Diastolic Left Ventricular Research Articles

Effect of renal denervation procedure on left ventricular mass, myocardial strain and diastolic function by CMR on a 12-month follow-up.

To investigate the effects of renal denervation (RDN) on left ventricular (LV) mass, myocardial strain and diastolic function in patients with treatment-resistant arterial hypertension by cardiac magnet resonance imaging on a 12-month follow-up. Sixteen patients (38% female) were examined before and 12months after RDN. LV morphology and strain were analyzed. Diastolic function was determined by early (EPFR) and atrial peak filling rates (APFR) derived from differential volume-time-curve analysis. Clinical visits included 24-h ambulant blood pressure monitoring (ABPM). Twelve months after RDN LV mass decreased from 80 ± 21g/m2 to 74 ± 20g/m2 (P < 0.05). Global radial (35 ± 12% vs. 41 ± 10%, P < 0.05) and longitudinal strain improved (-15 ± 4% vs. -17 ± 3%, P < 0.05). Global circumferential strain (-16 ± 5% vs. -18 ± 4%, P = 0.12) remained unchanged. The parameter of diastolic LV function PFRR (EPFR/APFR) improved following RDN (0.9 ± 0.4 vs. 1.1 ± 0.5, P < 0.05). Individual changes of LV mass were associated with an increase of EPFR (r = -0.54, P < 0.05) and a reduction of APFR by trend (r = 0.45, P = 0.08). Systolic ABPM showed a decrease by trend (152mmHg vs. 148mmHg, P = 0.08). After RDN we observed a reduction of LV mass, improvement of global strain and diastolic function.

The non-steroidal mineralocorticoid receptor antagonist finerenone prevents cardiac fibrotic remodeling

Mineralocorticoid receptor (MR) overactivation promotes cardiac fibrosis. We studied the ability of the non-steroidal MR antagonist finerenone to prevent fibrotic remodeling. In neonatal rat cardiac fibroblasts, finerenone prevented aldosterone-induced nuclear MR translocation. Treatment with finerenone decreased the expression of connective tissue growth factor (CTGF) (74 ± 15% of control, p = 0.005) and prevented aldosterone-induced upregulation of CTGF and lysyl oxidase (LOX) completely. Finerenone attenuated the upregulation of transforming growth factor ß (TGF-ß), which was induced by the Rac1 GTPase activator l-buthionine sulfoximine. Transgenic mice with cardiac-specific overexpression of Rac1 (RacET) showed increased left ventricular (LV) end-diastolic (63.7 ± 8.0 vs. 93.8 ± 25.6 µl, p = 0.027) and end-systolic (28.0 ± 4.0 vs. 49.5 ± 16.7 µl, p = 0.014) volumes compared to wild-type FVBN control mice. Treatment of RacET mice with 100 ppm finerenone over 5 months prevented LV dilatation. Systolic and diastolic LV function did not differ between the three groups. RacET mice exhibited overactivation of MR and 11ß hydroxysteroid dehydrogenase type 2. Both effects were reduced by finerenone (reduction about 36%, p = 0.030, and 40%, p = 0.032, respectively). RacET mice demonstrated overexpression of TGF-ß, CTGF, LOX, osteopontin as well as collagen and myocardial fibrosis in the left ventricle. In contrast, expression of these parameters did not differ between finerenone-treated RacET and control mice. Finerenone prevented left atrial dilatation (6.4 ± 1.5 vs. 4.7 ± 1.4 mg, p = 0.004) and left atrial fibrosis (17.8 ± 3.1 vs. 12.8 ± 3.1%, p = 0.046) compared to vehicle-treated RacET mice. In summary, finerenone prevented from MR-mediated structural remodeling in cardiac fibroblasts and in RacET mice. These data demonstrate anti-fibrotic myocardial effects of finerenone.

