Age-related Diastolic Dysfunction Research Articles

Endurance exercise upregulates mtp expression in aged Drosophila to ameliorate age-related diastolic dysfunction and extend lifespan.

Diastolic dysfunction is a major cardiac dysfunction, and an important predisposing factor is age. Although exercise training is often used for the prevention and treatment of cardiovascular disease nowadays, little is currently known about whether exercise interventions associated with the slowing of cardiac aging are related to mtp-related pathways. In the present study, the UAS/Tub-Gal4 system was used to knockdown whole-body mtp expression levels in Drosophila, which underwent 2 weeks of endurance training. By conducting different assays and quantifying different indicators, we sought to investigate the relationship between mtp, exercise, and age-related diastolic dysfunction. We found that (1) Drosophila in the mtpRNAi youth group exhibited age-related diastolic dysfunction and had a significantly shorter mean lifespan. (2) Endurance exercise could improve diastolic dysfunction and prolong lifespan in aged Drosophila. (3) Endurance exercise could increase the expression levels of apolpp and Acox3, and decrease the levels of TC, LDL-C, and TG in the aged group. In summary, aging causes age-associated diastolic dysfunction in Drosophila, and systemic knockdown of mtp causes premature age-associated diastolic dysfunction in young Drosophila. Besides, endurance exercise improves age-related diastolic dysfunction and prolongs lifespan.

Long-term dietary n3 fatty acid prevents aging-related cardiac diastolic and vascular dysfunction

AimsThe prevalence of left ventricular (LV) diastolic and vascular dysfunction increases with age, eventually leading to heart failure with preserved ejection fraction (HFpEF). A preventive strategy is an unmet medical need. We and others reported previously on the beneficial effects of omega-3 fatty acid alpha linolenic acid (ALA) on cardiovascular disorders in animal models and translational studies. We now investigate whether long-term dietary ALA could prevent LV diastolic dysfunction and vascular aging in a murine model. Methods and resultsWild-type C57BL/6 J mice were fed a chow or ALA diet for 12 months, starting at 6 months of age. Here, we show that aged (~18 months) mice recapitulate major hallmarks of HFpEF, including LV diastolic dysfunction with preserved ejection fraction, impaired vascular function, cardiac fibrosis, arterial stiffening and inflammation, as well as elevated B-type natriuretic peptide (BNP). Long-term ALA supplementation upregulated the mitochondrial tricarboxylic acid enzyme Idh2 and the antioxidant enzymes SOD1 and Gpx1. It also has been associated with reduced inflammation and ECM remodeling, accompanied by a significant downregulation of fibrosis biomarkers MMP-2 and TGF-β in both cardiac and vascular tissues obtained from aged mice. Our data exhibited the preventive effects of dietary ALA against LV diastolic dysfunction, impaired vasorelaxation, cardiac fibrosis, inflammation and arterial stiffening in aged mice. ConclusionsWe provide evidence and a simplified mechanistic insight on how long-term ALA supplementation is a successful strategy to prevent the development of age-related diastolic and vascular dysfunction.

Lifelong dietary omega-3 fatty acid reverses cardiac and vascular dysfunction via MMP-2 modulation in aged mice

