyte nuclei was 1.3 × 10¹¹ in the adult LV and 4.9 × 10¹⁰ in the young LV. In the adult LV the volume per myocyte was 39.5 × 10³ µm³ and the number of nuclei per myocyte was 4.2. The numerical density of myocytes was 24.1 × 10⁶ cm^?3 and the capillary volume fraction of the adult giraffe ventricle was 0.054. The significantly higher total number of myocyte nuclei in the adult LV, the high density of myocyte nuclei in the LV, and the number of nuclei per myocyte (which was unusually high compared to other mammalian, including human data), all suggest the presence of myocyte proliferation during growth of the animal to increase wall thickness and normalize LV wall tension as the neck lengthens and the need for higher blood pressure ensues. Anat Rec, 296:611–621, 2013. © 2013 Wiley Periodicals, Inc.     

Regression of left ventricular hypertrophy and aortic remodelling in NO-deficient hypertensive rats: effect of L-arginine and spironolactone

Aim: We investigated, whether the substrate for nitric oxide (NO) formation –l ‐arginine – and the aldosterone receptor antagonist – spironolactone – are able to reverse alterations of the left ventricle (LV) and aorta in N^ω‐nitro‐l ‐arginine methyl ester (l ‐NAME)‐induced hypertension. Methods: Six groups of male adult Wistar rats were investigated: controls after 4 and 7 weeks of experiment, rats treated with l ‐NAME for 4 weeks and three recovery groups: spontaneous‐reversion (4 weeks l ‐NAME + 3 weeks placebo), spironolactone‐induced reversion (4 weeks l ‐NAME + 3 weeks spironolactone) and l ‐arginine‐induced reversion (4 weeks l ‐NAME+ 3 weeks l ‐arginine). Blood pressure was measured by tail‐cuff plethysmography. Relative weight of the LV, myocardial fibrosis (based upon histomorphometry and hydroxyproline determination) and conjugated dienes in the LV and aortic cross‐sectional area, inner diameter and wall thickness were determined. NO‐synthase activity was investigated in the LV and aorta. Results: l ‐NAME administration induced hypertension, left ventricular hypertrophy (LVH), LV fibrosis, aortic thickening and diminution of NO‐synthase activity in the LV and aorta. Reduction in blood pressure and regression of LVH were observed in all recovery groups, yet reduction in LV fibrosis and aortic thickening were not. NO‐synthase activity was restored only in the l ‐arginine and spironolactone group. Conclusion: In our study, the reversion of hypertension and LVH was not dependent on the restoration of NO‐synthase activity. Moreover, LV fibrosis and aortic remodelling seem to be more resistant to conditions resulting in regression of LVH. Preserved level of fibrosis in the initial period of LVH regression might result in loss of structural homogeneity and possible functional alterations of the LV.     

Depressed contractile reserve and impaired calcium handling of cardiac myocytes from chronically unloaded hearts are ameliorated with the administration of physiological treatment dose of T3 in rats

Aim: Chronic cardiac unloading causes a time‐dependent upregulation of phospholamban (PLB) and depression of myocyte contractility in normal rat hearts. As thyroid hormone is known to decrease PLB expression, we examined whether thyroid hormone restores the depressed contractile performance of myocytes from chronically unloaded hearts. Methods: Cardiac unloading was induced by heterotopic heart transplantation in isogenic rats for 5 weeks. Animals were treated with either vehicle or physiological treatment dose of 3,5,3′‐triiodo‐l ‐thyronine (T3) that does not cause hyperthyroidism for the last 3 weeks (n = 20 each). Results: In vehicle‐treated animals, myocyte relaxation and [Ca²⁺]_i decay were slower in unloaded hearts than in recipient hearts. Myocyte shortening in response to high [Ca²⁺]_o was also depressed with impaired augmentation of peak‐systolic [Ca²⁺]_i in unloaded hearts compared with recipient hearts. In vehicle‐treated rats, protein levels of PLB were increased by 136% and the phosphorylation level of PLB at Ser16 were decreased by 32% in unloaded hearts compared with recipient hearts. By contrast, in the T3‐treated animals, the slower relaxation, delayed [Ca²⁺]_i decay, and depressed contractile reserve in myocytes from unloaded hearts were all returned to normal levels. Furthermore, in the T3‐treated animals, there was no difference either in the PLB protein level or in its Ser16‐phosphorylation level between unloaded and recipient hearts. Conclusion: These results suggest that the treatment with physiological treatment dose of thyroid hormone rescues the impaired myocyte relaxation and depressed contractile reserve at least partially through the restoration of PLB protein levels and its phosphorylation state in chronically unloaded hearts.     

