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Murine pressure overload models: A 30-MHz look brings a whole new "sound" into data interpretation
Abstract and Figures
Transverse aortic constriction (TAC) and Angiotensin II (AngII)subcutaneous osmotic pump infusion are frequently used murine models of pressure overload hypertrophy. The aim of this paper is to investigate time- and stressor dependent functional and structural changes using echocardiographic B-mode, M-mode and Doppler characterization. Ten weeks old male C57BL6/J wild-type mice received 4 weeks Angiotensin II (AngII, 1.5 mg/kg/day, n=19) or saline (n=10) infusion followed by echocardiography (Vevo2100, Visual Sonics), or underwent TAC (n=63) or a sham operation (n=30). In the TAC protocol, echocardiography was performed after 2 weeks (n=22 TAC, n=10 sham), after 4 weeks (n=20 TAC, n=10 sham) and after 10 weeks (n=21 TAC, n=10 sham). AngII infusion was associated with a mixed pressure and volume overload, with a variable contribution of volume overload caused by aortic valve insufficiency (grade 0.5-3.5/4). The degree of aortic valve insufficiency correlated with the degree of left ventricular dilation (r²=.671,p<.001). After TAC, all hypertrophic remodelling patterns known in human disease were observed:. 1) low-flow low-gradient with preserved EF, 2) concentric hypertrophy with normal EF and flow, 3) concentric hypertrophy with moderately decreased EF and/or flow, 4) eccentric hypertrophy with normal EF and flow, 5) eccentric hypertrophy with moderately decreased EF and/or flow, and 6) eccentric hypertrophy with severely depressed EF. Eccentric remodeling was time-dependent, with 5% of mice developing this phenotype at 2 weeks, 39% at 4 weeks and 59% at 10 weeks. Comprehensive echocardiographic analysis allows identification of homogeneous subgroups of mice subjected to hypertrophic stress, reducing variability in experimental results and facilitating clinical translation.
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... In mice, the model of TAC has been extensively used to examine signalling pathways that contribute to adverse cardiac remodelling and hypertrophy in the context of pressure overload and neurohumoral activation [112,225,252,260]. As shown in Table 2, mice that are subjected to TAC exhibit cardiac remodelling in two sequential stages: (1) an initial stage of concentric hypertrophy and stable systolic but impaired diastolic function, thereby resembling features of human HF with preserved ejection fraction (HFpEF) [90,252,260]. (2) over time, the mice decompensate and exhibit severe systolic HF accompanied by eccentric hypertrophy, thereby resembling features of human HFrEF [90,175,252,260]. However, the progression from HFpEF to HFrEF is not a mandatory sequela in the patients' course of HFpEF [47]. ...
... As shown in Table 2, mice that are subjected to TAC exhibit cardiac remodelling in two sequential stages: (1) an initial stage of concentric hypertrophy and stable systolic but impaired diastolic function, thereby resembling features of human HF with preserved ejection fraction (HFpEF) [90,252,260]. (2) over time, the mice decompensate and exhibit severe systolic HF accompanied by eccentric hypertrophy, thereby resembling features of human HFrEF [90,175,252,260]. However, the progression from HFpEF to HFrEF is not a mandatory sequela in the patients' course of HFpEF [47]. ...
... 200% 6 weeks after TAC. In addition, the temporal dynamics of the transition from HFpEF to HFrEF vary even within the same experimental group [90]. Further, in a recent study only a subset of mice (28%) that were subjected to TAC develop signs of HFrEF [181], thus indicating that some mice will not proceed from HFpEF to HFrEF after TAC at all. ...
