Progressive Diastolic Dysfunction Research Articles

Signature of diabetic cardiomyopathy progression using high-fat diet and streptozotocin mouse model: from subclinical to clinical with three-hit mouse model

Abstract Background Diabetic cardiomyopathy (DbCM) is a pre-heart failure (pre-HF) condition that usually exhibits early diastolic dysfunction and evolving systolic dysfunction, along with left ventricular (LV) remodelling. Although DbCM shows distinct pathophysiology, the transition from the subclinical to the symptomatic stage is not straightforward and usually involves multifaceted processes which are not fully understood. Purpose To define the signature of DbCM progression in a novel mouse model using longitudinal echocardiography and multi-omics approaches. Methods Male mice (C57BL/6) were fed with high-fat diet (HFD) or control diet (CD) for 24 weeks, with single dose of streptozotocin (STZ) or vehicle injection at 8 weeks (n=10 each). Serial functional and metabolic parameters were measured prior to endpoint single nuclei RNA sequencing (snRNA-seq) and mass spectrometry-based proteomics analysis with comparison to cardiac remodelling to define detailed mechanisms underlying DbCM progression. Results HFD/STZ mice developed type 2 diabetes mellitus (T2DM) based on higher fasting blood glucose and HbA1C levels, insulin resistance and decreased beta-cell function (HOMA-IR and HOMA-beta, respectively) compared to controls. Progressive diastolic dysfunction was evident in HFD/STZ mice compared to CD mice based on enlarged LVPW;d from 12 weeks (P<0.05), reduced MV E/A ratio (P<0.01) and IVRT (P<0.05) from 16 weeks, and increased cardiac filling pressure (Left atrial (LA) area and LA volume) at 24 weeks, with preserved systolic function. This was paralleled by elevated collagen deposition (Picrosirius red), myocyte cross-sectional area and Col1a1 expression in HFD/STZ versus CD mice (all P<0.05). snRNA-seq analysis indicated preferential monocyte migration into diabetic hearts (P<0.01) whilst inflammatory pathways were activated across all cardiac cell types. Proteomics analysis revealed elevated expression of the established inflammation marker, plasma C-reactive protein (CRP), in HFD/STZ versus CD mice (P<0.05), which was correlated with worsening diastolic function (MV E/A ratio: r=-0.839, P<0.01) and LV hypertrophy (LVPW;d: r=0.861, P<0.01). Conclusion Our HFD/STZ mouse model offers a ‘three-hit’ approach which effectively captures key stages of clinical DbCM progression: 1) T2DM with insulin resistance, 2) progressive diastolic dysfunction with elevated chronic filling pressure and cardiac remodelling, and 3) systemic inflammation. This improved HFD/STZ mouse model is therefore appropriate to support a detailed study of mechanisms underlying DbCM progression and subsequent translation.

Survivors of Pediatric Hematopoietic Stem Cell Transplantation Exhibit Progressive Diastolic Dysfunction Over Years of Follow-Up