Extracellular signal regulated kinase and SMAD signaling both mediate the angiotensin II driven progression towards overt heart failure in homozygous TGR(mRen2)27

Angiotensin (Ang) II is a key player in left ventricular (LV) remodeling and cardiac fibrosis. Its effects are thought to be transferred at least in part by mitogen-activated protein kinases (MAPK), transforming growth factor (TGF) ₁, and the Smad pathway. In this study we sought to elucidate whether Ang II related effects on LV dysfunction and fibrosis in vivo are mediated via MAPK or rather via Smad stimulation. We treated homozygous REN2 rats (7–11 weeks) with placebo, Ang II type 1 (AT₁) receptor blocker or tyrphostin A46 (TYR), an inhibitor of epidermal growth factor receptor tyrosine kinase that blocks extracellular signal-regulated kinase (ERK) activity. REN2 rats had LV hypertrophy (LVH) and LV dysfunction that progressed to heart failure between 10 and 13 weeks. Blood pressure normalized over time. Renin, N-terminal atrial natriuretic peptide (N-ANP), and ERK were activated while p38 MAPK was not. Treatment with AT₁ receptor blockade prevented LVH and right ventricular hypertrophy, normalized systolic and diastolic dP/dt, N-ANP levels, and reduced collagen apposition. Similarly, TYR reduced LVH, N-ANP levels, and collagen apposition. Myocardial ERK activation did not depend on AT₁ receptor signaling as it was not affected by AT₁ receptor blockade. TYR abolished myocardial ERK activity. Smad2 activation was inhibited by AT₁ receptor blockade but was unaltered by TYR. Ang II induced LV remodeling and fibrosis are dependent on both ERK and Smad2 activation. This process is prevented by both AT₁ receptor blockade and TYR, and therefore inhibition of either pathway is equally efficacious in restoring LV function and architecture.R.A.D.B. and S.P. contributed equally to this work     

Reduced cardiac stiffness following exercise is associated with preserved myocardial collagen characteristics in the rat

We determined whether the increment in cardiac end-diastolic compliance (a reduced diastolic stiffness constant) following endurance training is related to alterations in myocardial collagen characteristics. Sixteen weeks of habitual exercise (Ex) in rats, which produced left ventricular (LV) hypertrophy (LVH) [LV weight in g: Ex=1.01 (0.04), sedentary control?=?0.89 (0.04); P<0.05], resulted in a reduced LV end-diastolic (LVED) chamber stiffness [slope of the linearised LVED pressure versus LVED internal diameter relation in kPa?·?mm^?1: Ex=0.67 (0.03), control=0.80 (0.03); P<0.05]. The increased LVED chamber distensibility was associated with an attenuated myocardial stiffness [slope of the linearised LVED stress versus strain relation in g?·?cm^?2; Ex=15 (3), control=25?(2); P<0.05]. Although LV total collagen content (mg) was increased in the exercised rats [Ex=5.0?(0.3), control=4.1 (0.2); P<0.05], this was a reflection of the presence of LVH, as the myocardial collagen concentration (μg?·?mg^?1 LV wet weight) was unaltered [Ex=4.9 (0.2), control=4.6 (0.2)]. Furthermore, habitual exercise did not influence the percentage of myocardial collagen extracted following cyanogen bromide digestion (an index of collagen cross-linking), [i.e. Ex=38 (3), control=38 (3)], nor the proportion of myocardial collagen phenotypes I and III [I/III; Ex=3.04 (0.20), control=2.85 (0.22)]. In conclusion, exercise-induced increments in end-diastolic myocardial distensibility are unlikely to be a consequence of alterations in the properties of myocardial collagen.     