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Abstract: Heart failure is a consequence of various cardiovascular diseases and associated with poor prognosis. Despite progress in the treatment of heart failure in the past decades, prevalence and hospitalisation rates are still increasing. Heart failure is typically associated with cardiac remodelling. Here, inflammation and fibrosis are thought to play crucial roles. During cardiac inflammation, immune cells invade the cardiac tissue and modulate tissue-damaging responses. Cardiac fibrosis, however, is characterised by an increased amount and a disrupted composition of extracellular matrix proteins. As evidence exists that cardiac inflammation and fibrosis are potentially reversible in experimental and clinical set ups, they are interesting targets for innovative heart failure treatments. In this context, animal models are important as they mimic clinical conditions of heart failure patients. The advantages of mice in this respect are short generation times and genetic modifications. As numerous murine models of heart failure exist, the selection of a proper disease model for a distinct research question is demanding. To facilitate this selection, this review aims to provide an overview about the current understanding of the pathogenesis of cardiac inflammation and fibrosis in six frequently used murine models of heart failure. Hence, it compares the models of myocardial infarction with or without reperfusion, transverse aortic constriction, chronic subjection to angiotensin II or deoxycorticosterone acetate, and coxsackievirus B3-induced viral myocarditis in this context. It furthermore provides information about the clinical relevance and the limitations of each model, and, if applicable, about the recent advancements in their methodological proceedings.
... Frontiers in Cardiovascular Medicine explained by a reduction in contraction speed of the ventricular myocardium or a change of constriction diameter in the proleneoperated animals over time. A decline in pressure gradient over time in prolene-operated animals was also observed in another recent study (20). No difference was found when comparing suture size (Figures 7C-E). ...
Introduction
Transverse-aortic constriction (TAC) operation is a widely used animal model to induce hypertrophy and heart failure through left-ventricular pressure overload. In mice, the cardiac response to TAC exhibits considerable variability influenced by factors such as strain, sub-strain, age, sex and vendor.
Methods
To investigate the impact of suture material (silk versus prolene) and size (6-0 versus 7-0) on the TAC-induced phenotype, we performed surgeries on male C57BL6/N mice at 9 weeks of age defining the aortic constriction by a 27G needle, thereby employing most frequently used methodological settings. The mice were randomly assigned into four separate groups, 6-0 silk, 7-0 silk, 6-0 prolene and 7-0 prolene (10 mice per group). Echocardiography was conducted before TAC and every 4 weeks thereafter to monitor the development of heart failure. Repeated measures correlation analysis was employed to compare disease progression among the different groups.
Results
Our findings reveal a significant influence of the chosen suture material on TAC outcomes. Mice operated with prolene showed increased mortality, slower body weight gain, faster left-ventricular mass increase, and a faster decline in left-ventricular ejection fraction, fractional shortening and aortic pressure gradient compared to silk-operated mice. Moreover, despite non significant, using thinner suture threads (7-0) tended to result in a more severe phenotype compared to thicker threads (6-0) across all tested parameters.
Discussion
Collectively, our results highlight the importance of suture material selection in determining the cardiac phenotype induced by TAC and emphasize the need to consider this factor when comparing data across different research laboratories.
... These findings are consistent with previous reports. Hermans et al. (Hermans et al., 2014) applied TAC to C57BL/6J mice aged over 10 weeks and found considerable diversity in the extent of cardiac remodelling after 2-10 weeks of TAC, including Fig. 4. Variability in pre-TAC aortic arch dimension and its relationship with the severity of hypertrophy. (A) There is an age-independent variability in pre-TAC aortic arch dimension in C57BL/6J mice but not in C57BL/6NTac mice (n ¼ 17-21 per group). ...
Background
The mouse model of transverse aortic constriction (TAC) has been widely used as a cardiac stress in the investigation of the molecular mechanisms of cardiac hypertrophy. Recently, the International Knockout Mouse Consortium has selected the C57BL/6NTac (BL/6N) mouse strain to generate null alleles for all mouse genes; however, a range of genetic and cardiac phenotypic differences have been reported between this substrain and the commonly used C57BL/6J (BL/6J) substrain. It has been reported by Garcia-Menendez and colleagues that 12-week C57BL/6NTac mice are susceptible to heart failure but little is known about the cardiac remodeling in this substrain as cardiac function progresses from compensation to decompensation.
Methods
BL/6J and BL/6N mice were subjected to pressure overload via TAC. The impact of both age and duration of cardiac pressure overload induced by TAC on cardiac remodelling were systematically assessed.
Results
Our data showed that BL/6N mice developed eccentric hypertrophy with age- and time-dependent deterioration in cardiac function, accompanied by considerable interstitial fibrosis. In contrast, BL/6J mice were more resilient to TAC-induced cardiac stress and developed variable cardiac phenotypes independent of age and the duration of pressure overload. This was likely due to the greater variability in pre-TAC aortic arch dimension as measured by echocardiography. In addition to increased expression of brain natriuretic peptide and collagen gene type 1 and 3, BL/6N mice also had greater angiotensin II type 2 receptor (AT2R) gene expression than BL/6J counterparts at baseline and after 2-weeks TAC, which may contribute to the exacerbated interstitial fibrosis.