Patients who have undergone hematopoietic stem cell transplantation (HSCT) in childhood have a higher risk of diastolic heart failure (HF). The rate of progression of diastolic dysfunction in aging pediatric patients is unknown and is more difficult to assess in young patients secondary to changes in diastolic indices as they grow. HSCT recipients at our center were previously found to have decline in diastolic function indices at 1 year after HSCT. This study provides follow-up of this cohort, using age-normalized z-scores to assess whether the decline in diastolic function noted at 1-year post-HSCT persists, worsens, or improves over time. Patients age <21 years who underwent HSCT at Boston Children's Hospital/Dana-Farber Cancer Center between 2005 and 2008 with ≥3 surveillance echocardiograms, including 1 performed pre-HSCT, were included. Diastolic measures included mitral inflow (E/A ratio) and Doppler tissue imaging of left ventricular lateral wall (LV lateral e'), LV septal wall (septal e') and right ventricular free wall (RV e'). Systolic function was measured by LV ejection fraction (LVEF). Normalization by age was done using z-scores, and >±2 SD was defined as abnormal in linear modeling of diastolic dysfunction and systolic dysfunction over time. In a subset of patients with adequate post-HSCT images of the entire left atrium (LA), LA volume and LA strain analyses also were performed. The study cohort comprised 61 patients (41% female; median age at HSCT, 10.7 years; median follow-up, 7.4 years). Diastolic index z-scores declined by -.045/year for LV lateral e', -.06/year for LV septal e', and -.14/year for RV e' (P < .01). The E/A ratio z-score increased by .034/year (P=.028). Linear modeling demonstrated that LV lateral e' and LV septal e' would become abnormal at 25 and 20 years post-HSCT, respectively, whereas RV e' would become abnormal sooner, at 12.6 years. LVEF z-score declined by -.04/year (P < .01) and was estimated to become abnormal at 40 years post-HSCT. Exposure to total body irradiation (TBI) was associated with worsening diastolic indices, lower LVEF (P ≤ .002), and decreased LA reservoir strain (42.0% versus 45.0%; P=.016) and conduit strain (-31.5% versus -35.1%; P=.029), although there was significant overlap between TBI and anthracycline exposure. Treatment with anthracyclines even at low doses (median, 150 mg/m2) was associated with declining LVEF but not with changes in diastolic indices. Long-term survivors of childhood HSCT exhibit declines in both LV and RV diastolic function indices. These results inform the rate of progression of LV and RV diastolic dysfunction indices over time in long-term survivors of pediatric HSCT. A significant association was observed between TBI and diastolic dysfunction and a decline in LVEF. Treatment with anthracyclines even at low doses was associated with a mild decline in LVEF. Our results can inform a lifespan perspective on disease management in this population, encourage clinicians and patients to be vigilant in following guideline-directed surveillance echocardiography, and inform anticipatory responses by clinicians as patients transition from pediatric care to adult care.

Progressive diastolic dysfunction in survivors of pediatric differentiated thyroid carcinoma.

Pediatric differentiated thyroid cancer (DTC) has an excellent prognosis but unknown late effects of treatment. The initial cardiac evaluation showed subclinical diastolic dysfunction in 20% of adult survivors. The objective of this follow-up study was to determine the clinical course of this finding. This multicenter study, conducted between 2018 and 2020, re-evaluated survivors after 5 years. The primary endpoint was echocardiographic diastolic cardiac function (depicted by the mean of the early diastolic septal and early diastolic lateral tissue velocity (e' mean)). Secondary endpoints were other echocardiographic parameters and plasma biomarkers. Follow-up evaluation was completed in 47 (71.2%) of 66 survivors who had completed their initial evaluation. Of these 47 survivors, 87.2% were women. The median age was 39.8 years (range: 18.8-60.3), and the median follow-up after the initial diagnosis was 23.4 years (range: 10.2-48.8). Between the first and second evaluation, the e' mean significantly decreased by 2.1 cm/s (s.d. 2.3 cm/s, P < 0.001). The median left ventricular ejection fraction did not significantly change (58.0% vs 59.0%, P= NS). In the best explanatory model of e' mean, multivariate linear regression analysis showed that BMI and age were significantly associated with e' mean (β coefficient: -0.169, 95% CI: -0.292; -0.047, P = 0.008 and β coefficient: -0.177, 95% CI: -0.240; -0.113, P < 0.001, respectively). In these relatively young survivors of pediatric DTC, diastolic function decreased significantly during 5-year follow-up and is possibly more pronounced than in normal aging. This finding requires further follow-up to assess clinical consequences.

