scholarly journals Ultrastructural and cellular basis for the development of abnormal myocardial mechanics during the transition from hypertension to heart failure

2014 ◽  
Vol 306 (1) ◽  
pp. H88-H100 ◽  
Author(s):  
Sanjiv J. Shah ◽  
Gary L. Aistrup ◽  
Deepak K. Gupta ◽  
Matthew J. O'Toole ◽  
Amanda F. Nahhas ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Systolic Dysfunction ◽  
Radial Strain ◽  
Hypertensive Heart Disease ◽  
Tissue Doppler ◽  
Chronic Hypertension ◽  
Myocardial Mechanics ◽  
Cellular Basis ◽  
Intracellular Ca

Although the development of abnormal myocardial mechanics represents a key step during the transition from hypertension to overt heart failure (HF), the underlying ultrastructural and cellular basis of abnormal myocardial mechanics remains unclear. We therefore investigated how changes in transverse (T)-tubule organization and the resulting altered intracellular Ca2+ cycling in large cell populations underlie the development of abnormal myocardial mechanics in a model of chronic hypertension. Hearts from spontaneously hypertensive rats (SHRs; n = 72) were studied at different ages and stages of hypertensive heart disease and early HF and were compared with age-matched control (Wistar-Kyoto) rats ( n = 34). Echocardiography, including tissue Doppler and speckle-tracking analysis, was performed just before euthanization, after which T-tubule organization and Ca2+ transients were studied using confocal microscopy. In SHRs, abnormalities in myocardial mechanics occurred early in response to hypertension, before the development of overt systolic dysfunction and HF. Reduced longitudinal, circumferential, and radial strain as well as reduced tissue Doppler early diastolic tissue velocities occurred in concert with T-tubule disorganization and impaired Ca2+ cycling, all of which preceded the development of cardiac fibrosis. The time to peak of intracellular Ca2+ transients was slowed due to T-tubule disruption, providing a link between declining cell ultrastructure and abnormal myocardial mechanics. In conclusion, subclinical abnormalities in myocardial mechanics occur early in response to hypertension and coincide with the development of T-tubule disorganization and impaired intracellular Ca2+ cycling. These changes occur before the development of significant cardiac fibrosis and precede the development of overt cardiac dysfunction and HF.

scholarly journals Left Ventricular Myocardial Deformations in Hemodialysis Children by Speckle Tracking Echocardiography

2020 ◽  
Vol 14 ◽  
pp. 117954682093001
Author(s):  
Manal F Elshamaa ◽  
Fatma A Mostafa ◽  
Inas AES Sad ◽  
Ahmed M Badr ◽  
Yomna AEM Abd Elrahim
Keyword(s):  
Speckle Tracking ◽  
Longitudinal Strain ◽  
Speckle Tracking Echocardiography ◽  
Systolic Dysfunction ◽  
Global Longitudinal Strain ◽  
Radial Strain ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Myocardial Mechanics

Background: Cardiac systolic dysfunction was potentially found in adult patients with end-stage renal disease (ESRD) who have preserved left ventricular ejection fraction (EF%). In children with ESRD, little data are available on early changes in myocardial function. This study aimed to detect the early changes in myocardial mechanics in pediatric patients with ESRD using speckle tracking echocardiography (STE). Methods: Thirty ESRD children receiving hemodialysis (HD) and30 age-matched controls were prospectively studied. Patients underwent echocardiographic studies before and after HD. Left ventricular longitudinal strain (LS), circumferential strain (CS), and radial strain (RS) myocardial deformation parameters (strain, strain rate) were evaluated by STE. Results: The LS was significantly reduced in pre-HD and post-HD patients compared with controls ( P = .000). Controls showed the highest global longitudinal strain. The RS measurements did not differ significantly among the studied groups except for the inferior segment that is significantly reduced after HD compared with controls ( P < .05). The CS was significantly reduced in pre-HD and post-HD patients compared with controls at the lateral and posterior segments ( P = .035 and P = .013, respectively). Conclusion: Speckle-tracking echocardiography might detect early changes in myocardial mechanics in children with ESRD with preserved EF%.