SERUM URIC ACID AND LONGITUDINAL CHANGES IN LEFT VENTRICULAR STRUCTURE AND FUNCTION IN THE GENERAL POPULATION

Objective: Previous studies showed that serum uric acid as a marker of increased xanthine oxidase activity may be a useful prognosticator for incident heart failure particularly in patients with hypertension. However, population data on the longitudinal changes in left ventricular (LV) structure and function in relation to serum uric acid are sparse. We, therefore, assessed in the general population whether hyperuricemia predicts longitudinal changes in echocardiographic indexes reflecting LV structure and function. Design and method: In 641 randomly recruited Flemish participants (mean age 50.6 years, 50.9% women), we assessed echocardiographic indexes of LV structure and diastolic function at baseline and after 4.7 years. We regressed longitudinal changes in these indexes on baseline uric acid, and reported standardized effect sizes as a percentage of the SD of LV changes associated with a 1-SD of serum uric acid. Results: In multivariable-adjusted cross-sectional analyses, higher serum uric level correlated (P < 0.0018) with greater LV mass index (LVMI) and E/e′ ratio measured at follow-up. From examination 1 to 2, LVMI and E/e′ ratio increased by +3.6 ± 13.2 g/m2 and +0.37 ± 1.46, respectively (P < 0.0001). In longitudinal analyses, after full adjustment, higher baseline serum uric acid independently predicted a greater increase in LVMI (effect size: +14.8%; P = 0.0021) and E/e′ ratio (+21.6%; P < 0.0001) during follow-up. Compared to participants who had normal level of serum uric acid over time (n = 497), subjects with hyperuricemia at both visits (n = 65) experienced worse temporal changes in LVMI (+7.2 g/m2 vs +2.4 g/m2; P = 0.011) and E/e′ ratio (+0.97 vs +0.27; P = 0.0008). Conclusions: Hyperuricemia at baseline predicted worsening of LV diastolic function and LV remodeling over time. These findings suggest the importance of management of hyperuricemia in order to delay or prevent progression of adverse LV remodeling and dysfunction.

6 DIASTOLIC STRESS TESTING ECHOCARDIOGRAPHY (DST) ON PATIENTS WITH HYPERTENSIVE HEART DISEASE WITH POSSIBLY HIGH LEFT VENTRICULAR FILLING PRESSURE IN DR. M. DJAMIL GENERAL HOSPITAL PADANG

Background: The prevalence of hypertension tends to increase every year and develops at decades of 3 and 4 of life. Hypertension is a major risk factor of heart failure with a normal left ventricular (LV) ejection fraction (HFpEF). In everyday practice, it is often found complaints of tightness during activity but the results of echocardiography show normal diastolic function or diastolic dysfunction grade I with possibly high left ventricular filling pressure. In 2016, ASE and EACVI issued guidelines for diastolic stress testing (DST) echocardiography to distinguish the cause of shortness of breath whether or not it originated from the heart. The aim of this study to describe the variable hemodynamic responses during diastolic stress echocardiography on patients with hypertensive heart disease. Method: This was a descriptive retrospective study in patient with hypertensive heart disease complaining exertional dyspneu who underwent DST examination from April until November 2018. Resting echocardiography and DST characteristic data were taken from echocardiography laboratories registry and medical records in Dr. M. Djamil General Hospital Padang. Subject were excluded if any of concomitant disease which will affect the LV appeared. Results: Sixty patients underwent diastolic stress echocardiography. Twenty four patients classified as indeterminate and 36 patients were normal diastolic function. Both of this group are on the same age range, around in 50–60 years. Female dominated on this both group. On baseline echocardiography findings of left ventricle structures or functions there were no significant differences. But, on baseline of diastolic LV functions, we found significant differences of lateral e’(p: 0.004), lateral E/e’(p:0,002), and septal E/e’ (p: 0.011). Conclusion: Patients who fall into the indeterminate category, there is still the possibility of high LV filling pressure, so it needs to be proven by invasive strategy. Lower value of lateral e’, lateral E/e’ and septal E/e’ in hypertensive patients have chance of high LV filling pressure.