The effects of asymmetric ventricular filling on left–right ventricular interaction in the normal rat heart

Heart failure is characterised by ventricular dysfunction and with the potential for changes to ventricular volumes constraining the mechanical performance of the heart. The contribution of this interaction from geometric changes rather than fibrosis or metabolic changes is unclear. Using the constant pressure Langendorff-perfused rat heart, the volume interaction between left ventricle (LV) and right ventricle (RV) was investigated. RV diastolic stiffness (P?<?0.001) and developed pressure (P?<?0.001) were significantly lower than LV. When the RV was fixed at the end-diastolic volume (EDV) or EDV?+?50?%, both LV systolic and diastolic performance were unaffected with increasing LV balloon volume. However, at fixed LV volume, RV systolic performance was significantly decreased when LV volume increased to EDV?+?50?% when RV volume was increased incrementally between 50 and 300?μl (P?<?0.001). Systolic interaction in RV was noted as declining RV peak systolic load with increasing LV systolic pressure (P?<?0.05) and diastolic interaction was noted for RV when LV volume was increased from EDV to EDV?+?50?% (P?<?0.05). RV diastolic wall stress was increased with increasing LV balloon volume (P?<?0.05), but LV wall stress was unaltered at fixed RV balloon volume. Taken together, increasing LV volume above EDV decreased systolic performance and triggered ventricular constraint in the RV but the RV itself had no effect on the performance of the LV. These results are consistent with overload of the LV impairing pulmonary perfusion by direct ventricular interaction with potential alteration to ventilation–perfusion characteristics within the lung.     

Patient-specific finite element modeling of the Cardiokinetix Parachute® device: effects on left ventricular wall stress and function

The Parachute^® (Cardiokinetix, Inc., Menlo Park, California) is a catheter-based device intended to reverse left ventricular (LV) remodeling after antero-apical myocardial infarction. When deployed, the device partitions the LV into upper and lower chambers. To simulate its mechanical effects, we created a finite element LV model based on computed tomography (CT) images from a patient before and 6 months after Parachute^® implantation. Acute mechanical effects were determined by in silico device implantation (VIRTUAL-Parachute). Chronic effects of the device were determined by adjusting the diastolic and systolic material parameters to better match the 6-month post-implantation CT data and LV pressure data at end-diastole (ED) (POST-OP). Regional myofiber stress and pump function were calculated in each case. The principal finding is that VIRTUAL-Parachute was associated with a 61.2 % reduction in the lower chamber myofiber stress at ED. The POST-OP model was associated with a decrease in LV diastolic stiffness and a larger reduction in myofiber stress at the upper (27.1 %) and lower chamber (78.4 %) at ED. Myofiber stress at end-systole and stroke volume was little changed in the POST-OP case. These results suggest that the primary mechanism of Parachute^® is a reduction in ED myofiber stress, which may reverse eccentric post-infarct LV hypertrophy.     

Phosphodiesterase inhibition promotes the transition from compensated hypertrophy to cardiac dilatation in rats

The cellular signaling pathways responsible for the transition from compensated left ventricular hypertrophy (LVH) to LV dilatation (remodeling) and heart failure are unclear. As chronic administration of a beta-adrenoreceptor (beta-AR) agonist mediates the premature onset of cardiac remodeling without myocyte necrosis or myocardial dysfunction in LVH, we suggest that beta-AR activation is critical in promoting the transition from compensated LVH to cardiac dilatation. However, beta-AR mediated effects in the heart can occur via either the cyclic adenosine monophosphate (cAMP) system or via cAMP independent signaling pathways. To determine the role of cAMP in promoting adverse cardiac chamber remodeling, we evaluated whether phosphodiesterase inhibition (PDEI) promotes LV dilatation in rats with compensated LVH. The impact of chronic administration of the PDEI, pentoxifylline, on LV remodeling and function was assessed in spontaneously hypertensive rats (SHR) with compensated LVH. The PDEI mediated inotropic effects and increased cAMP concentrations in SHR. This dose of the PDEI administered for 4 months to SHR did not modify LV weight or influence intrinsic myocardial systolic function (as assessed in the absence of the PDEI) in SHR. However, the PDEI mediated the development of a right shift in LV end diastolic (LVED) pressure-internal dimension and LVED pressure-volume relations, LV wall thinning, and increments in myocardial soluble (non-cross-linked) collagen concentrations. In conclusion, chronic PDEI administration induces adverse geometric and interstitial cardiac remodeling in SHR, a finding that supports the notion that the beta-AR-cAMP system is important in mediating the progression to heart failure by promoting interstitial remodeling and LV dilatation in LVH.     