Conclusions
BL/6N and BL/6J mice have very different responses to TAC stimulation and these differences should be taken into consideration when using the substrains to investigate the mechanisms of hypertrophy and heart failure.
... Consistently, Millar catheter-based measurements identified a significant increase in LV end-systolic and LV end-diastolic pressure upon Chast overexpression (Fig. 5H), indicating that Chast overexpression results in early signs of pathological remodeling processes. This is in line with increased LV pressure values in other models of pathologic cardiac hypertrophy, such as abdominal aortic banding or angiotensin II infusion (19,20). GapmeR-mediated silencing of Chast 1 day after TAC with weekly follow-up treatments (Fig. 6, A and B) prevented cardiac hypertrophy, keeping animals at sham levels of heart weightto-tibia length (Fig. 6C) and cardiac stress markers Anp and b-Mhc (Fig. 6D) compared to mice treated with a scrambled control. ...
Recent studies highlighted long noncoding RNAs (lncRNAs) to play an important role in cardiac development. However, understanding of lncRNAs in cardiac diseases is still limited. Global lncRNA expression profiling indicated that several lncRNA transcripts are deregulated during pressure overload-induced cardiac hypertrophy in mice. Using stringent selection criteria, we identified Chast (cardiac hypertrophy-associated transcript) as a potential lncRNA candidate that influences cardiomyocyte hypertrophy. Cell fractionation experiments indicated that Chast is specifically up-regulated in cardiomyocytes in vivo in transverse aortic constriction (TAC)-operated mice. In accordance, CHAST homolog in humans was significantly up-regulated in hypertrophic heart tissue from aortic stenosis patients and in human embryonic stem cell-derived cardiomyocytes upon hypertrophic stimuli. Viral-based overexpression of Chast was sufficient to induce cardiomyocyte hypertrophy in vitro and in vivo. GapmeR-mediated silencing of Chast both prevented and attenuated TAC-induced pathological cardiac remodeling with no early signs on toxicological side effects. Mechanistically, Chast negatively regulated Pleckstrin homology domain-containing protein familyMmember 1 (opposite strand of Chast), impeding cardiomyocyte autophagy and driving hypertrophy. These results indicate that Chast can be a potential target to prevent cardiac remodeling and highlight a general role of lncRNAs in heart diseases. Copyright 2016 by the American Association for the Advancement of Science; all rights reserved.
... After the treatment was administered, the ventricular systolic and diastolic structures and functions were assessed through echocardiography. As illustrated in Fig. 1A and 1B as well as Table 1, aspirin treatment preserved normal ventricular function, whereas the TAC group developed significantly reduced chamber size, increased wall thickness, and increased % FS and % EF, which are consistent with concentric hypertrophy [24]. Deleterious ultrastructural changes that preceded gross morphological alterations typical of VH were observed through transmission electron microscopy. ...
Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid (aspirin) provide cardiovascular benefits through the irreversible inhibition of platelet cyclooxygenase 1; however, the possible anti-hypertrophic properties and potential mechanism of aspirin have not been investigated in detail. In this study, healthy wild-type male mice were randomly divided into three groups and subjected to transverse aortic constriction (TAC) or sham operation. The TAC-operated mice were treated with the human equivalent of low-dose aspirin (10 mg·kg(-1)·d(-1)); the remaining mice received an equal amount of phosphate buffered saline with 0.65% ethanol, which was used as a vehicle. A cardiomyocyte hypertrophy model induced by angiotensin II (10 nmol·L(-1)) was treated with the human equivalent of low (10 or 100 μmol·L(-1)) and high (1000 μmol·L(-1)) aspirin concentrations in plasma. Changes in the cardiac structure and function were assessed through echocardiography and transmission electron microscopy. Gene expression was determined through RT-PCR and western blot analysis. Results indicated that aspirin treatment abrogated the increased thickness of the left ventricular anterior and posterior walls, the swelling of mitochondria, and the increased surface area in in vivo and in vitro hypertrophy models. Aspirin also normalized the upregulated hypertrophic biomarkers, β-myosin heavy chain (β-MHC), atrial natriuretic peptide (ANP), and b-type natriuretic peptide (BNP). Aspirin efficiently reversed the upregulation of β-catenin and P-Akt expression and the TAC- or ANG II-induced downregulation of GSK-3β. Therefore, low-dose aspirin possesses significant anti-hypertrophic properties at clinically relevant concentrations for anti-thrombotic therapy. The downregulation of β-catenin and Akt may be the underlying signaling mechanism of the effects of aspirin.