IMPACT OF SINGLE-PILL COMBINATION OF VALSARTAN/AMLODIPINE ON LEFT VENTRICULAR HYPERTROPHY AND MYOCARDIAL STIFFNESS IN THE MIDDLE-AGED HYPERTENSIVE PATIENTS

Objective: to investigate effects of single-pill combination (SPC) of valsartan/amlodipine (V/A) on left ventricular (LV) and left atrial (LA) myocardial stiffness (MS) parameters and LV mass index (LVMI) in the middle-aged patients with stage II grade 1–2 essential arterial hypertension (EAH) without concomitant cardiovascular diseases. Design and method: Retrospective, cohort, open-label study. According to the medical records data a group of naïve patients 40–65 years old with stage II grade 1–2 EAH (n = 38, mean age 49.7 ± 7.0 years) was retrospectively formed. All the patients were treated with V/A SPC and all of them had achieved target office blood pressure (BP) <140/90 mmHg. In all included patients clinical and echocardiographic data (acquired using Vivid 7 Dimension system, GE) were available at baseline and on 12th week after reaching the target BP. LVMI, diastolic interventricular septum thickness (IVS) and diastolic LV posterior wall thickness (PWT) were used as a measures of LV hypertrophy. LV end-diastolic stiffness, LV end-systolic elastance (ESE), LV diastolic elastance, LA stiffness index, LA expansion index and tissue Doppler-derived LA strain were calculated as MS parameters. 2-D speckle tracking echocardiography data were acquired for determination of LV myocardial global longitudinal peak strain (LV GLPS). Results: at the end of follow-up LV ESE significantly (p < 0.001) decreased from 4.01 ± 1.12 to 3.46 ± 0.88 mmHg/ml. In the subgroup of patients with initially abnormal LV GLPS (less than 19.7%) this parameter significantly (p = 0.005) increased in absolute value from −16.14 ± 2.21 to −17.30 ± 2.13% (+8,45 ± 13.35%). All LV hypertrophy markers significantly decreased (p < 0.001 for all) – LVMI from 113.40 ± 22.24 to 103.52 ± 21.30 g/m2 (−8.58 ± 7.57%), IVS from 1.30 ± 0.20 to 1.23 ± 0.19 cm (−5.38 ± 5.29%) and PWT from 1.03 ± 0.11 to 0.95 ± 0.11 cm (−7.82 ± 9.29%). After the treatment with V/A SPC the number of patients with LV hypertrophy significantly (p = 0.039) reduced from 65.8% to 39.5%. Conclusions: in naïve 40–65 years old patients with stage II grade 1–2 EAH antihypertensive therapy with V/A SPC provides effective BP control, improves LV MS parameters and reduced LV hypertrophy.

Repeated Echocardiograms Do Not Provide Incremental Prognostic Value to Single Echocardiographic Assessment in Minimally Symptomatic Patients with Chronic Heart Failure: Results of the Bio-SHiFT Study

We aimed to compare the prognostic value of a single "baseline" echocardiogram with repeated echocardiography in stable chronic heart failure (CHF) patients. We hypothesized that repeated echocardiograms would contain incremental prognostic information. In the prospective Bio-SHiFT study, we performed 332 echocardiograms in 106 patients during a median follow-up of 2.3years. The endpoint comprised HF hospitalization, left ventricular (LV) assist device implantation, heart transplantation, and cardiovascular death. We compared hazard ratios (HRs; adjusted for N-terminal pro-brain natriuretic peptide) from Cox models for the first available measurement with HRs from joint models, which model individual trajectories based on the repeated measurements and link these to the time-to-event data. The mean age of the patients was 58.1years; 78.3% were male, 12.6% had New York Heart Association class>II, all had reduced ejection fraction, and the most common HF etiologies were cardiomyopathies (51%) and ischemia (40%). The endpoint occurred in 25 patients. Both the single measurements and the temporal trajectories were significantly associated with the endpoint (adjusted HR Cox model [95% CI] vs adjusted HR joint model [95% CI]): LV ejection fraction, 1.47 (0.93-2.31) vs 1.77 (1.13-2.93); diastolic LV diameter, 1.64 (1.09-2.47) vs 1.68 (1.12-2.57); systolic LV diameter, 1.72 (1.10-2.69) vs 1.68 (1.13-2.63); systolic left atrial diameter, 1.88 (1.18-3.00) vs 2.60 (1.48-4.97); E/A ratio, 2.73 (1.42-5.26) vs 3.87 (1.75-10.13); and E/e' ratio, 2.30 (1.38-3.84) vs 2.99 (1.68-6.19). None of the trajectories from the investigated parameters showed worsening prior to events. Although single baseline or repeatedly measured echocardiographic parameters were associated with the endpoint, all parameters remained on average stable during the 2.3years of follow-up in this largely minimally symptomatic CHF cohort. Thus, regular echocardiographic monitoring of systolic or diastolic LV function within this time frame does not carry incremental prognostic information over a single baseline measurement.