Shifting the pulsatility by increasing the change in rotational speed for a rotary LVAD using a native heart load control system

We have previously developed a native heart load control system for a continuous-flow left ventricular assist device (LVAD) ((EVAHEART^®; Sun Medical) and demonstrated that the rotational speed (RS) in synchronization with the cardiac cycle can alter pulsatility and left ventricular (LV) load under general anesthesia. In this study, we assessed the effects of different levels of increase in RS on pulsatility and LV load in the chronic awake phase. We implanted the EVAHEART via left thoracotomy in 7 normal goats (59.3 ± 4.6 kg). Two weeks after implantation, we examined the effects of co-pulse mode (increased RS in the systolic phase) and counter-pulse mode (increased RS in the diastolic phase), as well as shifting the change in RS from 250 to 500 rpm, and 750 rpm in both modes on pulsatility and LV load. Pulsatility was assessed using pulse pressure and mean dP/dt max of aortic pressure. LV load was assessed using stroke work and left ventricle end-diastolic volume determined from LV pressure–volume loops. In the co-pulse mode, pulsatility values increased as the change in RS increased. By contrast, in the counter-pulse mode, these values decreased as the change in RS increased. LV load increased significantly in the co-pulse mode compared with the counter-pulse mode, but there were no significant differences among the three levels of RS increase in either mode. Increasing RS to varying degrees with our newly developed system could contribute to pulsatility. However, it appeared to have little effect on LV load in normal hearts.     

Left ventricular pressure–volume relationships during normal growth and development in the adult rat – studies in 8‐ and 50‐week‐old male Wistar rats

Aims: Left ventricular (LV) pressure–volume relations provide relatively load‐independent indexes of systolic and diastolic LV function, but few data are available on pressure–volume relations during growth and development in the normal adult heart. Furthermore, to quantify intrinsic ventricular function the indexes should be normalized for heart weight. However, in many studies the indexes are reported in absolute terms, or body weight‐correction is used as a surrogate for heart weight‐correction. Methods: We determined pressure–volume relations in young (8‐week‐old, n = 13) and middle‐aged (50‐week‐old, n = 19) male Wistar rats in relation to their heart and body weights. The animals were anaesthetized and a 2F pressure‐conductance catheter was introduced into the LV to measure pressure–volume relations. Results: Heart and body weights were significantly higher in the 50‐week‐old rats, whereas the heart‐to‐body weight ratio was significantly lower (2.74 ± 0.32 vs. 4.41 ± 0.37 mg g^?1, P < 0.001). Intrinsic systolic function, quantified by the slopes of the end‐systolic pressure–volume relation (E_ES), the dP/dt_MAX vs. end‐diastolic volume relation (S‐dP), and the preload recruitable stroke work relation (PRSW), normalized for heart weight, was slightly decreased in the 50‐week‐old rats (S‐dP: ?6%, P < 0.004; PRSW: ?3%, P < 0.06). Heart weight‐corrected diastolic indexes were not significant different. The absolute indexes qualitatively showed the same results, but body‐weight corrected pressure–volume indexes showed improved systolic function and significantly depressed diastolic function. Conclusions: Intrinsic systolic function slightly decreases from the juvenile to the middle‐aged period in normal male Wistar rats. Furthermore, correction of pressure–volume indexes for body weight is not an adequate surrogate for heart weight‐correction in these animals.     

Chronic sympathetic activation promotes downregulation of β-adrenoceptor-mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction

It is uncertain if downregulation of β-adrenoceptor signaling pathway is promoted by an enhanced adrenergic tone at an early stage of cardiac disease, or it develops secondary to detrimental local myocardial changes in advanced heart failure. We examined the integrity of β-adrenoceptor signaling pathway upon chronic infusion of isoproterenol, a β-adrenoceptor agonist, at a dose producing no structural left ventricular (LV) remodeling and systolic dysfunction. Subcutaneous isoproterenol infusion (400 μg kg⁻¹ h⁻¹ over 16 days) to guinea pigs using osmotic minipumps produced no change in cardiac weights, LV internal dimensions, myocyte cross-sectional area, extent of interstitial fibrosis, and basal contractile function. Isolated, perfused heart preparations from isoproterenol-treated guinea pigs exhibited attenuated responsiveness to acute β-adrenoceptor stimulation, as evidenced by reduced LV developed pressure increase, less shortening of LV epicardial monophasic action potential and effective refractory period, and less myocardial cyclic adenosine monophosphate elevation, in response to isoproterenol exposure, when compared to saline-treated controls. Pharmacological responses to forskolin, an activator of the adenylate cyclase catalytic subunit, were well preserved in isoproterenol-treated hearts. Downregulation of β-adrenoceptor-mediated effects upon chronic isoproterenol infusion was associated with markedly reduced stimulatory G-protein α-subunit (G_sα) myocardial expression levels. No change in expression levels of β-adrenoceptors, G-protein-coupled receptor kinase 2, inhibitory G-protein α-subunit (G_iα2), and Ca_v1.2 and K_v7.1 ion channels was determined in isoproterenol-treated hearts. We therefore conclude that sustained adrenergic overstimulation may promote downregulation of myocardial β-adrenoceptor-mediated effects independently of structural LV remodeling and systolic failure, an effect attributed to β-adrenoceptor uncoupling from adenylate cyclase due to reduced G_sα-protein expression.     