Transverse aortic constriction (TAC) is a widely-used animal model for pressure overload-induced cardiac hypertrophy and heart failure (HF). The severity of TAC-induced adverse cardiac remodeling is correlated to the degree and duration of aorta constriction. Most studies of TAC are performed with a 27-gauge needle, which is easy to cause a tremendous left ventricular overload and leads to a rapid HF, but it is accompanied by higher mortality attributed to tighter aortic arch constriction. However, a few studies are focusing on the phenotypes of TAC applied with a 25-gauge needle, which produces a mild overload to induce cardiac remodeling and has low post-operation mortality. Furthermore, the specific timeline of HF induced by TAC applied with a 25-gauge needle in C57BL/6 J mice remains unclear. In this study, C57BL/6 J mice were randomly subjected to TAC with a 25-gauge needle or sham surgery. Echocardiography, gross morphology, and histopathology were applied to evaluate time-series phenotypes in the heart after 2, 4, 6, 8, and 12 weeks. The survival rate of mice after TAC was more than 98%. All mice subjected to TAC maintained compensated cardiac remodeling during the first two weeks and began to exhibit heart failure characteristics after 4 weeks upon TAC. At 8 weeks post-TAC, the mice showed severe cardiac dysfunction, hypertrophy, and cardiac fibrosis compared to sham mice. Moreover, the mice raised a severe dilated HF at 12 weeks. This study provides an optimized method of the mild overload TAC-induced cardiac remodeling from the compensatory period to decompensatory HF in C57BL/6 J mice.
The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (AT1R) is believed to mediate most functions of ANG II in the system. AT1R utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between AT1R signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. AT1R remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.
Double stranded RNA-dependent protein kinase (PKR) is a eukaryotic initiation factor 2α kinase that inhibits mRNA translation under stress conditions. PKR also mediates inflammatory and apoptotic signaling independent of translational regulation. Congestive heart failure (CHF) is associated with cardiomyocyte hypertrophy, inflammation, and apoptosis, but the role of PKR in left ventricular (LV) hypertrophy and development of CHF has not been examined.
We observed an increased myocardial PKR expression and translocation of PKR into the nucleus in humans and mice with CHF. To determine the impact of PKR in the development of CHF, PKR knockout and wild-type mice were exposed to pressure overload produced by transverse aortic constriction (TAC). Though heart size increased similarly in wild-type and PKR knockout mice after TAC, PKR knockout mice exhibited very little pulmonary congestion, well preserved LV ejection fraction and contractility, and significantly less myocardial fibrosis as compared to wild-type mice. Bone marrow-derived cells (BMDCs) from wild-type mice did not abolish the cardiac protective effect observed in PKR knockout mice, while BMDCs from PKR knockout mice had no cardiac protective effect in wild-type mice. Mechanistically, PKR knockout attenuated TAC-induced TNF-α expression and leukocyte infiltration, and lowered cardiac expression of pro-apoptotic factors (Bax and Caspase-3) so that PKR knockout hearts were more resistant to TAC-induced cardiomyocyte apoptosis. PKR depletion in isolated cardiomyocytes also conferred protection against TNF-α or LPS-induced apoptosis.
PKR is a maladaptive factor up-regulated in hemodynamic overload that contributes to myocardial inflammation, cardiomyocyte apoptosis and development of CHF.
Toll-interacting protein (Tollip) is a critical regulator of the Toll-like receptor-mediated signalling pathway. However, the role of Tollip in chronic pressure overload-induced cardiac hypertrophy remains unclear. This study aimed to determine the functional significance of Tollip in the regulation of aortic banding-induced cardiac remodelling and its underlying mechanisms.