Progressive diastolic dysfunction in survivors of pediatric differentiated thyroid carcinoma

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The Role of Epicardial Adipose Tissue in the Development of Atrial Fibrillation, Coronary Artery Disease and Chronic Heart Failure in the Context of Obesity and Type 2 Diabetes Mellitus: A Narrative Review

Cardiovascular diseases (CVDs) are a significant burden globally and are especially prevalent in obese and/or diabetic populations. Epicardial adipose tissue (EAT) surrounding the heart has been implicated in the development of CVDs as EAT can shift from a protective to a maladaptive phenotype in diseased states. In diabetic and obese patients, an elevated EAT mass both secretes pro-fibrotic/pro-inflammatory adipokines and forms intramyocardial fibrofatty infiltrates. This narrative review considers the proposed pathophysiological roles of EAT in CVDs. Diabetes is associated with a disordered energy utilization in the heart, which promotes intramyocardial fat and structural remodeling. Fibrofatty infiltrates are associated with abnormal cardiomyocyte calcium handling and repolarization, increasing the probability of afterdepolarizations. The inflammatory phenotype also promotes lateralization of connexin (Cx) proteins, undermining unidirectional conduction. These changes are associated with conduction heterogeneity, together creating a substrate for atrial fibrillation (AF). EAT is also strongly implicated in coronary artery disease (CAD); inflammatory adipokines from peri-vascular fat can modulate intra-luminal homeostasis through an “outside-to-inside” mechanism. EAT is also a significant source of sympathetic neurotransmitters, which promote progressive diastolic dysfunction with eventual cardiac failure. Further investigations on the behavior of EAT in diabetic/obese patients with CVD could help elucidate the pathogenesis and uncover potential therapeutic targets.

A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome.

AimHeart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P1) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function.Methods31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing adult and aged animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799.ResultsEchocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in adult and aged animals: in adult animals E/e’ was evaluated at 21.8 ± 1.4 for Ob-ZSF1-CTRL, 19.5 ± 1.2 for Ob-ZSF1-SAR247799 p<0.01, and 19.5 ± 2.3 for Le-ZSF1-CTRL (median ± IQR). In aged animals E/e’ was evaluated at 23.15 ± 4.45 for Ob-ZSF1-CTRL, 19.5 ± 5 for Ob-ZSF1-SAR247799 p<0.01, and 16.69 ± 1.7 for Le-ZSF1-CTRL, p<0.01 (median ± IQR). In aged animals, SAR247799 reduced cardiac hypertrophy (g/mm mean ± SEM of heart weight/tibia length 0.053 ± 0.001 for Ob-ZSF1-CTRL vs 0.046 ± 0.002 for Ob-ZSF1-SAR247799 p<0.01, Le-ZSF1-CTRL 0.035 ± 0.001) and myocardial perivascular collagen content (p<0.001), independently of any changes in microvascular density. In adult animals, SAR247799 improved endothelial function as assessed by the very low frequency bands of systolic blood pressure variability (mean ± SEM 67.8 ± 3.41 for Ob-ZSF1-CTRL 55.8 ± 4.27 or Ob-ZSF1-SAR247799, p<0.05 and 57.3 ± 1.82 Le-ZSF1-CTRL), independently of any modification of arterial blood pressure. In aged animals, SAR247799 reduced urinary protein/creatinine ratio, an index of glomerular injury, (10.3 ± 0.621 vs 8.17 ± 0.231 for Ob-ZSF1-CTRL vs Ob-ZSF1-SAR247799, respectively, p<0.05 and 0.294 ± 0.029 for Le-ZSF1-CTRL, mean ± SEM) and the fractional excretion of electrolytes. Circulating lymphocytes were not decreased by SAR247799, confirming lack of S1P1 desensitization.ConclusionsThese experimental findings suggest that S1P1 activation with SAR247799 may be considered as a new therapeutic approach for LVH and diastolic dysfunction, major components of HFpEF.

Cardiovascular Effects of Autologous Bone Marrow-Derived Mesenchymal Stromal Cell Therapy With Early Tacrolimus Withdrawal in Renal Transplant Recipients: An Analysis of the Randomized TRITON Study.