Left Atrial Function and Volume an Independent Markers of Cardiovascular Involvement in Early Chronic Kidney Disease

Aim: value of left atrium (LA) volume and function evaluated by strain analysis in the detection of myocardial involvement in early chronic kidney disease (CKD) patients with coexistent of hypertension. Methods: 33 patients with CKD stage 2 or stage 3, with mild hypertension compared with 32 age matched hypertensive patients with normal kidney function and 30 healthy control subjects, all participants underwent trans thoracic echocardiography to assess left ventricular (LV) systolic and diastolic function, LV mass and LA volume index (LAVI) by 2D and pulsed wave Doppler imaging, and LA segmental strain measured by tissue Doppler imaging (TDI). Results: Stage 3 CKD had the most reduced diastolic function compared with other groups. (LAVI) was higher significantly in both CKD group (36.2+8.4 ml/m2) and HT group (34.31+4.75 ml/m2) compared to control group (22.18+3 ml/m2) (p=0.001), LAVI was significantly higher in stage 3 compared with stage 2 CKD (p=0.001), Global systolic strain (GS)was significantly reduced in CKD group (17.48+4.3%) compared to both HT group (27.92+5.17%) and controls (31.75+6.8%) (p=0.001), GS was significantly lower in HT group compared with controls (p=0.014), systolic strain of four left atrial walls were different significantly between CKD group and both HT and control groups. there was high significant difference between stage 2 and stage 3 CKD as regard left atrial lateral and anterior walls systolic strain (p=0.001), inferior and septal wall systolic strain were significantly lower in stage 3 compared to stage 2 CKD. Conclusion: LA dysfunction and enlargement are evident in patients with early CKD, LA systolic strain was reduced in CKD earlier than LA enlargement which occur later, hence LA systolic strain and volume index could be used to detect myocardial involvement in early CKD.

Evaluation of cardiovascular risk by growth-differentiation factor-15 and tissue Doppler imaging in children with subclinical hypothyroidism.