Abstract Background Aging has a remarkable effect on the cardiovascular system, and negatively causes structural and functional changes in the heart including diastolic/systolic dysfunction and left ventricular (LV) dyssynchrony, as well as, arterial stiffness which may develop to heart failure with preserved ejection fraction (HFpEF) in aged adults. We recently showed that the plant-derived omega-3-fatty-acid α-linolenic-acid (ALA) has emerged to confer potential protective effects against cardiovascular disease. Since cardiovascular aging is a chronic process, we hypothesized that a lifelong effective dietary supplementation with ALA will reverse or prevent age-related diastolic and arterial dysfunction during aging. Purpose Here, we test the hypotheses that (1) lifelong dietary ALA will prevent LV diastolic and arterial dysfunction in aged mice and that (2) lifelong dietary ALA will prevent the age-related cardiovascular dysfunction through modiulation of matrix-metalloproteinase-2 (MMP-2) in the heart and arteries. Methods and results 6-month-old (young) wild-type C57BL/6J mice were fed a low (0.03%), as control, or high ALA (7.3%) diet for more than 12 months. Our results show that aged (>18 months) mice on low ALA diet recapitulate major hallmarks of HFpEF, including diastolic dysfunction with preserved left ventricular ejection fraction, cardiac interstitial fibrosis, impaired acetylcholine-induced relaxation of aortic segments, and arterial stiffness. Intriguingly, we revealed that lifelong ALA-rich diet prevents diastolic dysfunction, vascular relaxation capacity, reduced pulse wave velocity, interstitial fibrosis, and coincident hemodynamic abnormalities in aged mice. Lifelong dietary ALA-in the prevention strategy-was associated with remarkably reduced cardiac and aortic MMP-2 and COX-2 expression, lower levels of pro-inflammatory cytokine TNF-α, and increased isocitrate dehydrogenase 2 (Idh2) expression, decreased function of which has previously been associated with cardiac dysfunction. Conclusions Our data support that lifelong ALA-rich diet restores normal cardiac and vascular function in aged mice with LV diastolic and arterial dysfunction and prevents development of age-related cardiovascular dysfunction through the modulation of MMP-2 signaling. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): 1. Swiss National Science Foundation (number 324730_182328)2. the Kardio Stiftung, Baden, Switzerland

Comparisons of Left Atrial Functional Parameters with Left Ventricular Diastolic Dysfunction in a Large Taiwanese Population with Normal Left Ventricular Ejection Fraction According to Age.

Recent studies have shown that left atrial (LA) volume is a sensitive morphophysiological indicator of the severity of LV dysfunction and may also be a useful index of cardiovascular risk. In this study, we performed comparisons among left atrial (LA) functional parameters for predicting age-related diastolic dysfunction. Echocardiography was performed in 2248 healthy participants with a low possibility of heart disease according to the decennium of age, and reference values were established. Progressive diastolic dysfunction paralleled increasing age and could be well identified by traditional and advanced echocardiographic parameters, including mitral inflow pattern, tissue Doppler parameters, and LA volume. Regarding LA functional parameters analyzed based on the decennium of age, left atrial ejection fraction (LAEF) and emptying fraction could not represent aging diastolic dysfunction well, but LA expansion index ((Volmax - Volmin) × 100% / Volmin) could. Volmax indicated maximal LA volume and Volmin indicated minimal LA volume. In assessments of diastolic dysfunction with receiver operating characteristic curve analysis, the best cut-off value of LA expansion index was < 100%, with an area under the curve (AUC) of 0.86, sensitivity of 80%, and specificity of 74%. LAEF < 30% (AUC 0.76, sensitivity 67%, specificity 70%) and LA emptying fraction < 50% (AUC 0.80, sensitivity 72%, specificity 71%) were also useful but performed less well. Compared with other LA functional parameters, LA expansion index can well represent age-related diastolic dysfunction.