BackgroundAfter renal transplantation, there is a need of immunosuppressive regimens that effectively prevent allograft rejection while minimizing cardiovascular complications. This substudy of the TRITON trial evaluated the cardiovascular effects of autologous bone marrow–derived mesenchymal stromal cells (MSCs) in renal transplant recipients.Methods and ResultsRenal transplant recipients were randomized to MSC therapy, infused at weeks 6 and 7 after transplantation, with withdrawal at week 8 of tacrolimus or standard tacrolimus dose. Fifty‐four patients (MSC group=27; control group=27) underwent transthoracic echocardiography at weeks 4 and 24 after transplantation and were included in this substudy. Changes in clinical and echocardiographic variables were compared. The MSC group showed a benefit in blood pressure control, assessed by a significant interaction between changes in diastolic blood pressure and the treatment group (P=0.005), and a higher proportion of patients achieving the predefined blood pressure target of <140/90 mm Hg compared with the control group (59.3% versus 29.6%, P=0.03). A significant reduction in left ventricular mass index was observed in the MSC group, whereas there were no changes in the control group (P=0.002). The proportion of patients with left ventricular hypertrophy decreased at 24 weeks in the MSC group (33.3% versus 70.4%, P=0.006), whereas no changes were noted in the control group (63.0% versus 48.1%, P=0.29). Additionally, MSC therapy prevented progressive left ventricular diastolic dysfunction, as demonstrated by changes in mitral deceleration time and tricuspid regurgitant jet velocity.ConclusionsMSC strategy is associated with improved blood pressure control, regression of left ventricular hypertrophy, and prevention of progressive diastolic dysfunction at 24 weeks after transplantation.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT03398681.

C18. Cardiac AA amyloidosis presenting with refractory heart failure complicated by polymorphic ventricular tachycardia: a case report

Abstract Background Systemic AA amyloidosis is a rare infiltrative disease representing a complication of chronic inflammatory disorders. Cardiac involvement is rare and is associated with a poor prognosis. Early recognition is imperative as appropriate measures, and treatment of the underlying disease may prevent death from refractory heart failure and fatal arrhythmias. Case Summary A 53-years-old male patient with psoriatic arthritis presented with heart failure and nephrotic syndrome. Electrocardiogram revealed first-degree AV block, low voltage QRS complexes, and prolonged QT interval. On echocardiography, a normal systolic function of hypertrophic left ventricle with signs of diastolic dysfunction was present. An abdominal fat pad punch biopsy was able to confirm amyloid deposition. Self-terminated polymorphic ventricular arrhythmia was recorded by 24-hour Holter. Immunosuppressive, anti-inflammatory, anti-arrhythmic, and heart failure agent were promptly instituted, which are ineffective. Discussion Restrictive cardiomyopathy is the hallmark finding in cardiac amyloidosis that caused by the interstitial deposits of amyloid fibrils. Clinically, this manifests in progressive diastolic dysfunction, elevated left ventricular filling pressures, and heart failure with preserved ejection. The presence of rapidly progressed heart and renal failure with characteristic features of ECG should prompt further evaluation to confirm an infiltrative cardiomyopathy. This is highly suggestive that the natural course of cardiac amyloidosis often unpredictable and can be aggressive if left undiagnosed and untreated.

C18. Cardiac AA amyloidosis presenting with refractory heart failure complicated by polymorphic ventricular tachycardia: a case report

Abstract Background Systemic AA amyloidosis is a rare infiltrative disease representing a complication of chronic inflammatory disorders. Cardiac involvement is rare and is associated with a poor prognosis. Early recognition is imperative as appropriate measures, and treatment of the underlying disease may prevent death from refractory heart failure and fatal arrhythmias. Case Summary A 53-years-old male patient with psoriatic arthritis presented with heart failure and nephrotic syndrome. Electrocardiogram revealed first-degree AV block, low voltage QRS complexes, and prolonged QT interval. On echocardiography, a normal systolic function of hypertrophic left ventricle with signs of diastolic dysfunction was present. An abdominal fat pad punch biopsy was able to confirm amyloid deposition. Self-terminated polymorphic ventricular arrhythmia was recorded by 24-hour Holter. Immunosuppressive, anti-inflammatory, anti-arrhythmic, and heart failure agent were promptly instituted, which are ineffective. Discussion Restrictive cardiomyopathy is the hallmark finding in cardiac amyloidosis that caused by the interstitial deposits of amyloid fibrils. Clinically, this manifests in progressive diastolic dysfunction, elevated left ventricular filling pressures, and heart failure with preserved ejection. The presence of rapidly progressed heart and renal failure with characteristic features of ECG should prompt further evaluation to confirm an infiltrative cardiomyopathy. This is highly suggestive that the natural course of cardiac amyloidosis often unpredictable and can be aggressive if left undiagnosed and untreated.