Subclinical hypothyroidism, defined as increased TSH serum levels and normal serum free T4 concentrations, has been associated with an increased risk of heart disease in adults. But, data in children and adolescents are scanty and treatment of subclinical hypothyroidism is controversial. Growth differentiation factor-15 (GDF-15) is a promising biomarker of cardiac remodeling. This study aimed to evaluate the cardiovascular risk factors in children with subclinical hypothyroidism, measured with tissue Doppler echocardiography (TDE), and conventional echocardiography and GDF-15 level. The study comprised a total of 41 pediatric patients with subclinical hypothyroidism (SH) (mean age 9.6 ± 4.7 years) and 31 healthy children (mean age 11.2 ± 3.4 years) as the control group. Subclinical hypothyroidism was defined as a thyroid-stimulating hormone level higher than 4 mIU/l and a normal free-thyroxine level (0.6-1.8 ng/dl). Tissue Doppler echocardiography was performed to all individuals in the control group and patient group at the beginning of the study. Global systolic function as assessed by left ventricular ejection fraction was compared between groups. The serum GDF-15 level was measured. There were no significant differences in demographic parameters between the SH and control groups. The left ventricular internal diameter end systole, interventricular septal end diastole, left ventricular posterior wall end diastole, and tricuspid annular plane systolic excursion values were significantly different between the SH and control groups (p = 0.038, 0.028, 0.005, and 0.000, respectively). The mean mitral isovolumic relaxation time value of the SH group was 57.2 ± 9.3 ms, compared to 44.5 ± 5.6 ms for the control group (p = 0.000). The mean tricuspid isovolumic contraction time value of the SH group was 58.7 ± 9.4 ms, and that of the control group was 45.1 ± 5.3 ms (p = 0.000). The mean tricuspid isovolumic relaxation time value of the SH group was 58.03 ± 9.5 ms, and that of the control group was 45.1 ± 5.3 ms (p = 0.000). There were no significant differences in the other m-mode or pulse Doppler echocardiography values between two groups. The GDF-15 value of the SH group was 382.6 ± 268.2 pg/mL, and that of the control group was 473.6 ± 337.9 pg/mL; this difference was not significant. Patients with subclinical hypothyroidism versus healthy individuals had some changes in echocardiographic parameters that indicate involvement of diastolic function of the left ventricle. They were significantly different when compared SH group and the control group. This study demonstrated ventricle diastolic dysfunction in pediatric patients with hypothyroidism. The results of our study suggest that cardiac follow-up may be useful in patients with subclinical hypothyroidism and clinical trials are needed to explore therapeutic effects of T4 and T3 administration in this patients.

Pressure and Volume Characteristics of the Left Ventriclе in Its Diastolic and Systolic Dysfunction

Cardiomyopathy in rats has been developed after 4 weeks doxorubicin administration(2 mg / kg weekly). Echocardiographic study of rats in 8 weeks from onset of doxorubicin administration showed preponderanceof systolic dysfunction (67 %) with decrease of left ventricular (LV) ejection fraction (EF) by 30 %. Simultaneous registration of LV pressureand volume showed that diastolic LV volume was preserved in doxorubicin-treated rats due to considerable lengthening of the diastole,the heart rate was reduced by 22 %. These hearts also showed slowing of relaxation, reduced maximal rate of pressure development andstroke work, as well as significant reduction in peripheral arterial resistance. Diastolic dysfunction differed from the systolic one by normalsystolic EF and preserved LV contractility index as well as lower diastolic LV pressure throughout the diastole. Based on thesedata, four compensatory mechanisms associated with cardiomyopathy were distinguished - 1) slowing of myocardial relaxation, prolongingmyofibrillar active state, 2) reduction of peripheral arterial resistance for easier LV ejection, 3) heart rate reduction, prolonging diastolicpause and thus facilitating better LV filling and 4) increased pressure in the small circle, also contributing to the LV rapid filling.

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.

Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS).

AimsTransthyretin amyloidosis (ATTR amyloidosis) is a heterogeneous disorder with cardiac, neurologic, and mixed phenotypes. We describe the phenotypic and genotypic profiles of this disease in continental Western Europe as it appears from the Transthyretin Amyloidosis Survey (THAOS).Methods and resultsTHAOS is an ongoing, worldwide, longitudinal, observational survey established to study differences in presentation, diagnosis, and natural history in ATTR amyloidosis subjects. At data cut-off, 1411 symptomatic subjects from nine continental Western European countries were enrolled in THAOS [1286 hereditary (ATTRm) amyloidosis; 125 wild-type ATTR (ATTRwt) amyloidosis]. Genotypes and phenotypes varied notably by country. Four mutations (Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu), and ATTRwt, were associated with a mainly cardiac phenotype showing symmetric left ventricular (LV) hypertrophy, normal diastolic LV dimensions and volume, and mildly depressed LV ejection fraction (LVEF). Morphologic and functional abnormalities on echocardiogram were significantly more severe in subjects with cardiac (n‘= 210), compared with a mixed (n = 298), phenotype: higher median (Q1–Q3) interventricular septal thickness [18 (16–21) vs. 16 (13–20) mm; P = 0.0006]; and more frequent incidence of LVEF <50% (38.1 vs. 17.5%; P = 0.0008). Subjects with cardiac mutations or ATTRwt (or cardiac or mixed phenotype) had a lower survival rate than subjects in other genotype (or the neurologic phenotype) categories (P < 0.0001, for both).ConclusionATTR amyloidosis genotypes and phenotypes are highly heterogeneous in continental Western Europe. A geographic map of the different disease profiles and awareness that a subset of subjects have a dominant cardiac phenotype, mimicking hypertrophic cardiomyopathy, at presentation can facilitate the clinical recognition of this underdiagnosed disease.Trial registrationClinicalTrials.gov: NCT00628745.