scholarly journals Cardiac 12/15 lipoxygenase–induced inflammation is involved in heart failure

2009 ◽  
Vol 206 (7) ◽  
pp. 1565-1574 ◽  
Author(s):  
Yosuke Kayama ◽  
Tohru Minamino ◽  
Haruhiro Toko ◽  
Masaya Sakamoto ◽  
Ippei Shimizu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Systolic Dysfunction ◽  
Pressure Overload ◽  
Eicosatetraenoic Acid ◽  
Wild Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Novel Target

To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, Alox15 encoding the protein 12/15 lipoxygenase (LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that Alox15 transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in Alox15 transgenic mice with advancing age and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein 1 (MCP-1) was up-regulated in Alox15 transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenoic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells but not in cardiomyocytes. Inhibition of MCP-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in Alox15 transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac MCP-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition.

scholarly journals BET Protein-Mediated Transcriptional Regulation in Heart Failure

2021 ◽  
Vol 22 (11) ◽  
pp. 6059
Author(s):  
Talha Ijaz ◽  
Michael A. Burke
Keyword(s):  
Heart Failure ◽  
Gene Transcription ◽  
Transforming Growth Factor Beta ◽  
Gene Networks ◽  
Complex Disease ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Systolic Dysfunction ◽  
Disease Process

Heart failure is a complex disease process with underlying aberrations in neurohormonal systems that promote dysregulated cellular signaling and gene transcription. Over the past 10 years, the advent of small-molecule inhibitors that target transcriptional machinery has demonstrated the importance of the bromodomain and extraterminal (BET) family of epigenetic reader proteins in regulating gene transcription in multiple mouse models of cardiomyopathy. BETs bind to acetylated histone tails and transcription factors to integrate disparate stress signaling networks into a defined gene expression program. Under myocardial stress, BRD4, a BET family member, is recruited to superenhancers and promoter regions of inflammatory and profibrotic genes to promote transcription elongation. Whole-transcriptome analysis of BET-dependent gene networks suggests a major role of nuclear-factor kappa b and transforming growth factor-beta in the development of cardiac fibrosis and systolic dysfunction. Recent investigations also suggest a prominent role of BRD4 in maintaining cardiomyocyte mitochondrial respiration under basal conditions. In this review, we summarize the data from preclinical heart failure studies that explore the role of BET-regulated transcriptional mechanisms and delve into landmark studies that define BET bromodomain-independent processes involved in cardiac homeostasis.

scholarly journals Heart failure with Preserved EF: A Bird Eye View

2013 ◽  
Vol 52 (190) ◽  
Author(s):  
Fahad Aziz ◽  
Luqman-Arfath Thazhatauveetil-Kunhahamed ◽  
Chijioke Enweluzo ◽  
Misbah Zaeem
Keyword(s):  
Heart Failure ◽  
Diastolic Dysfunction ◽  
Early Recognition ◽  
Systolic Function ◽  
Diastolic Heart Failure ◽  
Systolic Dysfunction ◽  
Hypertensive Heart Disease ◽  
Left Ventricular ◽  
Morbidity Rate ◽  
Annual Mortality

The concept of ‘‘diastolic’’ heart failure grew out of the observation that many patients who have the symptoms and signs of heart failure had an apparently normal left ventricular (LV) ejection fraction. Thus it was assumed that since systolic function was ‘‘pre- served’’ the problem must lie in diastole, although it is not clear by whom or when this assumption was made. Diastolic heart failure is associated with a lower annual mortality rate of approximately 8% as compared to annual mortality of 19% in heart failure with systolic dysfunction, however, morbidity rate can be substantial. Thus, diastolic heart failure is an important clinical disorder mainly seen in the elderly patients with hypertensive heart disease. Early recognition and appropriate therapy of diastolic dysfunction is advisable to prevent further progression to diastolic heart failure and death. There is no specific therapy to improve LV diastolic function directly. Medical therapy of diastolic dysfunction is often empirical and lacks clear-cut pathophysiologic concepts. Nevertheless, there is growing evidence that calcium channel blockers, beta-blockers, ACE-inhibitors and ARB as well as nitric oxide donors can be beneficial. Treatment of the underlying disease is currently the most important therapeutic approach.Keywords: diastolic heart failure; doppler echocardiography; treatment.