The SRSF4-GAS5-Glucocorticoid Receptor Axis Regulates Ventricular Hypertrophy.

[Figure: see text].

Release the Pressure! Does Jugular Venous Pressure Predict Rejection in Cardiac Biopsy?

<h3>Purpose</h3> Rejection in heart transplant recipients is often diagnosed by surveillance biopsies as most patients are asymptomatic. Nevertheless, rejection, if left untreated, can produce progressive diastolic dysfunction followed by systolic heart failure. This in turn will cause an increase in central venous pressure due to decreased ventricular compliance. With this in mind we sought out to determine if elevated central venous pressures measured invasively at the time of the biopsy correlated with the presence of rejection. <h3>Methods</h3> Patients undergoing an endomyocardial biopsy between June and October 2020 were included. The invasive JVP was measured before and after the procedure by measuring the height of the blood column in the side port of the sheath open to the atmospheric pressure. The biopsy results were reported according to the 2004 ISHLT revision. Differences in median JVP for each biopsy result group (0, 1R, 2R, 3R) were compared using a Mann-Whitney test. The histogram density for each biopsy group was graphed using a Kernel density plot. <h3>Results</h3> Eighty-four patients underwent one or more endomyocardial biopsies, with a total of 374 biopsies performed. Of all procedures, 187 were grade 0 for rejection, 168 were grade 1R and 18 were grade 2R. One patient had Grade 3R rejection (not shown in illustration) The median JVP was not statistically different between the three groups and the numerical difference was not clinically meaningful (figure 1 A). The Kernel density plot (figure 1 B) demonstrates the similarities between the groups. The lack of correlation between invasive JVP and rejection persists if data from the first 2 weeks post heart transplant are excluded. <h3>Conclusion</h3> In our dataset, there was no clinical or statistical difference in median invasive JVP and rejection grade between the biopsy result groups. One limitation is that we only had one patient with severe rejection (3R). Overall, our findings reinforce the need for surveillance biopsies.

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.

Estrogen Modulates the Differential Expression of Cardiac Myocyte Chymase Isoforms and Diastolic Function

Background and objectiveCardiac angiotensin II (Ang II) is involved in the diastolic dysfunction in postmenopausal women. Chymases, a family of serine proteases with chymotryptic activity, play a significant role in cardiac Ang II formation from its substrate Ang‐(1–12) in both human and rodent models. While human tissue expresses only the α‐form of chymase, α‐ and β‐forms exist in rodents. Five of the ten rat mast cell proteases (rMCP‐1–5) display chymase activity, and rats express predominantly the β‐chymase isoforms. This study was designed to assess the differences in enzymatic activity among these rMCP isoforms in Ang II formation, particularly in the cardiomyocyte (CM), and the effects of estrogen status on MCP gene expression and activities in female rat models.Methods and resultsUsing conventional polymerase chain reaction (PCR) (Fig. 1A), real‐time PCR (Fig. 1B) and DNA sequencing (Fig. 1C), we demonstrated that MCP‐1, MCP‐2, MCP‐4, and MCP‐5 mRNAs are expressed in the CM of both spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto rats (WKY). While rMCP‐1 and rMCP‐5 gene transcripts were higher than other isoforms in both rat strains, WKY CM exhibits higher levels of rMCP‐1 and rMCP‐5 mRNAs compared to the SHR CM (Fig. 2). Ovariectomy (OVX) increased the expression of rMCP‐1 and rMCP‐5 mRNAs in WKY. In SHR, OVX was associated with a blunted increase in rMCP‐1 mRNA compared to OVX normotensive WKY. Chymase activity, measured by HPLC as Ang II formation from Ang‐(1–12), significantly correlated with rMCP‐1 and rMCP‐5 mRNA expression in both rat strains. Both rMCP‐1 and rMCP‐5 mRNA expressions were positively correlated with progressive diastolic dysfunction (increasing the ratio of early mitral inflow velocity‐to‐early mitral annular velocity, E/e′) and increases in left ventricular internal diameter end diastole.ConclusionThese data show rMCP‐1 and rMCP‐5 as the Ang II forming chymase isoforms participating in diastolic dysfunction due to ovariectomy in rodents.Support or Funding InformationThis work was funded by grants from the National Heart Lung and Blood Institute (CMF and LG) P01‐HL051952 and the National Institute on Aging (LG) AG033727 of the National Institute of Health.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Estrogen modulates the differential expression of cardiac myocyte chymase isoforms and diastolic function.