Intact DNA Repair in Differentiated Cardiomyocytes is Essential for Maintaining Cardiac Function in Response to Physiological Stimulus

IntroductionDNA in every cell is continuously damaged and DNA repair mechanisms are essential for protection against DNA damage‐induced aging‐related diseases. Evidence indicates that DNA damage is associated with heart failure. We have shown that unrepaired endogenously generated DNA damage drives the early onset of progressive heart failure (de Boer et al. Cardiovasc Res, 2018;114:S105). Here we studied the effects of a physiological stimulus on cardiac function in a mouse model with deficient DNA repair.MethodsTo increase the burden of spontaneous DNA damage, we generated mice with cardiomyocyte‐restricted inactivation of DNA repair endonuclease XPG (αMHC‐Xpgc/−). To induce physiological left ventricular (LV) hypertrophy, mice were exposed to 11 weeks of voluntary wheel running. Subsequently, LV geometry, function and structure were studied at age 16 weeks.ResultsCardiomyocyte‐restricted inactivation of Xpg resulted in systolic as well as diastolic LV dysfunction, demonstrated by decreases in fractional shortening, LVdP/dtP40 and LVdP/dtmin and increases in LV end‐diastolic lumen diameter (LVEDD) and relaxation time constant tau compared to WT (Table). In addition, expression level of hypertrophy maker gene β‐myosin heavy chain (β‐MHC) was elevated. Physical activity has been shown to be beneficial for maintaining and improving cardiac function in mice after myocardial infarction (de Waard et al. Circ Res, 2007;100:1097). In contrast, exercise failed to ameliorate LV remodeling and dysfunction in αMHC‐Xpgc/−, as it produced further increases in LVEDD, tau and β‐MHC compared to sedentary αMHC‐Xpgc/− (Table). Moreover, myocardial collagen content and the number of γH2A. X positive nuclei, a marker for DNA damage, were increased, suggesting that αMHC‐Xpgc/− showed increased susceptibility to exercise.ConclusionCardiomyocyte‐restricted loss of DNA repair protein Xpg increases cardiac vulnerability to develop heart failure in response to exercise training. These findings underscore the importance of genomic stability for maintenance of cardiac function, not only during basal conditions, but also in response to a physiological stimulus.Support or Funding InformationSupported by a NHF Grant 2007B024 and CVON‐ARENA (CVON2011‐11).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of airway obstruction and hyperinflation on electrocardiographic axes in COPD