Genome-wide association of echocardiographic dimensions,brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study

Background

Echocardiographic left ventricular (LV) measurements, exercise responses to standardized treadmill test (ETT) and brachial artery (BA) vascular function are heritable traits that are associated with cardiovascular disease risk. We conducted a genome-wide association study (GWAS) in the community-based Framingham Heart Study.

Methods

We estimated multivariable-adjusted residuals for quantitative echocardiography, ETT and BA function traits. Echocardiography residuals were averaged across 4 examinations and included LV mass, diastolic and systolic dimensions, wall thickness, fractional shortening, left atrial and aortic root size. ETT measures (single exam) included systolic blood pressure and heart rate responses during exercise stage 2, and at 3 minutes post-exercise. BA measures (single exam) included vessel diameter, flow-mediated dilation (FMD), and baseline and hyperemic flow responses. Generalized estimating equations (GEE), family-based association tests (FBAT) and variance-components linkage were used to relate multivariable-adjusted trait residuals to 70,987 SNPs (Human 100K GeneChip, Affymetrix) restricted to autosomal SNPs with minor allele frequency ≥0.10, genotype call rate ≥0.80, and Hardy-Weinberg equilibrium p ≥ 0.001.

Results

We summarize results from 17 traits in up to 1238 related middle-aged to elderly men and women. Results of all association and linkage analyses are web-posted at http://ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. We confirmed modest-to-strong heritabilities (estimates 0.30–0.52) for several Echo, ETT and BA function traits. Overall, p < 10^-5 in either GEE or FBAT models were observed for 21 SNPs (nine for echocardiography, eleven for ETT and one for BA function). The top SNPs associated were (GEE results): LV diastolic dimension, rs1379659 (SLIT2, p = 1.17*10^-7); LV systolic dimension, rs10504543 (KCNB2, p = 5.18*10^-6); LV mass, rs10498091 (p = 5.68*10^-6); Left atrial size, rs1935881 (FAM5C, p = 6.56*10^-6); exercise heart rate, rs6847149 (NOLA1, p = 2.74*10^-6); exercise systolic blood pressure, rs2553268 (WRN, p = 6.3*10^-6); BA baseline flow, rs3814219 (OBFC1, 9.48*10^-7), and FMD, rs4148686 (CFTR, p = 1.13*10^-5). Several SNPs are reasonable biological candidates, with some being related to multiple traits suggesting pleiotropy. The peak LOD score was for LV mass (4.38; chromosome 5); the 1.5 LOD support interval included NRG2.

Conclusion

In hypothesis-generating GWAS of echocardiography, ETT and BA vascular function in a moderate-sized community-based sample, we identified several SNPs that are candidates for replication attempts and we provide a web-based GWAS resource for the research community.

     

大鼠肥厚心脏卸负荷后心室逆重塑相关的信号通路改变

目的： 研究肥厚心脏心室重塑及逆重塑过程中Akt/GSK3β、MAPKs和NF-κB信号通路的变化。方法：以Lewis大鼠行腹主动脉缩窄术,建立压力超负荷性心肌肥厚模型。将肥厚心脏移植到同源Lewis大鼠腹部,建立压力卸负荷模型。对各组心肌取材进行病理学评价。Western blotting法检测心肌组织中相关信号通路蛋白的表达。结果：在心肌肥厚大鼠心脏中Akt/GSK3β、MAPKs和NF-κB磷酸化水平均显著升高,移植卸负荷后除p38 MAPK和JNK外,其它蛋白磷酸化水平均显著降低。结论：肥厚心脏经异位移植卸负荷后产生逆重塑现象,Akt/GSK3β、ERK1/2和NF-κB信号通路的改变参与其中,该结果为临床心室逆重塑的研究提供了实验依据。     