335 Effects of Healthy Aging on Left Atrial Phasic Function Using Strain Analysis

Left atrial size and function are increasingly recognised as functional and prognostic biomarkers. Age related changes in phasic LA volumes and function are associated with age related diastolic dysfunction. We hypothesised that there is an age-related decline in diastolic function with compensatory changes in LA strain, with alterations in phasic LA function. 102 healthy volunteers had a TTE and phasic LA volumes and 2D LA strain measurements performed. LAmax volumes were similar across all ages (p=1.0). LAmin volume was significantly higher in group ‘c’ vs groups ‘a’ and ‘b’ (p<0.001 and p=0.042, respectively). LAPreP volume was significantly increased between each age bracket (p<0.01 for all). LA reservoir strain was significantly reduced in group ‘c’ vs groups ‘a’ and ‘b’ (p=0.003 and p=0.018, respectively). LA conduit strain progressively declined between each age bracket (p<0.015), with LA contractile strain increasing in groups ‘b’ and ‘c’ vs group ‘a’ (p=0.006 and p<0.001, respectively). LA conduit strain is altered early with a compensatory increase in LA contractile strain, whilst LA reservoir strain shows progressive reduction with increasing age. These phasic functional changes are reflected by an early increase in LAPreP volume and subsequent increase in LAmin.Tabled 1Age (yrs)LAmax (ml/m2)LAmin (ml/m2)LAPreP (ml/m2)LA reservoir strain (%)LA conduit strain (%)LA contractile strain (%)18-30(a)25.2±7.310.3±3.2113.5±3.61,236.8±5.8123.4±5.71,213.4±2.71,231-50(b)26.9±4.711.7±2.6316.6±3.7335.5±6.2319.4±5.5316.1±3.751+(c)27.3±6.513.6±419.3±4.631.7±6.614.6±5.116.9±3.41(a) vs (c) p<0.05; 2(a) vs (b) p<0.05; 3(b) vs (c) p<0.05 Open table in a new tab

Abstract 903: Rapamycin Treatment Reduces Myocardial Stiffness and Promotes Cardiomyocyte Relaxation to Restore Diastolic Function in Old Murine Hearts

Aging is associated with a decline in diastolic function and is a strong risk factor for heart failure with preserved ejection fraction (HFpEF), which has no effective treatment. We previously showed that late-life rapamycin treatment can reverse age-related cardiac dysfunction in mice. However, the mechanisms of the reversal of diastolic dysfunction have not been established. The objective of this study is to determine the mechanisms by which rapamycin reverses age-related diastolic dysfunction. To study the effects of rapamycin on myocardial stiffness, we assessed the passive length-tension relationship of demembranated trabecular muscle from young, old control and old rapamycin-treated mice. We observed a substantial increase in the slope of the length-tension curve with aging, indicating an age-related increase in myocardial stiffness. The age-related increase in myocardial stiffness was significantly reduced by rapamycin treatment, by a mechanism independent of titin isoform shift. We measured the force-calcium relationship of the demembranated trabeculae and revealed an age-related increase in Ca 2+ sensitivity, as indicated by a left-shift of the force-pCa curve, which was partially restored after rapamycin treatment (pCa50: 5.59±0.04 for young controls; 5.76±0.04 for old controls; and 5.65±0.04 for old rapamycin-treated group). To investigate the changes at myofibril level, we assessed kinetic properties of control and rapamycin-treated myofibrils following maximal (pCa 4.0) and submaximal (pCa 5.6) Ca 2+ activation. Myofibrils from rapamycin-treated mice displayed increased rate of the fast phase of relaxation (kREL, fast) compared to old control at both maximal and submaximal Ca 2+ levels, potentially due to reduced myofibril Ca 2+ sensitivity. Studies have detected age-related reductions in expression and activity of SERCA2, which is responsible for SR calcium reuptake during diastole. In this study, we showed that rapamycin increased SERCA2 expression, which may improve cardiomyocyte relaxation. In summary, our results suggest that rapamycin normalizes age-related increases in myocardial stiffness and Ca 2+ sensitivity and improves myofibril relaxation kinetics, therefore, improving diastolic function.

Enhanced beta-1 adrenergic receptor responsiveness in coronary arterioles following intravenous stromal vascular fraction therapy in aged rats.

Our past study showed that a single tail vein injection of adipose-derived stromal vascular fraction (SVF) into old rats was associated with improved dobutamine-mediated coronary flow reserve. We hypothesize that i.v. injection of SVF improves coronary microvascular function in aged rats via alterations in beta adrenergic microvascular signaling. Female Fischer-344 rats aged young (3 months, n=32) and old (24 months, n=30) were utilized, along with two cell therapies intravenously injected in old rats four weeks prior to sacrifice: 1x107 green fluorescent protein (GFP+) SVF cells (O+SVF, n=21), and 5x106 GFP+ bone-marrow mesenchymal stromal cells (O+BM, n=6), both harvested from young donors. Cardiac ultrasound and pressure-volume measurements were obtained, and coronary arterioles were isolated from each group for microvessel reactivity studies and immunofluorescence staining. Coronary flow reserve decreased with advancing age, but this effect was rescued by the SVF treatment in the O+SVF group. Echocardiography showed an age-related diastolic dysfunction that was improved with SVF to a greater extent than with BM treatment. Coronary arterioles isolated from SVF-treated rats showed amelioration of the age-related decrease in vasodilation to a non-selective β-AR agonist. I.v. injected SVF cells improved β-adrenergic receptor-dependent coronary flow and microvascular function in a model of advanced age.