BackgroundCOPD influences cardiac function and morphology. Changes of the electrical heart axes have been largely attributed to a supposed increased right heart load in the past, whereas a potential involvement of the left heart has not been sufficiently addressed. It is not known to which extent these alterations are due to changes in lung function parameters. We therefore quantified the relationship between airway obstruction, lung hyperinflation, several echo- and electrocardiographic parameters on the orientation of the electrocardiographic (ECG) P, QRS and T wave axis in COPD.MethodsData from the COPD cohort COSYCONET were analyzed, using forced expiratory volume in 1 s (FEV1), functional residual capacity (FRC), left ventricular (LV) mass, and ECG data.ResultsOne thousand, one hundred and ninety-five patients fulfilled the inclusion criteria (mean ± SD age: 63.9 ± 8.4 years; GOLD 0–4: 175/107/468/363/82). Left ventricular (LV) mass decreased from GOLD grades 1–4 (p = 0.002), whereas no differences in right ventricular wall thickness were observed. All three ECG axes were significantly associated with FEV1 and FRC. The QRS axes according to GOLD grades 0–4 were (mean ± SD): 26.2° ± 37.5°, 27.0° ± 37.7°, 31.7° ± 42.5°, 46.6° ± 42.2°, 47.4° ± 49.4°. Effects of lung function resulted in a clockwise rotation of the axes by 25°-30° in COPD with severe airway disease. There were additional associations with BMI, diastolic blood pressure, RR interval, QT duration and LV mass.ConclusionSignificant clockwise rotations of the electrical axes as a function of airway obstruction and lung hyperinflation were shown. The changes are likely to result from both a change of the anatomical orientation of the heart within the thoracic cavity and a reduced LV mass in COPD. The influences on the electrical axes reach an extent that could bias the ECG interpretation. The magnitude of lung function impairment should be taken into account to uncover other cardiac disease and to prevent misdiagnosis.

Left ventricular concentric remodelling and functional impairment in women with ischaemia with no obstructive coronary artery disease and intermediate coronary flow reserve: a report from the WISE-CVD study.

Women with evidence of ischaemia but no obstructive coronary artery disease (INOCA) often have coronary microvascular dysfunction (CMD). Although invasively measured coronary flow reserve (CFR) is useful for the diagnosis of CMD, intermediate CFR values are often found of uncertain significance. We investigated myocardial flow reserve and left ventricular (LV) structural and functional remodelling in women with suspected INOCA and intermediate CFR. Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) study participants who had invasively measured intermediate CFR of 2.0≤ CFR ≤3.0 (n = 125) were included for this analysis. LV strain, peak filling rate (PFR) and myocardial perfusion reserve index (MPRI) were obtained by cardiac magnetic resonance imaging. Participants were divided: (i) Group 1 (n = 66) high MPRI ≥ 1.8, and (ii) Group 2 (n = 59) low MPRI < 1.8. The mean age was 54 ± 12 years and CFR was 2.46 ± 0.27. MPRI was significantly different but CFR did not differ between groups. LV relative wall thickness (RWT) trended higher in Group 2 and circumferential peak systolic strain and early diastolic strain rate were lower (P = 0.039 and P = 0.035, respectively), despite a similar LV ejection fraction and LV mass. PFR was higher in Group 1 and LV RWT was negatively related to PFR (r = -0.296, P = 0.001). In women with suspected INOCA and intermediate CFR, those with lower MPRI had a trend towards more adverse remodelling and impaired diastolic LV function compared with those with higher MPRI. CFR was similar between the two groups. These findings provide evidence that both coronary microvessel vasomotion and structural and functional myocardial remodelling contribute to CMD.

Isoproterenol-induced heart failure in rat heart: Evaluation and cardioprotective strategy

It is well established that cardiac remodelling plays a pivotal role in the development of heart failure (HF), a leading cause of death worldwide. Meanwhile, a preclinical rat model of isoproterenol (Iso)-induced HF causes sympathetic hyperactivity, an important factor of cardiac remodelling, hemodynamic changes and cardiac fibrosis development. Several studies showed that metoprolol, a β1-adrenergic receptor (β1-AR) blocker prevents cardiac dysfunction following prolonged β-AR stimulation in different preclinical models. We evaluated the cardioprotective effects of metoprolol on cardiac remodelling and diastolic function in a severe Iso-induced HF model using echocardiography and cardiac pressure measurement. Rats received Iso injections (Iso; 5 mg/kg/day, N = 5), metoprolol (Meto; 24 mg/kg/day) + Iso 5 (Iso + Meto, N = 6), or vehicle ( N = 9) for 7 days. Left ventricular (LV) dimensions and function were followed-up by echocardiography before and after the treatment to assess LV hypertrophy. After echocardiography, LV end-diastolic pressure (LVEDP) was recorded to assess ventricular compliance and rat hearts were used for cardiac remodelling analysis. One week of Iso injections significantly increased LVEDP (+ 48%) and was associated with a major LV hypertrophy, characterised by a significant increase in LV mass (+ 33%) and a thickening of the LV walls observed by echocardiography. Simultaneous treatment with metoprolol prevented diastolic dysfunction and LV remodelling. Hypertrophy and fibrosis will be analysed in each group by histology (on-going experiments). Metoprolol afforded a cardioprotective effect on cardiac remodelling and diastolic dysfunction in Iso-induced HF model. Echocardiography and LVEDP measurements validate the reversibility of hypertrophic HF, and Iso-induced HF developed in rat could represent an effective and predictive preclinical model for evaluating antihypertrophic and antifibrotic agents.