Chymases, a family of serine proteases with chymotryptic activity, play a significant role in cardiac angiotensin II (Ang II) formation from its substrate Ang-(1-12) in both human and rodent models. No studies, to date, have assessed the differences in enzymatic activity among these isoforms in Ang II formation, particularly in the cardiomyocyte (CM). Using PCR and DNA sequencing, we demonstrated that MCP-1, MCP-2, MCP-4, and MCP-5 mRNAs are expressed in the CM of both spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). While rMCP-1 and rMCP-5 gene transcripts were higher than that of other isoforms in both rat strains, WKY CM exhibits higher levels of rMCP-1 and rMCP-5 mRNAs compared to the SHR CM. Ovariectomy (OVX) increased the expression of rMCP-1 and rMCP-5 mRNAs in WKY. In SHR, OVX was associated with a blunted increase in rMCP-1 mRNA compared to OVX normotensive WKY. Chymase activity, measured as Ang II formation from Ang-(1-12), significantly correlated with rMCP-1 and rMCP-5 mRNA expression in both rat strains. Both rMCP-1 and rMCP-5 mRNA expressions were positively correlated with progressive diastolic dysfunction (increasing the ratio of early mitral inflow velocity-to-early mitral annular velocity, E/e') and expanding chamber dimensions or increasing left ventricular internal diameter end diastole. These data show rMCP-1 and rMCP-5 as the Ang II forming chymase isoforms participating in the loss of normal cardiac function due to OVX in rodents.

Miocardiopatías infiltrativas. Aporte de la ecocardiografía

Infiltrative cardiomyopathies are characterised by the deposit of abnormal substances within the ventricular wall that cause stiffness and thus progressive diastolic dysfunction, which typically precedes systolic dysfunction. These conditions can be classified into two large groups, depending on their phenotype: those that simulate ischaemic heart disease or dilated cardiomyopathy, and those that simulate hypertrophic or hypertensive cardiomyopathy. The first group includes, sarcoidosis, haemochromatosis, and Wegener's granulomatosis, while the second group includes, amyloidosis, Anderson-Fabry disease, Danon disease, Friedreich's ataxia, myocardial oxalosis, and mucopolysaccharidosis. In this chapter, a description will be made of the most relevant aspects of the echocardiography approach into the most common infiltrative cardiomyopathies, highlighting the most notable findings that should make one suspect each one these diseases, and to establish the need to widen the study with other diagnostic methods.

Galectin-3 Reflects the Echocardiographic Grades of Left Ventricular Diastolic Dysfunction.