Prevalence of Positive 99 mTc-DPD Scintigraphy as an Indicator of the Prevalence of Wild-type Transthyretin Amyloidosis in the Elderly.

Senile or wild-type transthyretin (wtTTR) amyloidosis is an age-related disease caused by the deposition of wtTTR amyloid protein. In contrast to light chain amyloidosis, 99 mTc-DPD scintigraphy (DPD scan) is a useful diagnostic modality for wtTTR amyloidosis.We retrospectively analyzed patients older than 30 years who underwent DPD scanning for non-cardiac reasons at our hospital between June 2014 and March 2017 (n = 9,581). Transthoracic echocardiography was used to assess left ventricular hypertrophy (LVH), as well as systolic and diastolic function.A positive DPD scan was observed in only six patients (0.06%). All six of these patients were older than 70 years, and they constitute only 0.4% of patients in this age group (6/1652). Among the patients with a positive DPD scan, four showed concentric LVH and two showed a normal wall thickness. With respect to the severity of diastolic dysfunction and pulmonary artery pressure, patients with a positive DPD scan showed the expected E' and pulmonary artery systolic pressure for their age.Even considering the limited sensitivity of a positive DPD scan detecting wtTTR amyloidosis, the incidence of a positive DPD scan in non-cardiac patients indicated that wtTTR amyloid deposition does not seem to be a major cause for age-related diastolic dysfunction, nor does appear to have a high incidence in patients with heart failure with preserved EF in the elderly.

Adipose-derived cells improve left ventricular diastolic function and increase microvascular perfusion in advanced age.

An early manifestation of coronary artery disease in advanced age is the development of microvascular dysfunction leading to deficits in diastolic function. Our lab has previously shown that epicardial treatment with adipose-derived stromal vascular fraction (SVF) preserves microvascular function following coronary ischemia in a young rodent model. Follow-up studies showed intravenous (i.v.) delivery of SVF allows the cells to migrate to the walls of small vessels and reset vasomotor tone. Therefore we tested the hypothesis that the i.v. cell injection of SVF would reverse the coronary microvascular dysfunction associated with aging in a rodent model. Fischer 344 rats were divided into 4 groups: young control (YC), old control (OC), old + rat aortic endothelial cells (O+EC) and old + GFP+ SVF cells (O+SVF). After four weeks, cardiac function and coronary flow reserve (CFR) were measured via echocardiography, and hearts were explanted either for histology or isolation of coronary arterioles for vessel reactivity studies. In a subgroup of animals, microspheres were injected during resting and dobutamine-stimulated conditions to measure coronary blood flow. GFP+ SVF cells engrafted and persisted in the myocardium and coronary vasculature four weeks following i.v. injection. Echocardiography showed age-related diastolic dysfunction without accompanying systolic dysfunction; diastolic function was improved in old rats after SVF treatment. Ultrasound and microsphere data both showed increased stimulated coronary blood flow in O+SVF rats compared to OC and O+EC, while isolated vessel reactivity was mostly unchanged. I.v.-injected SVF cells were capable of incorporating into the vasculature of the aging heart and are shown in this study to improve CFR and diastolic function in a model of advanced age. Importantly, SVF injection did not lead to arrhythmias or increased mortality in aged rats. SVF cells provide an autologous cell therapy option for treatment of microvascular and cardiac dysfunction in aged populations.

Isometric handgrip echocardiography: A noninvasive stress test to assess left ventricular diastolic function.