scholarly journals Sensitive marker for Evaluation of Hypertensive Heart Disease: Extracellular Volume and Myocardial Strain

2020 ◽  
Author(s):  
Junqiao Niu ◽  
Zeng Mu ◽  
Yan Wang ◽  
Jun Liu ◽  
Jia Wang ◽  
...  
Keyword(s):  
Heart Disease ◽  
Longitudinal Strain ◽  
Systolic Dysfunction ◽  
Myocardial Strain ◽  
Extracellular Volume ◽  
Radial Strain ◽  
Hypertensive Heart Disease ◽  
Local Strain ◽  
Left Ventricular ◽  
Control Group

Abstract Background : Evaluation of tissue fibrosis and myocardial hypertrophy in left ventricular (LV) remodeling is the basis of post-treatment evaluation of hypertensive heart disease（HHD). Extracellular volume (ECV) and myocardial strain parameters can indirectly reflect the changes of both. Our objective was to analyze the characteristics of ECV and strain parameters in LV myocardium of HHD with varying degrees of systolic dysfunction, and to explore the changes of both after treatment for hypertension.Methods: A total of 62 HHD patients were divided into 3 groups according to ejection fraction (EF<30%, 30%≦EF<50%, EF≧50%). Twenty-one of these patients underwent cardiac magnetic resonance（CMR）reexamination more than six months after receiving antihypertensive medication. The initial T1 time and post-enhancement T1 time of each segment were measured, and the ECV was calculated. Radial strain (RS), circumferential strain (CS) and longitudinal strain (LS) of LV were measured by cvi42 software, and the differences in CMR parameters between different groups and before and after treatment were compared.Results: ①The mean, basal and middle ECV value of HHD groups with different EF were all higher than that of the control group ( p <0.05), but the difference between HHD groups was not statistically significant. ② With the decrease of EF, the absolute value of both the global or local strain decreased. Strain is related to LVMI and ECV. ③In general, ECV, global RS (GRS) and global CS（GCS） improved after treatment, but the improvement of LS impairment in HHD patients is difficult.Conclusions: ECV and myocardial strain parameters are more sensitive to myocardial abnormalities, and ECV, GRS and GCS are more sensitive to treatment. Although it is difficult to improve longitudinal strain impairment in HHD patients, it is more important for prognosis evaluation. ECV and myocardial strain parameters can be used as good makers for long-term monitoring of the efficacy of HHD patients.

Abstract 156: Enalapril prevents Development of Dilated Cardiomyopathy in Lamin A/C Mutant Mice

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Abdelaziz Beqqali ◽  
Ingrid van Rijsingen ◽  
Inge van der Made ◽  
Stephanie van den Oever ◽  
Yigal Pinto
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Dilated Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Systolic Dysfunction ◽  
Treatment Strategies ◽  
Mutant Gene ◽  
Current Treatment ◽  
Response To Treatment ◽  
Lamin A