Inhibition of left ventricular remodelling preserves chamber systolic function in pressure-overloaded mice

Controversy exists whether the development of left-ventricular hypertrophy (LVH) is a mechanism able to prevent cardiac dysfunction under conditions of pressure overload. In the present study we re-assessed the long-term effects of attenuating LVH by using L- and D-propranolol, which are equally able to inhibit the development of LVH induced by aortic banding. The aortic arch was banded proximal to the left common carotid artery in 71 CD-1 mice that were then assigned randomly to receive L-propranolol, D-propranolol (both 80 mg/kg per day) or vehicle. Concurrently, sham-operated mice were given L-propranolol, D-propranolol or vehicle. LV dimension and performance were evaluated under isoflurane anaesthesia by cine-magnetic resonance imaging, echocardiography and cardiac catheterization up to 8 weeks after surgery. After 2 weeks of pressure overload, the vehicle-treated banded mice had enhanced LV weight, normal chamber size and increased relative wall thickness (concentric hypertrophy), whereas L-propranolol- or D-propranolol-banded mice showed a markedly blunted hypertrophic response, i.e. normal chamber size and normal relative wall thickness, as well as preserved systolic LV chamber function. After 4 weeks, the vehicle-treated banded mice showed LV enlargement with a reduced relative wall thickness (eccentric remodelling) and a clear-cut deterioration in LV systolic function. In contrast, L-propranolol- or D-propranolol-treated banded mice showed normal chamber size with a normal relative wall thickness and preserved systolic function. A distinct histological feature was that in banded mice, L-or D-propranolol attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. At the 8-week stage, LV dysfunction was present in propranolol-treated banded mice although it was much less severe than in vehicle-treated banded mice. It is concluded that (i) deterioration of LV systolic performance is delayed if LV hypertrophy is inhibited, (ii) banding-induced deterioration of LV systolic function is associated with LV eccentric remodelling and (iii) the antihypertrophic effect of propranolol is due to a selective action on cardiomyocytes rather than on collagen accumulation     

Effects of pressure overload on the passive mechanics of the rat left ventricle

Both myocyte growth and changes in the extracellular matrix may affect the passive mechanics of the left ventricle (LV). Pressure-volume (PV) relationships and midwall two-dimensional strainsversus passive loading were measured in isolated rat hearts 2 and 6 weeks after ascending aortic banding. Collagen area fractions and perimysial fibril orientations were determined with picrosirius-polarization microscopy, and the equatorial region of the LV was modeled with finite element analysis of a transversely isotropic cylinder with the same material properties in hypertrophy and control. Compared with weight-matched shams, heart weight increased at 2 (19%) and 6 (22%) weeks, as did LV wall thickness (6% and 31%, respectively). The PV curve became less compliant with hypertrophy; only circumferential strain decreased after hypertrophy. Collagen area fractions were not different at either subendocardium or subepicardium (3.37±1.06versus 3.96±0.76 at 2 weeks and 3.61±1.30versus 4.22±1.50 at 6 weeks for banded and sham, respectively; subendocardium). Collagen and muscle fiber orientations also did not change with hypertrophy. The finite element model predicted trends in the strains similar to those found experimentally. Thus, in this model of pressure-overload hypertrophy, the decreases in compliance and circumferential strain of the passive LV are not due to changes in the percentage of extracellular matrix, but rather to global geometric changes.     

Telomere length and adrenergic-induced left ventricular dilatation and systolic chamber dysfunction in rats

Purpose

The mechanisms responsible for telomere shortening in heart failure are uncertain. We evaluated whether left ventricular (LV) dilatation and systolic chamber dysfunction produced by chronic β-adrenergic receptor (β-AR) activation is associated with leukocyte or cardiac telomere shortening.

Methods

Following 6 months of daily injections of the β-AR agonist, isoproterenol (0.02 mg/kg/day) or the saline vehicle to rats, the extent of LV dilatation and LV systolic chamber dysfunction were determined using echocardiography and isolated perfused heart procedures, and relative telomere length of leukocyte (LTL) and cardiac (CTL) deoxyribonucleic acid were determined using a quantitative real-time polymerase chain reaction assay.