Cycle exercise echocardiography is a useful tool to "unmask" diastolic dysfunction; however, this approach can be limited by respiratory and movement artifacts. Isometric handgrip avoids these issues while reproducibly increasing afterload and myocardial oxygen demand. Isometric handgrip echocardiography (IHE) can differentiate normal from abnormal diastolic function. First recruited 19 young healthy individuals (mean age, 24 ± 4 years) to establish the "normal" response. To extend these observations to a more at-risk population, we performed IHE on 17 elderly individuals (mean age, 72 ± 6 years) with age-related diastolic dysfunction. The change in the ratio of mitral valve inflow velocity to lateral wall tissue velocity (E/e'), a surrogate for left ventricular filling pressure, was used to assess the diastolic stress response in each group. In the young subjects, isometric handgrip increased heart rate and mean arterial pressure (25 ± 12 bpm and 26 ± 17 mmHg, respectively), whereas E/e' changed minimally (0.6 ± 0.9). In the elderly subjects, heart rate and mean arterial pressure were similarly increased with isometric handgrip (19 ± 16 bpm and 25 ± 11 mmHg, respectively), whereas E/e' increased more dramatically (2.3 ± 1.7). Remarkably, 11 of the 17 elderly subjects had an abnormal diastolic response (ΔE/e': 3.4 ± 1.1), whereas the remaining 6 elderly subjects showed very little change (ΔE/e': 0.3 ± 0.7), independent of age or the change in myocardial oxygen demand. IHE is a simple, effective tool for evaluating diastolic function during simulated activities of daily living.

Osteoglycin prevents the development of age-related diastolic dysfunction during pressure overload by reducing cardiac fibrosis and inflammation

The small leucine-rich proteoglycan osteoglycin has been implicated in matrix homeostasis in different organs, including the ischemic heart. However, whether osteoglycin modulates cardiac hypertrophy, fibrosis or inflammation in hypertensive heart disease and during aging remains unknown. Angiotensin-II-induced pressure overload increases cardiac osteoglycin expression, concomitant with the onset of inflammation and extracellular matrix deposition. Interestingly aging led to decreased cardiac levels of osteoglycin, yet absence of osteoglycin did not affect organ structure or cardiac function up to the age of 18months. However, Angiotensin-II infusion in combination with aging resulted in exaggerated cardiac fibrosis and inflammation in the osteoglycin null mice as compared to wild-type mice, resulting in increased diastolic dysfunction as determined by magnetic resonance imaging. In vitro, stimulation of bone marrow derived macrophages from osteoglycin null mice with Angiotensin-II resulted in significantly higher levels of ICAM-1 as well as pro-inflammatory cytokines and chemokines IL-1β and MCP-1 as compared to WT cells. Further, stimulation of human cardiac fibroblasts with osteoglycin reduced cell proliferation and inhibited TGF-β induced collagen gene expression. In mouse cardiac tissue, osteoglycin expression inversely correlated with TGF-β expression and in cardiac biopsies of aortic stenosis patients, osteoglycin expression is significantly higher than in control biopsies. Interestingly, osteoglycin levels were higher in patients with less severe myocardial fibrosis and overall in the aortic stenosis patients osteoglycin levels negatively correlated with collagen content in the myocardium. In conclusion, osteoglycin expression is increased in the heart in response to pressure overload and its absence results in increased cardiac inflammation and fibrosis resulting in increased diastolic dysfunction.

Exercise training reverses age-induced diastolic dysfunction and restores coronary microvascular function.

