A Rat Model of Pressure Overload Induced Moderate Remodeling and Systolic Dysfunction as Opposed to Overt Systolic Heart Failure

Background: Sudden cardiac death due to ventricular tachyarrhythmia (VT) accounts for a large number of deaths in patients with heart failure. Several cellular events which occur during pathological remodeling of the failing ventricle are implicated in the genesis of VT, including action potential prolongation, dysregulation of intercellular coupling, and fibrosis. Interestingly, transgenic mice over-expressing constitutively active PKD (caPKD) develop severe heart failure without interstitial fibrosis, an otherwise prominent feature of the disease. The goal here was to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing myocardium. Methods and Results: We performed echocardiographic, electrocardiographic, and in vivo electrophysiologic studies in 8 –10 week old caPKD mice (n=12). Similar studies were performed in mice with load-induced heart failure induced by surgical pressure overload (sTAB, n=10), a model of heart failure with prominent interstitial fibrosis. caPKD and sTAB mice showed similar degrees of ventricular dilation (LV systolic dimension caPKD 2.4±0.8 mm vs 3.0±0.9 sTAB, p=0.18) and severe systolic dysfunction (% fractional shortening caPKD 25±11 vs 28±11 sTAB, p=0.62). Yet, caPKD mice showed minimal interstitial fibrosis, comparable to unoperated controls. With the exception of ventricular refractory period, which was higher in caPKD (48±11 msec vs 36±7 TAB and 40±8 WT, p<0.05), other electrocardiographic and electrophysiologic variables were similar among the 3 groups (p=NS), including heart rate, QT duration, and mean VT threshold. As expected, VT (≥3beats) was readily inducible by programmed stimulation in sTAB mice (7/10). By contrast, VT was less inducible in caPKD mice (4/12; p=0.1 vs TAB and <0.05 vs WT), and uninducible in unoperated controls (0/12). VT was polymorphic in both models, but episodes of VT were both slower (VT cycle length caPKD 58±4.0 msec vs 48±1 sTAB, p=0.016) and longer in caPKD mice (caPKD 1.8±0.7 sec vs 0.47±0.3 sTAB, p=0.038). Conclusion: Interstitial fibrosis contributes to the inducibility, maintenance, and rate of VT in heart failure. These findings highlight the importance of anti-remodeling therapies known to target fibrosis in heart disease.

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Cacao Bean Polyphenols Inhibit Cardiac Hypertrophy and Systolic Dysfunction in Pressure Overload-induced Heart Failure Model Mice

Planta Medica ◽

10.1055/a-1191-7970 ◽

2020 ◽

Vol 86 (17) ◽

pp. 1304-1312

Author(s):

Nurmila Sari ◽

Yasufumi Katanasaka ◽

Hiroki Honda ◽

Yusuke Miyazaki ◽

Yoichi Sunagawa ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Gene Transcription ◽

Binding Protein ◽

Systolic Dysfunction ◽

Pressure Overload ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal

AbstractPathological stresses such as pressure overload and myocardial infarction induce cardiac hypertrophy, which increases the risk of heart failure. Cacao bean polyphenols have recently gained considerable attention for their beneficial effects on cardiovascular diseases. This study investigated the effect of cacao bean polyphenols on the development of cardiac hypertrophy and heart failure. Cardiomyocytes from neonatal rats were pre-treated with cacao bean polyphenols and then stimulated with 30 µM phenylephrine. C57BL/6j male mice were subjected to sham or transverse aortic constriction surgery and then orally administered with vehicle or cacao bean polyphenols. Cardiac hypertrophy and function were examined by echocardiography. In cardiomyocytes, cacao bean polyphenols significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy and hypertrophic gene transcription. Extracellular signal-regulated kinase 1/2 and GATA binding protein 4 phosphorylation induced by phenylephrine was inhibited by cacao bean polyphenols treatment in the cardiomyocytes. Cacao bean polyphenols treatment at 1200 mg/kg significantly ameliorated left ventricular posterior wall thickness, fractional shortening, hypertrophic gene transcription, cardiac hypertrophy, cardiac fibrosis, and extracellular signal-regulated kinase 1/2 phosphorylation induced by pressure overload. In conclusion, these findings suggest that cacao bean polyphenols prevent pressure overload-induced cardiac hypertrophy and systolic dysfunction by inhibiting the extracellular signal-regulated kinase 1/2-GATA binding protein 4 pathway in cardiomyocytes. Thus, cacao bean polyphenols may be useful for heart failure therapy in humans.

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Ginsenoside Rb1 inhibits autophagy through regulation of Rho/ROCK and PI3K/mTOR pathways in a pressure-overload heart failure rat model

Journal of Pharmacy and Pharmacology ◽

10.1111/jphp.12900 ◽

2018 ◽

Vol 70 (6) ◽

pp. 830-838 ◽

Cited By ~ 12

Author(s):

Tianrui Yang ◽

Yunbo Miao ◽

Tong Zhang ◽

Ninghui Mu ◽

Libo Ruan ◽

...