Results

β-AR activation resulted in LV dilatation as indexed by increased LV diastolic diameters (9.2 ± 0.6 vs. 8.4 ± 0.9 mm, P = 0.01) and increased diastolic volume intercepts at zero pressure of the LV diastolic pressure–volume relationship (isolated, perfused heart preparation) (0.40 ± 0.06 vs. 0.37 ± 0.08 ml, P = 0.03). Moreover, β-AR activation resulted in LV systolic chamber dysfunction as indexed by reductions in LV endocardial fractional shortening (0.40 ± 0.05 vs. 0.45 ± 0.06, P = 0.01) and the slope of the LV systolic pressure–volume relation (609 ± 176 vs. 901 ± 230, P = 0.01). Although LTL decreased with age in rats receiving either the β-AR agonist or the saline vehicle (P < 0.05), neither CTL (?0.10 ± 0.14 vs. ?0.15 ± 0.12, P = 0.3) nor LTL (?0.11 ± 0.19 vs. ?0.15 ± 0.18, P = 0.5) were modified by β-AR activation.

Conclusion

In conclusion, chronic β-AR activation sufficient to produce LV dilatation and systolic chamber dysfunction is not associated with alterations in leukocyte or cardiac telomere length. Telomere shortening in chronic heart failure is unlikely to be attributed to chronic β-AR activation.     

The Effect of Overweight/Obesity on Cardiovascular Responses to Acute Psychological Stress in Men Aged 50-70 Years

BackgroundTo determine the effect of adiposity in males aged 50-70 years on cardiovascular responses to acute psychological stress.MethodsLean (BMI 20-25 kg/m²) (n = 21) and overweight/obese (BMI 27-35 kg/m²) (n = 21) men aged 50-70 years were subjected to psychological stress. Systolic blood pressure, diastolic blood pressure, heart rate, total peripheral resistance, and cardiac output were measured by a Finometer during resting (60 min), stress (30 min), and recovery (90 min).ResultsThe lean group had a significantly higher SBP stress reactivity when compared to the overweight/obese group (51.5 ± 3.7% vs. 41.0 ± 2.9% (mean ± SEM); p < 0.05). A significant effect of time was observed for systolic blood pressure, diastolic blood pressure, heart rate, total peripheral resistance, and cardiac output (p < 0.0001 for all). There were significant time × body type interactions for systolic blood pressure, diastolic blood pressure, heart rate, total peripheral resistance, and cardiac output (p < 0.05 for all). Total peripheral resistance during recovery was higher in the lean compared to the overweight/obese group (p < 0.05). In the lean group, systolic and diastolic blood pressure variability remained elevated after stress (p < 0.05) but returned to resting levels in the overweight/obese group (p > 0.05).ConclusionModerate adiposity in men was associated with reduced systolic blood pressure % reactivity, total peripheral resistance, and blood pressure variability after psychological stress. Overweight/obese men appear to be at no greater risk of unfavorable cardiovascular responses to stress.Key Words: Stress, Blood pressure, Obesity, Adults     

高血压无左室肥厚患者舒张功能改变的观察

目的：探讨高血压无左室肥厚患者舒张功能的改变。方法：高血压无左室肥厚患者、高血压伴左室肥厚患者与正常血压者各４０例,均进行超声心动图检查和动态血压检测。结果：高血压伴左室肥厚组、高血压无左室肥厚组与正常对照组比较,二尖瓣血流Ｅ峰、Ａ峰、Ｅ／Ａ比率、等容舒张时间及舒张早期减速度均有明显差异（Ｐ＜００５,Ｐ＜００１）,而高血压左室肥厚组与高血压无左室肥厚组两组间,则无明显差异（Ｐ＞００５）。３个组的左室射血分数（ＥＦ）无明显差异（Ｐ＞００５）。动态血压监测显示,高血压左室肥厚组与高血压无左室肥厚组２４ｈ平均收缩压和舒张压、白昼平均收缩压和舒张压、血压负荷有显著差异（Ｐ＜００５,Ｐ＜０．０１）,而夜间平均收缩压、舒张压无显著差异（Ｐ＞００５）。结论：高血压患者在出现左室肥厚前可出现舒张功能异常,可能与夜间血压持续升高有关。