In a rat model of ageing that is free of atherosclerosis or hypertension, E/A, a diagnostic measure of diastolic filling, decreases, and isovolumic relaxation time increases, indicating that both active and passive ventricular relaxation are impaired with advancing age. Resting coronary blood flow and coronary functional hyperaemia are reduced with age, and endothelium-dependent vasodilatation declines with age in coronary resistance arterioles. Exercise training reverses age-induced declines in diastolic and coronary microvascular function. Thus, microvascular dysfunction and inadequate coronary perfusion are likely mechanisms of diastolic dysfunction in aged rats. Exercise training, initiated at an advanced age, reverses age-related diastolic and microvascular dysfunction; these data suggest that late-life exercise training can be implemented to improve coronary perfusion and diastolic function in the elderly. The risk for diastolic dysfunction increases with advancing age. Regular exercise training ameliorates age-related diastolic dysfunction; however, the underlying mechanisms have not been identified. We investigated whether (1) microvascular dysfunction contributes to the development of age-related diastolic dysfunction, and (2) initiation of late-life exercise training reverses age-related diastolic and microvascular dysfunction. Young and old rats underwent 10weeks of exercise training or remained as sedentary, cage-controls. Isovolumic relaxation time (IVRT), early diastolic filling (E/A), myocardial performance index (MPI) and aortic stiffness (pulse wave velocity; PWV) were evaluated before and after exercise training or cage confinement. Coronary blood flow and vasodilatory responses of coronary arterioles were evaluated in all groups at the end of training. In aged sedentary rats, compared to young sedentary rats, a 42% increase in IVRT, a 64% decrease in E/A, and increased aortic stiffness (PWV: 6.36±0.47 vs.4.89±0.41, OSED vs. YSED, P<0.05) was accompanied by impaired coronary blood flow at rest and during exercise. Endothelium-dependent vasodilatation was impaired in coronary arterioles from aged rats (maximal relaxation to bradykinin: 56.4±5.1% vs. 75.3±5.2%, OSED vs. YSED, P<0.05). After exercise training, IVRT, a measure of active ventricular relaxation, did not differ between old and young rats. In old rats, exercise training reversed the reduction in E/A, reduced aortic stiffness, and eliminated impairment of coronary blood flow responses and endothelium-dependent vasodilatation. Thus, age-related diastolic and microvascular dysfunction are reversed by late-life exercise training. The restorative effect of exercise training on coronary microvascular function may result from improved endothelial function.

Left Atrial Volume and Pulmonary Artery Diameter Are Noninvasive Measures of Age-Related Diastolic Dysfunction in Mice.

Impaired cardiac diastolic function occurs with aging in many species and may be difficult to measure noninvasively. In humans, left atrial (LA) volume is a robust measure of chronic diastolic function as the LA is exposed to increased left ventricular filling pressures. We hypothesized that LA volume would be a useful indicator of diastolic function in aging mice. Further, we asked whether pressures were propagated backwards affecting pulmonary arteries (PAs) and right ventricle (RV). We measured LA, PA, and RV infundibulum dimensions with echocardiography and used mouse-specific Doppler systems and pressure catheters for noninvasive and invasive measures. As C57BL/6 mice aged from 3 to 29-31 months, LA volume almost tripled. LA volume increases correlated with traditional diastolic function measures. Within groups of 14- and 31-month-old mice, LA volume correlated with diastolic function measured invasively. In serial studies, mice evaluated at 20 and 24 months showed monotonic increases in LA volume; other parameters changed less predictably. PA diameters, larger in 30-month-old mice than 6-month-old mice, correlated with LA volumes. Noninvasive LA volume and PA diameter assessments are useful and state independent measures of diastolic function in mice, correlating with other measures of diastolic dysfunction in aging. Furthermore, serial measurements over 4 months demonstrated consistent increases in LA volume suitable for longitudinal cardiac aging studies.