First, we observed that Tollip was down-regulated in human failing hearts and murine hypertrophic hearts, as determined by western blotting and RT-PCR. Using cultured neonatal rat cardiomyocytes, we found that adenovirus vector-mediated overexpression of Tollip limited angiotensin II-induced cell hypertrophy; whereas knockdown of Tollip by shRNA exhibited the opposite effects. We then generated a transgenic (TG) mouse model with cardiac specific-overexpression of Tollip and subjected them to aortic banding (AB) for 8 weeks. When compared with AB-treated wild-type mouse hearts, Tollip-TGs showed a significant attenuation of cardiac hypertrophy, fibrosis, and dysfunction, as measured by echocardiography, immune-staining, and molecular/biochemical analysis. Conversely, a global Tollip-knockout mouse model revealed an aggravated cardiac hypertrophy and accelerated maladaptation to chronic pressure overloading. Mechanistically, we discovered that Tollip interacted with AKT and suppressed its downstream signalling pathway. Pre-activation of AKT in cardiomyocytes largely offset the Tollip-elicited anti-hypertrophic effects.
Our results provide the first evidence that Tollip serves as a negative regulator of pathological cardiac hypertrophy by blocking the AKT signalling pathway.
We explored whether subclinical alterations of sarcoplasmic reticulum (SR) Ca(2+) release through cardiac ryanodine receptors (RyR2) aggravate cardiac remodeling in mice carrying a human RyR2(R4496C+/-) gain-of-function mutation in response to pressure overload.
RyR2 dysfunction causes increased diastolic SR Ca(2+) release associated with arrhythmias and contractile dysfunction in inherited and acquired cardiac diseases, such as catecholaminergic polymorphic ventricular tachycardia (CPVT) and heart failure (HF).
Functional and structural properties of wild-type (WT) and CPVT-associated RyR2(R4496C+/-) hearts were characterized under conditions of pressure overload induced by transverse aortic constriction (TAC).
WT and RyR2(R4496C+/-) hearts had comparable structural and functional properties at baseline. After TAC, RyR2(R4496C+/-) hearts responded with eccentric hypertrophy, substantial fibrosis, ventricular dilatation and reduced fractional shortening, ultimately resulting in overt HF. RyR2(R4496C+/-)-TAC cardiomyocytes showed increased incidence of spontaneous SR Ca(2+) release events, reduced Ca(2+) transient peak amplitude and SR Ca(2+) content as well as reduced SR Ca(2+)-ATPase2a and increased Na(+)/Ca(2+)-exchange protein expression. HF phenotype in RyR2(R4496C+/-)-TAC mice was associated with increased mortality due to pump failure, but not tachyarrhythmic events. RyR2-stabilizer K201 markedly reduced Ca(2+) spark frequency in RyR2(R4496C+/-)-TAC cardiomyocytes. Mini-osmotic pump infusion of K201 prevented deleterious remodeling and improved survival in RyR2(R4496C+/-)-TAC mice.
The combination of subclinical congenital alteration of SR Ca(2+) release and pressure overload promotes eccentric remodeling and HF death in RyR2(R4496C+/-) mice, and pharmacological RyR2 stabilization prevents this deleterious interaction. These findings imply potential clinical relevance for patients with acquired or inherited gain-of-function of RyR2-mediated SR Ca(2+) release.