BackgroundThe level of Galectin-3 (Gal-3) protein purportedly reflects an ongoing cardiac fibrotic process and has been associated with ventricular remodeling, which is instrumental in the development of heart failure with preserved ejection fraction (HFpEF) syndrome. The aim of this study was to investigate the potential use of Gal-3 in improved characterization of the grades of diastolic dysfunction as defined by echocardiography.MethodsSeventy HFpEF patients undergoing routine echocardiography were prospectively enrolled in the present monocentric study. Blood samples for measurements of Gal-3 and amino-terminal pro-brain natriuretic peptide (NT-proBNP) were collected within 24 hours pre- or post-echocardiographic examination. The classification of patients into subgroups based on diastolic dysfunction grade permitted detailed statistical analyses of the derived data.ResultsThe Gal-3 serum levels of all patients corresponded to echocardiographic indices, suggesting HFpEF (E/A, P=0.03 and E/E', P=0.02). Gal-3 was also associated with progressive diastolic dysfunction, and increased levels corresponded to the course of disease (P=0.012). Detailed analyses of ROC curves suggested that Gal-3 levels could discriminate patients with grade III diastolic dysfunction (area under the curve [AUC]=0.770, P=0.005).ConclusionsGal-3 demonstrates remarkable effectiveness in the diagnosis of patients suffering from severe grade diastolic dysfunction. Increasing levels of Gal-3 possibly reflect the progressive course of HFpEF, as classified by the echocardiographic grades of diastolic dysfunction.

Comorbidities and Cardiometabolic Disease: Relationship With Longitudinal Changes in Diastolic Function

ObjectivesThis study sought to evaluate the course, correlates, and prognosis of longitudinal changes in left ventricular (LV) diastolic dysfunction (DD) in the community-based Framingham Heart Study. BackgroundRelationships of clinical risk factors to longitudinal progression of DD are incompletely understood. MethodsDiastolic function was assessed by echocardiography performed at consecutive examinations (visits 1 and 2, mean interval 5.6 years) in 1,740 participants (64 ± 8 years of age at visit 1, 59% women) with normal LV systolic function and no atrial fibrillation. ResultsOf 1,615 individuals with normal-to-mild DD at visit 1, 198 (12%) progressed to ≥ moderate DD at visit 2. Progression was more likely in women and with advancing age (p < 0.0001). Of 125 individuals with ≥ moderate DD at visit 1, 25 (20%) regressed to normal-to-mild DD by visit 2. Regression of DD was associated with younger age (p < 0.03). In stepwise regression models, age, female sex, baseline and changes in systolic blood pressure, diastolic blood pressure, body mass index, serum triglycerides, and diabetes were positively associated with worsening diastolic function (all p < 0.05). Noncardiac comorbidity tracked with progressive DD. Cardiovascular disease (CVD) or death events occurred in 44 of 1,509 participants free of CVD at visit 2, during 2.7 ± 0.6 years of post-visit 2 follow-up. Presence of ≥ moderate DD was associated with higher risk (age- and sex-adjusted hazard ratio for CVD or death: 2.14; 95% confidence interval: 1.06 to 4.32; p = 0.03). ConclusionsIn a community-based cohort of middle-aged to older adults, cardiometabolic risk factors and noncardiac comorbidities were associated with DD progression. Moderate or worse DD was associated with higher risk of CVD or death.

Predictors of Prognosis in Light-Chain Amyloidosis and Chronological Changes in Cardiac Morphology and Function

Immune light-chain (AL) amyloidosis with cardiac involvement is associated with a high mortality despite improved therapeutic regimens, but there are few reports on prognostic predictors and chronological changes in cardiac morphology and function. Prognosis and its predictors were evaluated in 36 consecutive patients with cardiac AL amyloidosis. Chronological changes in cardiac morphology and function were also evaluated. The median follow-up period was 0.95 years. The median survival time and the 3-year death-free rate after diagnosis in all-cause and cardiac deaths were 0.85 and 1.06 years and 26% and 36%, respectively. Differences in the median survival time due to left ventricular (LV) wall thickness at diagnosis were not evident. Being female and diastolic wall strain (DWS), as a measure of diastolic stiffness, were independent predictors of all-cause death in the multivariable analysis. The receiver operating characteristic analysis revealed that a DWS cut-off value of 0.189 had a sensitivity of 78% and a specificity of 72% for predicting all-cause death within 1 year after diagnosis (area under the curve = 0.726). The LV size and the stroke volume decreased and DWS worsened during the short-term follow-up period in patients who died within 1 year compared with patients who were alive after 1 year. The prognosis for patients with cardiac AL amyloidosis was poor, and DWS may be a significant predictor of prognosis. Narrowing of the LV cavity and progressive diastolic dysfunction were evident in patients with a poor prognosis.