Exercise Training Reverses Age‐induced Coronary Microvascular Dysfunction

The risk for diastolic dysfunction increases with advancing age. We tested the hypotheses that 1) microvascular dysfunction underlies age‐related diastolic dysfunction, and 2) exercise training (ET) reverses age‐related microvascular and diastolic dysfunction. Old and young male Fischer 344 rats underwent 10 weeks of daily ET or remained sedentary cage controls. Cardiac function was assessed before and after ET. At the end of training, coronary blood flow was measured at rest and during treadmill exercise. The reactivity of the coronary resistance vasculature was assessed in isolated coronary arterioles. E/a ratio decreased with age and was partially restored by ET. Isovolumic relaxation time increased with age and this increase was reversed by ET. Resting blood flow to the left ventricular (LV) endocardium and the right ventricular free wall was decreased in old rats; however, ET increased resting blood flow to the septum, papillary muscles, LV endocardium and epicardium. Exercise hyperemia was reduced by age in the septum, and the LV endocardium and epicardium, but these age‐related reductions were reversed by ET. Age‐induced impairments of both contractile and relaxation responses of coronary arterioles were reversed by ET. Thus, microvascular dysfunction contributes to development of diastolic dysfunction with advancing age; however, ET at an advanced age reverses microvascular dysfunction and improves diastolic function.

Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium.

Age-related diastolic dysfunction is a major factor in the epidemic of heart failure. In patients hospitalized with heart failure, HFpEF is now as common as heart failure with reduced ejection fraction. We now have many successful treatments for heart failure with reduced ejection fraction, while specific treatment options for HFpEF patients remain elusive. The lack of treatments for HFpEF reflects our very incomplete understanding of this constellation of diseases. There are many pathophysiological factors in HFpEF, but aging appears to play an important role. Here, we propose that aging of the myocardium is itself a specific pathophysiological process. New insights into the aging heart, including hormonal controls and specific molecular pathways, such as microRNAs, are pointing to myocardial aging as a potentially reversible process. While the overall process of aging remains mysterious, understanding the molecular pathways of myocardial aging has never been more important. Unraveling these pathways could lead to new therapies for the enormous and growing problem of HFpEF.

Discovery of a Natural Heart-Rejuvenating Molecule in Mice

Age-related diastolic dysfunction is a common cause of congestive heart failure: No specific treatments repair the stiff and thickened myocardium.

Low glial angiotensinogen improves body habitus, diastolic function, and exercise tolerance in aging male rats

Long-term systemic blockade of the renin-angiotensin system (RAS) with either an angiotensin (Ang) II type 1 receptor antagonist or an angiotensin-converting enzyme inhibitor attenuates age-related cardiac remodeling and oxidative damage, and improves myocardial relaxation. However, the role of the brain RAS in mediating the development of diastolic dysfunction during aging is not known. We hypothesized that low brain RAS protects against the development of age-related diastolic dysfunction and left ventricular remodeling. Sixty-week-old transgenic male ASrAOGEN rats (n =9), with normal circulating Ang II and functionally low brain Ang II, because of a GFAP promoter-linked angiotensinogen antisense targeted to glia, and age-matched and sex-matched Hannover Sprague-Dawley (SD; n= 9) rats, with normal levels of both circulating and brain Ang II, underwent echocardiograms to evaluate cardiac structure and function. Postmortem hearts were further compared for histological, molecular, and biochemical changes consistent with cardiac aging. ASrAOGEN rats showed preserved systolic and diastolic function at mid-life and this was associated with a lower, more favorable ratio of the phospholamban-SERCA2 ratio, reduced incidence of histological changes in the left ventricle, and increased cardiac Ang-(1-7) when compared with the in-vivo functional, and ex-vivo structural and biochemical indices from age-matched SD rats. Moreover, ASrAOGEN rats had lower percent body fat and a superior exercise tolerance when compared with SD rats of the same age. Our data indicate that the central RAS plays a role in the maintenance of diastolic function and exercise tolerance in mid-life and this may be related to effects on body habitus.

Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice

Age-related diastolic dysfunction has been attributed to an increased passive stiffness, which is regulated by extracellular matrix (ECM). We recently showed that matrix metalloproteinase (MMP)-9, an ECM mediator, increases in the left ventricle (LV) with age. The aim of this study, accordingly, was to determine the role of MMP-9 in cardiac ageing. We compared LV function in young (6-9 months), middle-aged (12-15 months), old (18-24 months) and senescent (26-34 months) wild-type (WT) and MMP-9 null mice (n ≥ 12/group). All groups had similar fractional shortenings and aortic peak velocities, indicating that systolic function was not altered by ageing or MMP-9 deletion. The mitral ratios of early to late diastolic filling velocities were reduced in old and senescent WT compared with young controls, and this reduction was attenuated in MMP-9 null mice. Concomitantly, the increase in LV collagen content was reduced in MMP-9 null mice (n = 5-6/group). To dissect the mechanisms of these changes, we evaluated the mRNA expression levels of 84 ECM and adhesion molecules by real-time qPCR (n = 6/group). The expression of pro-fibrotic periostin and connective tissue growth factor (CTGF) increased with senescence, as did transforming growth factor-β (TGF-β)-induced protein levels and Smad signalling, and these increases were blunted by MMP-9 deletion. In senescence, MMP-9 deletion also resulted in a compensatory increase in MMP-8. MMP-9 deletion attenuates the age-related decline in diastolic function, in part by reducing TGF-β signalling-induced periostin and CTGF expression and increasing MMP-8 expression to regulate myocardial collagen turnover and deposition.

Pulmonary atresia with intact ventricular septum: how good is a biventricular repair?

In this issue of EJCTS, Romeih et al. [1] present some interesting and provocative data regarding long-term outcome for biventricular repair of pulmonary atresia with intact ventricular septum (PAIVS). Debate relative to timing, technique and surgical indications has been going on for decades, and major centres still employ diverse management strategies for this relatively uncommon malformation [2]. The current cross-sectional study is very well conceived and designed, employing state-of-the-art imaging tools to assess exercise capacity and pharmacological stress response in a small group of (asymptomatic) long-term survivors of biventricular repair of PAIVS. Of note, all patients had a tricuspid Z-value >− 2.5 at birth, with 2 or more right ventricular (RV) segments present. This set of qualifications suggests that the study group represents the more favourable end of the spectrum of PAIVS as understood in the era of operation. Whatever the actual right ventricular outflow tract strategy employed, all patients had important pulmonary insufficiency at late followup, despite the universal presence of age-related RV diastolic dysfunction. Reduction in exercise capacity and limitation of response to pharmacological stress were also age-related. From clinical experience, the carefully documented current findings are not unexpected, and, of course, this cohort represents only children qualifying for an early biventricular repair. There is a growing body of data, some cited by the authors, suggesting that Fontan patients (with varying anatomy, and without arrhythmias) can achieve or surpass the exercise capacity of patients undergoing biventricular repair [3]. Of course, this is only a part of the Fontan story, but an important observation nonetheless, and the one which invites comparative studies using the same techniques. Effects of age at initial repair (as opposed to followup interval) and the risk-benefit analysis of valved repair strategies would also be of interest. The authors must be commended on this excellent study which does address some important questions relating to late follow-up for biventricular repair of PAIVS.

Differential effects of late-life initiation of low-dose enalapril and losartan on diastolic function in senescent Fischer 344 × Brown Norway male rats

No proven pharmacological therapies to delay or reverse age-related diastolic dysfunction exist. We hypothesized that late-life low-dose (non-blood-pressure-lowering) angiotensin-converting enzyme inhibition vs. angiotensin II receptor blockade would be equally efficacious at mitigating diastolic dysfunction in the senescent Fischer 344 × Brown Norway rat. Enalapril (10mg/kg/day; n = 9) initiated at 24months of age and continued for 6months, increased myocardial relaxation (e'), reduced Doppler-derived indices of filling pressure (E/e'), favorably lowered the ratio of phospholamban-SERCA2 and reduced oxidative stress markers, Rac1 and nitrotyrosine, in aged hearts. Treatment with losartan (15mg/kg/day; n = 9) similarly mitigated signs of cardiac oxidative stress, but impairments in diastolic function persisted when compared with untreated rats (n = 7). Our findings favor the idea that the lusitropic benefit of low-dose angiotensin-converting enzyme inhibitor initiated late in life may be related to an antioxidant-mediated modulation of SERCA2, resulting in improved relaxation rather than via overt effects on cardiac structure or blood pressure.