In the American Heart Association (AHA) / American College of Cardiology (ACC) and European Society of Cardiology (ESC) / European Association of Cardiothoracic Surgery (EACTS) guidelines,(1,2) severe aortic stenosis (AS) is defined as a peak aortic jet velocity >4.0 m/s, a mean gradient >40 mmHg, and/or an aortic valve area (AVA) <1.0 cm(2) and it is considered a class I indication for aortic valve replacement (AVR) if the patient has symptoms or LV systolic dysfunction defined as LV ejection fraction (LVEF) <50%. However, the cardiologist is often confronted with patients with discordant echocardiographic findings, the most frequent being the combination of a small calculated AVA (<1.0 cm(2)) consistent with the presence of severe AS with a low mean gradient (<40 mmHg) suggesting the presence of moderate AS. This type of discordance may raise uncertainty about the actual severity of the stenosis and thus about the therapeutic management, particularly if the patient is symptomatic. Such AVA-gradient discordance is often related to the presence of low LV outflow, which may, even if modest, lead to an important reduction in gradient and thus to underestimation of stenosis severity. A low-flow state is generally defined as a stroke volume index < 35 ml/m(2) and it may occur not only in patients with reduced LVEF (i.e. classical low-flow) but also in those with preserved LVEF.(3) This latter entity was first described in 2007 by Hachicha et al. and was named "paradoxical" low-flow AS.(4) Subsequently, Dumesnil et al. proposed a new classification whereby patients with a priori severe AS on the basis of AVA and a preserved LVEF (i.e. >50%) are separated into 4 groups according to flow (stroke volume index< or ≥35 ml/m(2)) and gradient (< or ≥ 40 mmHg) as follows: 1) Normal-Flow, High Gradient (NF/HG); 2) Normal-Flow, Low-Gradient (NF/LG); 3) Low-Flow, High-Gradient (LF/HG); and 4) Low-Flow, Low-Gradient (LF/LG).(5) In this issue of the journal, Eleid et al. report the characteristics, outcomes, and impact of therapy in a large series of 1704 patients stratified according to this classification.(6) The main findings of this elegant study are: 1) Among patients with AVA<1.0 cm(2) and LVEF ≥50%, those with LF/LG have lower survival compared to patients with the other flow/gradient patterns but, nevertheless, the outcome of these patients is markedly improved by AVR. 2) Patients with NF/LG have favourable survival with medical management and impact of AVR on their outcome is neutral, thereby suggesting that these patients are likely at a less advanced stage of their disease than patients with other flow/gradient patterns.
Identifying the key factor mediating pathological cardiac hypertrophy is critically important for developing the strategy to protect against heart failure. Bone morphogenetic protein-4 (BMP4) is a mechanosensitive and proinflammatory gene. In this study, we investigated the role of BMP4 in cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy. The in vivo pathological cardiac hypertrophy models were induced by pressure-overload and angiotensin (Ang) II constant infusion in mice, and the in vitro model was induced by Ang II exposure to cultured cardiomyocytes. The expression of BMP4 increased in pressure overload, Ang II constant infusion-induced pathological cardiac hypertrophy, but not in swimming exercise-induced physiological cardiac hypertrophy in mice. BMP4 expression also increased in Ang II-induced cardiomyocyte hypertrophy in vitro. In turn, BMP4 induced cardiomyocyte hypertrophy, apoptosis, and cardiac fibrosis, and these pathological consequences were inhibited by the treatment with BMP4 inhibitors noggin and DMH1. Moreover, Ang II-induced cardiomyocyte hypertrophy was inhibited by BMP4 inhibitors. The underlying mechanism that BMP4-induced cardiomyocyte hypertrophy and apoptosis was through increasing NADPH oxidase 4 expression and reactive oxygen species-dependent pathways. Lentivirus-mediated overexpression of BMP4 recapitulated hypertrophy and apoptosis in cultured cardiomyocytes. BMP4 inhibitor DMH1 inhibited pressure overload-induced cardiac hypertrophy in mice in vivo. The plasma BMP4 level of heart failure patients was increased compared with that of subjects without heart failure. In summary, we conclude that BMP4 is a mediator and novel therapeutic target for pathological cardiac hypertrophy.
Key Findings
What is the topic of this review?
This review describes the use of high spatial and temporal resolution ultrasound imaging for the evalution of cardiovascular function.
What advances does it highlight?
This short reveiw succintly highlights the advances in the use of high‐resolution ultrasound in the assessment of rodent cardiac function, with emphasis on the differences between human and rodent echocardiography and on the main principles involved in completing a successful echocardiographic study in preclinical models.
The high temporal and spatial resolution of echocardiography makes it a powerful and reliable tool for the non‐invasive study of cardiac phenotype and disease in both adult and embryonic preclinical models. This overview of the use of high‐resolution ultrasound for echocardiography highlights the present and potential applications of the technique.