Keyword(s):

Heart Failure ◽

Rat Model ◽

Pressure Overload ◽

Ginsenoside Rb1

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Dietary carbohydrates restriction inhibits the development of cardiac hypertrophy and heart failure

Cardiovascular Research ◽

10.1093/cvr/cvaa298 ◽

2020 ◽

Author(s):

Michinari Nakamura ◽

Natalija Odanovic ◽

Yasuki Nakada ◽

Satomi Dohi ◽

Peiyong Zhai ◽

...

Keyword(s):

Heart Failure ◽

Ketone Body ◽

Control Diet ◽

Systolic Dysfunction ◽

Pressure Overload ◽

Serine Threonine Kinase ◽

Pathological Hypertrophy ◽

Low Carbohydrate ◽

Biochemical Analyses ◽

Gsk 3Β

Abstract Aims A diet with modified components, such as a ketogenic low-carbohydrate (LC) diet, potentially extends longevity and healthspan. However, how an LC diet impacts on cardiac pathology during haemodynamic stress remains elusive. This study evaluated the effects of an LC diet high in either fat (Fat-LC) or protein (Pro-LC) in a mouse model of chronic hypertensive cardiac remodelling. Methods and results Wild-type mice were subjected to transverse aortic constriction, followed by feeding with the Fat-LC, the Pro-LC, or a high-carbohydrate control diet. After 4 weeks, echocardiographic, haemodynamic, histological, and biochemical analyses were performed. LC diet consumption after pressure overload inhibited the development of pathological hypertrophy and systolic dysfunction compared to the control diet. An anti-hypertrophic serine/threonine kinase, GSK-3β, was re-activated by both LC diets; however, the Fat-LC, but not the Pro-LC, diet exerted cardioprotection in GSK-3β cardiac-specific knockout mice. β-hydroxybutyrate, a major ketone body in mammals, was increased in the hearts of mice fed the Fat-LC, but not the Pro-LC, diet. In cardiomyocytes, ketone body supplementation inhibited phenylephrine-induced hypertrophy, in part by suppressing mTOR signalling. Conclusion Strict carbohydrate restriction suppresses pathological cardiac growth and heart failure after pressure overload through distinct anti-hypertrophic mechanisms elicited by supplemented macronutrients.

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Exercise Training for Heart Failure Patients with and without Systolic Dysfunction: An Evidence-Based Analysis of How Patients Benefit

Cardiology Research and Practice ◽

10.4061/2011/837238 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Neil Smart

Keyword(s):

Heart Failure ◽

Exercise Training ◽

Systolic Function ◽

Controlled Trial ◽

Systolic Dysfunction ◽

Systolic Heart Failure ◽

Evidence Based ◽

Heart Failure Patients ◽

Age Related ◽

Clinical Benefits

Significant benefits can be derived by heart failure patients from exercise training. This paper provides an evidence-based assessment of expected clinical benefits of exercise training for heart failure patients. Meta-analyses and randomized, controlled trials of exercise training in heart failure patients were reviewed from a search of PubMed, Cochrane Controlled Trial Registry (CCTR), CINAHL, and EMBASE. Exercise training improves functional capacity, quality of life, hospitalization, and systolic and diastolic function in heart failure patients. Heart failure patients with preserved systolic function (HFnEF) participating in exercise training studies are more likely to be women and are 5–7 years older than their systolic heart failure (CHF) counterparts. All patients exhibit low functional capacities, although in HFnEF patients this may be age related, therefore subtle differences in exercise prescriptions are required. Published works report that exercise training is beneficial for heart failure patients with and without systolic dysfunction.

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Abstract 159: Ablation of the Hypertension Candidate Gene ATP2B1 Leads To Deficient Calcium Cycling, Systolic Dysfunction and Heart Failure Following Pressure Overload

Circulation Research ◽

10.1161/res.115.suppl_1.159 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Nicholas P Stafford ◽

Min Zi ◽

Ludwig Neyses ◽

Elizabeth J Cartwright

Keyword(s):