Splenectomy‐Induced Diastolic Dysfunction With Normal Ejection Fraction

BackgroundUnderstudied and often disregarded, the spleen is perceived as redundant, non‐vital or even a vestigial organ. Conversely, epidemiological studies indicate splenectomy (or splenic injury) increase the prevalence of cardiovascular diseases and associated risk factors, suggesting the physiological function of the spleen is not yet realized. Recent investigations have examined the role of the spleen in experimental heart failure, however, the effect of long‐term splenectomy on cardiac function in healthy models remains to be determined. Thus, the aim of this study was to reconcile the observations made in the epidemiological studies by investigating cardiac function and morphology following splenectomy in healthy rodents.MethodsSplenectomized and sham male Wistar rats were assessed at 5, 9, and 18 weeks post‐surgery by echocardiography, invasive hemodynamics, cardiac histology, and thromboelastography. Serum IL‐10 was measured by ELISA and left ventricular free wall was used for the analysis of select molecular markers.ResultsSplenectomy caused progressive left ventricular diastolic dysfunction (i.e., increases in dP/dt min, Tauw, and LVEDP), with no evidence of cardiac decompensation or systolic dysfunction. Left ventricular remodeling (fibrosis, hypertrophy and decreases in capillary to myocyte cross sectional area) were associated with decreases in serum IL‐10 and ventricular BNP expression. Increases in blood coagulability following splenectomy are associated with increased risk of developing thromboembolic pulmonary hypertension. In our model however, we found no evidence of pulmonary arterial hypertension or lung remodeling despite a ~2‐fold increase in coagulability.ConclusionsSplenectomy in healthy rodents caused progressive diastolic dysfunction and significant cardiac remodeling (i.e., fibrosis, hypertrophy and decreased capillary density), demonstrating an underappreciated role of the spleen in cardiac homeostasis. Future studies need to characterize the mechanism(s) by which the spleen contributes to a healthy cardiovascular phenotype.Support or Funding InformationThis work was supported by the J.P. Bickell Foundation (to JA Simpson), the Natural Sciences and Engineering Research Council (to JA Simpson and KR Brunt), and the Ontario Veterinary College Pet Fund (to SL Blois). JA Simpson is a new investigator with the H&amp;SF of Ontario.

Clinical symptoms of right ventricular failure in experimental chronic pressure load are associated with progressive diastolic dysfunction

BackgroundRight ventricular failure (RVF) due to pressure load is a major cause of death in congenital heart diseases and pulmonary hypertension. The mechanisms of RVF are unknown. We used an experimental approach based upon clinical signs of RVF to delineate functional and biological processes associated with RVF. Methods and resultsWistar rats were subjected to a pulmonary artery banding (PAB n=12) or sham surgery (CON, n=7). After 52±5days, 5/12 PAB rats developed clinical symptoms of RVF (inactivity, ruffled fur, dyspnea, ascites) necessitating termination (PAB+CF). We compared these to PAB rats with RVF without clinical symptoms (PAB−). PAB resulted in reduced cardiac output, RV stroke volume, TAPSE, and increased end diastolic pressure (all p<0.05 vs. CON) in all rats, but PAB+CF rats were significantly more affected than PAB−, despite similar pressure load (p=ns). Pressure–volume analysis showed enhanced contractility (end systolic elastance) in PAB− and PAB+CF, but diastolic function (end diastolic elastance, end diastolic pressure) deteriorated especially in PAB+CF. In PAB+CF capillary density was lower than in PAB−. Gene-array analysis revealed downregulation of both fatty acid oxidation and carbohydrate metabolism in PAB+CF. ConclusionChronic PAB led to different degrees of RVF, with half of the rats developing severe clinical symptoms of RVF, associated with progressive deterioration of diastolic function, hypoxia-prone myocardium, increased response to oxidative stress and suppressed myocardial metabolism. This model represents clinical RVF and allows for unraveling of mechanisms involved in the progression from RV adaptation to RV failure and the effect of intervention on these mechanisms.