It has been shown that endothelial NO synthase (eNOS) uncoupling occurs in hypertension and atherosclerosis. However, its causal role in vascular pathogenesis has not been characterized previously. Here, we challenged eNOS preuncoupled hyperphenylalaninemia (hph)-1 mice (deficient in eNOS cofactor tetrahydrobiopterin biosynthetic enzyme GTPCHI) with angiotensin II (Ang II; 0.7 mg/kg per day, 14 days). Both wild-type and hph-1 groups developed hypertension similarly up to day 6 to 7. Thereafter, ≈14% of Ang II-infused (0.7 mg/kg per day) hph-1 mice (n=72) started to die suddenly of ruptured abdominal aortic aneurysm (AAA). Among the survivors, 65% developed AAA, resulting in a total morbidity rate of 79%. In contrast, none of the Ang II-infused wild-type mice died or developed AAA. Ang II progressively deteriorated eNOS uncoupling in hph-1 mice while augmenting tetrahydrobiopterin and nitric oxide (NO(·)) deficiencies. The abundance of the tetrahydrobiopterin salvage enzyme dihydrofolate reductase in the endothelium was decreased in hph-1 mice and further diminished by Ang II infusion. Intriguingly, restoration of dihydrofolate reductase expression by oral administration of folic acid or overexpression of dihydrofolate reductase completely prevented AAA formation in Ang II-infused hph-1 mice while attenuating progressive uncoupling of eNOS. Folic acid also attenuated vascular remodeling and inflammation characterized by medial elastin breakdown and augmented matrix metalloproteinase 2 activity and activation of matrix metalloproteinase 9, as well as macrophage infiltration. In conclusion, these data innovatively suggest a causal role of eNOS uncoupling/tetrahydrobiopterin deficiency in AAA formation. Therefore, oral folic acid administration, endothelium-targeted dihydrofolate reductase gene therapy, and perhaps other countermeasures directed against eNOS uncoupling could be used as new therapeutics for AAA.
The changes in left ventricular (LV) structure and geometry that evolve after myocardial injury or overload usually involve chamber dilation and/or hypertrophy. Such architectural remodeling can be classified as eccentric or concentric. Consideration of LV volume, mass, and relative wall thickness (or mass/volume) allows classification of LV remodeling that includes virtually all LV remodeling changes that are seen in health and disease. These various architectural changes generally include the development of LV hypertrophy in a pattern that is closely related to the type of injury or overload, and they are accompanied by differences in cardiac function and hemodynamics. Some patterns of remodeling are associated with adverse outcomes whereas others appear to be adaptive and physiologic without adverse consequences. Considering all patients with LV hypertrophy as a homogenous group is inconsistent with our understanding of the various remodeling patterns that are discussed in this review.
This prospective cohort study in patients with aortic stenosis (AS) aimed to identify surrogates of myocardial fibrosis that are easy to derive in clinical practice, allow the differentiation of low-gradient severe AS from moderate AS, and have an impact on clinical outcome.
In patients with symptomatic aortic AS, a characteristic subgroup (i.e., up to one-third) exhibits severe AS with a concomitant low mean valve gradient either with preserved or reduced ejection fraction (EF). It is hypothesized that these patients tend to have an advanced stage of myocardial fibrosis and poor clinical outcome.
Eighty-six patients with moderate or severe AS were examined by echocardiography including conventional aortic valve assessment, mitral ring displacement, and strain-rate imaging. Replacement fibrosis was quantified by late-enhancement magnetic resonance imaging. Biopsy samples were taken from patients with severe AS (n = 69) at aortic valve replacement. All patients were followed for 9 months.
Patients were divided into 4 groups according to aortic valve area (<1.0 cm(2)), mean valve gradient ≥40 mm Hg, and EF (<50%): group 1, moderate AS (n = 17); group 2, severe AS/high gradient (n = 49); group 3, severe AS/low gradient/preserved EF (n = 11); and group 4, severe AS/low gradient/decreased EF (n = 9). At baseline, a significant decrease in mitral ring displacement and systolic strain rate was detected in patients with low-gradient AS. In low-gradient groups, a higher degree of interstitial fibrosis in biopsy samples and more late-enhancement magnetic resonance imaging segments were observed. A close inverse correlation was found between interstitial fibrosis and mitral ring displacement (r = -0.79, p < 0.0001). Clinical outcome was best for patients in group 1, whereas mortality risk increased substantially in groups 2 through 4.
In severe AS, a low gradient is associated with a higher degree of fibrosis, decreased longitudinal function, and poorer clinical outcome despite preserved EF. Mitral ring displacement differentiates between moderate AS and low-gradient/severe AS with preserved EF.