Dilated Cardiomyopathy (DCM) is one of the leading causes of heart failure due to systolic dysfunction. Mutations in the LMNA gene, which encodes the nuclear lamina proteins Lamin A and C, are the most common cause of familial DCM. Current treatment strategies to improve the prognosis are limited to implantable cardioverter-defibrillator and heart transplantation. Patients with LMNA-related DCM are treated in accordance with international guidelines for the management of heart failure with little consideration of the possible influence of the etiology on the response to treatment. Recent studies suggest that this might result in inappropriate therapy in some patients. The influence of genetic factors in determining the response (and timing) of drug therapy is largely unstudied in DCM. Therefore, our aim is to determine the efficacy of existing heart failure drugs in preventing or delaying LMNA-related DCM. We used a well-established mouse model of Lamin A/C mimicking human LMNA-related DCM. Mice heterozygous for the Lmna mutant gene (n=20 per group) were treated with Metoprolol (β-blocker) or Enalapril (ACE-inhibitor) before the onset of DCM and were functionally evaluated by serial echocardiography and ECG until 75 weeks of age. Hearts were harvested for histological analysis and molecular characterization. Interestingly, the experimental group treated with Enalapril had a preserved overall cardiac function comparable to wildtype mice. Mice treated with Metoprolol however, displayed progressive heart failure, and an aggravated cardiac function compared to untreated Lmna +/- mice. Both the beneficial effects of Enalapril in preventing development of systolic dysfunction as well as the detrimental effect of Metoprolol were confirmed by expression of molecular stress markers and degree of cardiac fibrosis. Our results suggest that Enalapril is effective in preventing Lmna+/- induced cardiomyopathy in mice. Strikingly, Metoprolol increases cardiac dysfunction and stress in Lmna+/- mice. Further studies will determine whether Enalapril is also effective in preventing LMNA-related DCM in patients, and whether omitting Metoprolol from the standard cocktail of prescribed heart failure medicine is beneficial for LMNA patients.

Abstract 3444: Arachidonic 12-lipoxygenase Promotes the Development of Cardiac Fibrosis and Heart Failure via Induction of Monocyte Chemoattractant Protein-1

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yosuke Kayama
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Fibrosis ◽  
Systolic Dysfunction ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
12 Lipoxygenase

To elucidate the molecular mechanisms of heart failure, we examined expression of 8800 genes in the heart of hypertensive heart failure model (Dahl salt-sensitive rats). DNA chip analysis revealed that 12-lipoxygenase (12-LOX) was markedly upregulated in the failing heart. 12-LOX is a key enzyme of the arachidonic cascade that metabolizes eicosanoid. Until recently, 12-LOX has been reported to play an important role in the development of atherogenesis, diabetes, and neurogenerative disease. However, the role of 12-LOX in heart failure has not been examined. To determine whether increased expression of 12-LOX causes heart failure, we established transgenic mice that overexpress 12-LOX only in cardiomyocytes. Echocardiogra-phy showed that 12-LOX transgenic mice developed systolic dysfunction from as early as 16 weeks old. Histological analysis revealed that cardiac fibrosis was increased in 12-LOX transgenic mice with advancing age, which was associated with infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (MCP-1) was upregulated in 12-LOX transgenic mice compared to those of wild-type mice. In vitro experiments demonstrated that treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12-LOX, increased MCP-1 expression in cardiac fibroblast and endothelial cells but not in cardiomyocytes. To determine the role of MCP-1 in the heart of 12LOX transgenic mice, we treated these mice with 7ND, an inhibitor of MCP-1, for 32 weeks. Chronic treatment with 7ND attenuated infiltration of macrophages into the myocardium and prevented systolic dysfunction and cardiac fibrosis in 12-LOX transgenic mice. Likewise, disruption of 12-LOX significantly reduced expression of MCP-1 and infiltration of macrophages in the heart, thereby inhibiting cardiac remodeling after myocardial infarction. Our in vitro and in vivo results suggest that cardiac 12-LOX is critically involved in the development of heart failure and that inhibition of 12-LOX will be a novel target for the treatment of this condition.

scholarly journals The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin

2021 ◽  
Author(s):  
Vincenzo Quagliariello ◽  
Michelino De Laurentiis ◽  
Domenica Rea ◽  
Antonio Barbieri ◽  
Maria Gaia Monti ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Longitudinal Strain ◽  
Cardiac Fibrosis ◽  
Myocardial Strain ◽  
Radial Strain ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Intracellular Ca ◽  
Pro Inflammatory Cytokines