Heart Failure ◽

Systolic Dysfunction ◽

Pressure Overload ◽

Early Response ◽

Left Ventricular ◽

Calcium Handling ◽

Calcium Cycling ◽

Lung Weight ◽

Hypertrophic Growth ◽

Ventricular Elastance

Mutations in ATP2B1 encoding the ubiquitous calcium extrusion pump Plasma Membrane Calcium ATPase 1 (PMCA1) have recently identified it as having the strongest association of any gene to hypertension, yet the role of PMCA1 in the pressure-overloaded heart is not known. To investigate this we generated a novel mouse line carrying cardiomyocyte-specific deletion of PMCA1 (PMCA1 cko ) and challenged them with transverse aortic constriction (TAC) alongside littermate ‘floxed’ controls (PMCA1 f/f ). After two weeks, echocardiographic analysis revealed signs of systolic dysfunction and left ventricular (LV) dilation in PMCA1 cko hearts as evidenced by reduced fractional shortening and increased diastolic diameter (both p<0.05), whilst function in PMCA1 f/f TAC controls remained preserved. This was accompanied by an increase in normalised lung weight in PMCA1 cko mice compared to sham operated and TAC controls (p<0.05) indicative of pulmonary congestion and a progression into LV failure, despite comparable hypertrophic growth amongst the two TAC cohorts. Hemodynamic analysis following LV catheterisation revealed contractility, as measured by left ventricular elastance (E es ), to be increased in controls after TAC (PMCA1 f/f TAC 12.69 ± 1.63 vs sham 7.02 ± 1.11 mmHg/μl, p<0.05), a change which was not reciprocated in knockout hearts (PMCA1 cko TAC 7.70 ± 1.19 vs sham 7.22 ± 1.55 mmHg/μl). To examine whether altered calcium handling could be the underlying cause of the observed phenotype, cardiomyocytes were isolated following one week TAC and loaded with Indo-1, prior to the onset of failure in PMCA1 cko hearts. Compatible with an increase in E es , systolic calcium levels were higher in PMCA1 f/f myocytes following pressure overload compared to sham controls (p<0.05), whilst PMCA1 cko TAC myocytes displayed equivalent peak calcium levels to their respective sham controls. These results suggest that PMCA1 may play a necessary role in enhancing calcium cycling during the early response to pressure overload, and that disrupting this gene may increase the susceptibility to heart failure under these conditions. This may provide first evidence of a novel genetic basis for the development of heart failure in a proportion of hypertensive patients.

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MO191MANAGEMENT OF HYPERKALAEMIA TO FACILITATE RAASI THERAPY IN PATIENTS WITH HEART FAILURE IN A BESPOKE UK CLINIC

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab092.0069 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Ibrahim Ali ◽

Philip A Kalra

Keyword(s):

Heart Failure ◽

Serum Potassium ◽

Left Ventricular Systolic Dysfunction ◽

Care Pathway ◽

Beta Blockers ◽

Angiotensin Receptor Blockers ◽

Systolic Dysfunction ◽

Systolic Heart Failure ◽

Left Ventricular

Abstract Background and Aims Best practice for treatment of patients with chronic heart failure involves beta-blockers and renin-angiotensin-aldosterone system inhibitors (RAASi) such as ACE inhibitors (ACE-i), angiotensin receptor blockers (ARB), mineralocorticoid antagonists (MRA) and neprolysin inhibitor/ARB. However, use of these agents, and optimisation of their dosage, is frequently limited by hyperkalaemia, the incidence of which is increased by the co-prevalence of chronic kidney disease (CKD). Management of patients in a bespoke Hyperkalaemia Clinic can be advantageous in facilitating optimal use of RAASi. Method A Hyperkalaemia Clinic was opened in July 2019 in this tertiary renal centre within an NHS trust that hosts 4 district hospital heart failure services. Referrals of patients with left ventricular systolic dysfunction whose RAASi could not be optimised because of hyperkalaemia were encouraged from heart failure specialist nurses and cardiologists. Management of the patients incorporated commencement of patiromer at 8.4g daily and increases in RAASi was usually devolved to the referring team. This report describes the activity and short-term outcomes of the first 17 months after opening of the clinic (follow up until 1st January 2021). Results 34 patients with systolic heart failure and problems with RAASi-associated hyperkalaemia were referred to the clinic. Mean age was 74 (range 44-88) years, 28% had stage 3a, 28% 3b and 8% stage 4 CKD. ACE-I or ARB were being used in 73% of patients at referral, 73% were using beta blockers and 50% MRA with loop diuretic use in 70%. At first visit 64% had normokalaemia, and 36% serum potassium 5.4-6.0 mmol/L. During follow-up, 6 (18%) patients discontinued patiromer due to gastrointestinal side effects, 3 no longer required the binder because of decrease in RAASi use and 2 patients died (one each from stroke and sepsis). One patient was switched to an alternative potassium binder. As of 1st January 2021, patiromer was still being administered to 22 (65%) patients, 8 of which had received this for >12 months; all patients remained normokalaemic and none of them required magnesium supplementation. An increase in RAASi therapy had occurred in only 12 (35%) patients. Conclusion Our experience demonstrates the relative simplicity of managing hyperkalaemia via a bespoke clinic in cardio-renal patients. As this was nephrology-led, optimised management was dependent upon the assertive and collaborative involvement of the referring heart failure teams who helped with biochemical monitoring and alteration of RAASi therapy. However, less than half of the patients benefitted from an increase in RAASi therapy after normalisation of serum potassium, and there was definitely scope for improving this component of the care pathway via more direct multi-disciplinary interaction with the heart failure teams.

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Chronic Rapamycin Therapy Ameliorates Hypertrophy and Systolic Dysfunction in Severe Chronic Heart Failure Due to Pressure Overload

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2010.06.030 ◽

2010 ◽

Vol 16 (8) ◽

pp. S9

Author(s):

Kalkidan Bishu ◽

Selma Mohammed ◽

Tomohito Ohtani ◽

Sudhir Kushwaha ◽

Xiaolei Xu ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Systolic Dysfunction ◽

Pressure Overload ◽

Severe Chronic Heart Failure

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

Journal of Experimental Medicine ◽

10.1084/jem.20082596 ◽

2009 ◽

Vol 206 (7) ◽

pp. 1565-1574 ◽

Cited By ~ 75

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.

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