Abstract BackgroundEmpagliflozin, a selective inhibitor of the sodium glucose co-transporter 2, reduced the risk of hospitalization for heart failure and cardiovascular death in type 2 diabetic patients in the EMPA‐REG OUTCOME trial. Recent trials evidenced several cardio-renal benefits of empagliflozin in non-diabetic patients through the involvement of biochemical pathways that are still to be deeply analyzed . We aimed to evaluate the effects of empagliflozin on myocardial strain of non-diabetic mice treated with doxorubicin (DOXO) through the analysis of NLRP3 inflammasome and Myd88-related pathways resulting in anti-apoptotic and anti-fibrotic effects.Methods Preliminary cellular studies were performed on mouse cardiomyocytes (HL-1 cell line) exposed to doxorubicin alone or combined to empagliflozin. The following analysis were performed: determination of cell viability (through a modified MTT assay), study of intracellular ROS production, lipid peroxidation (quantifying intracellular malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed: expression of NLRP3 inflammasome, MyD88 myddosome and p65/NF-κB associated to secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin (DOXO, n=6), empagliflozin (EMPA, n=6) or doxorubicin combined to empagliflozin (DOXO-EMPA, n=6). DOXO was injected intraperitoneally. Radial and longitudinal strain were analysed through transthoracic echocardiography (Vevo 2100). Cardiac fibrosis and apoptosis were histologically studied through Picrosirius red and TdT-mediated dUTP nick-end labelling (TUNEL) assay, respectively. Tissue NLRP3, Myd88 and cytokines were quantified after treatments.ResultsCardiomyocytes exposed to doxorubicin increased the intracellular Ca2+ content and expression of several pro-inflammatory markers associated to cell death; co-incubation with empagliflozin reduced significantly the magnitude of the effects. In preclinical study, empagliflozin prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin (radial strain (RS) 30.3 % in EMPA-DOXO vs 15.7% in DOXO mice ; longitudinal strain (LS) -17% in EMPA-DOXO vs -11,7% in DOXO mice (p<0.001 for both). A significant reduction of cardiac fibrosis and apoptosis were also seen. A reduced expression of pro-inflammatory cytokines, NLRP3, MyD88 and NF-kB in heart, liver and kidneys was also seen in DOXO-EMPA group compared to DOXO mice (p<0.001)ConclusionEmpagliflozin reduced fibrosis, apoptosis and inflammation in doxorubicin-treated mice through the involvement of NLRP3 and MyD88-related pathways, resulting in a significant improvement of myocardial strain. These findings provides the proof of concept for translational studies designed to reduce adverse cardiovascular outcomes in non-diabetic cancer patients treated with doxorubicin.

scholarly journals Fat cardiomyopathy in patients with severe degree of obesity. Case report

2021 ◽  
Vol 93 (9) ◽  
pp. 1073-1077
Author(s):  
Sofia V. Miklishanskaya ◽  
Olga V. Stukalova ◽  
Lilia V. Solomasova ◽  
Nikolai A. Mazur
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Cardiac Remodeling ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Systolic Heart Failure ◽  
Tissue Doppler ◽  
Structure And Function ◽  
Severe Degree ◽  
And Function

Currently, the world is constantly increasing the number of people with obesity. As was shown by the Framingham study, obesity is a risk factor for many cardiovascular diseases. The effect of obesity on the structure and function of the heart is manifested in the form of cardiac remodeling, the effect on energy metabolism in the heart and infiltration of both myocardium with lipids, and an increase in the accumulation of adipose tissue in the pericardium, imbalance of adipokines and activation of inflammatory markers. Cardiac remodeling occurs primarily due to thickening of the left ventricle (LV) walls and an increase in the LV myocardium mass. Systolic dysfunction of the heart is less common in obese individuals compared with diastolic dysfunction. However, more modern methods (tissue Doppler, visualization of the deformation of the chambers of the heart strain imaging) reveal a subclinical decrease in systolic function in people with obesity. It is not fully known whether obesity is associated with systolic dysfunction, regardless of other risk factors. In any case, it has been proven that heart failure in people with obesity can develop independently of other risk factors. As an illustration, we give an example when the presence of obesity and concomitant pathology (arterial hypertension, diabetes) led to the development of systolic dysfunction with a decrease in the LV ejection fraction to 35% (fat cardiopathy), which show the potential for the influence of both obesity itself and in combination with concomitant diseases to lead to severe systolic heart failure.

Sign in / Sign up

Export Citation Format

Share Document