Urocortin 2 Gene Transfer Reduces the Adverse Effects of a Western Diet on Cardiac Function in Mice.

Diabetes mellitus is associated with increased risk of heart failure. It has been previously demonstrated in mice that a single injection of adeno-associated virus 8 encoding urocortin 2 (AAV8.UCn2) increases glucose disposal in models of insulin resistance and improves the function of the failing heart. The present study tested the hypothesis that UCn2 gene transfer would reduce diabetes-related left ventricular (LV) dysfunction. Eight-week-old C57BL6 male mice were fed a Western diet (WD; 45% fat, 35% carbohydrate) for 40 weeks. At week 30, they received saline or AAV8.UCn2 (2 × 1013 genome copies/kg) via intravenous injection. Ten weeks after gene transfer, fasting blood glucose, glucose tolerance, and cardiac function were measured via echocardiography and in vivo measurement of LV contractile function, and the results were compared to those of mice fed normal chow (NC; 10% fat; 70% carbohydrate). The contents of key LV signaling proteins were also measured to probe mechanisms. WD increased 12 h fasting glucose (WD: 190 ± 11 mg/dL, n = 8; NC: 105 ± 12 mg/dL, n = 7; p = 0.0004). WD tended to reduce LV peak +dP/dt (p = 0.08) and LV peak -dP/dt (p = 0.05). LV ejection fraction was unchanged. Among WD-fed mice, UCn2 gene transfer reduced 12 h fasting glucose (WD-UCn2: 149 ± 6 mg/dL, n = 8; WD-Saline: 190 ± 11 mg/dL, n = 8; p = 0.012), increased LV peak +dP/dt (p < 0.001) and LV peak -dP/dt (p = 0.013), and reduced Tau (p < 0.02), indicating beneficial effects on systolic and diastolic LV function. In addition, among WD-fed mice, UCn2 gene transfer increased LV ejection fraction (p < 0.005) and the velocity of circumferential fiber shortening (p = 0.0005). Finally, a reduction was seen in fatty infiltration of the liver in WD-fed mice that had received UCn2 gene transfer. LV samples from WD-UCn2 mice showed increased phosphorylation of the protein kinase A catalytic domain (p = 0.03). In conclusion, UCn2 gene transfer increased LV systolic and diastolic function and reduced blood glucose in mice with diabetes-related LV dysfunction, indicating that UCn2 gene transfer may be of potential therapeutic benefit.

Dual Roles of the Mineral Metabolism Disorders Biomarkers in Prevalent Hemodilysis Patients: In Renal Bone Disease and in Vascular Calcification.

SummaryBackgroundVascular calcification (VC) is highly prevalent in dialysis (HD) patients, and its mechanism is multifactorial. Most likely that systemic or local inhibitory factor is overwhelmed by promoters of VC in these patients. VC increased arterial stiffness, and left ventricular hypertrophy. Thus, the present study aimed to investigate the association of VC and myocardial remodeling and to analyze their relationship with VC promoters (fibroblast growth factor 23-FGF23, Klotho, intact parathormon-iPTH, vitamin D) in 56 prevalent HD patients (median values: age 54 yrs, HD vintage 82 months).MethodsBesides routine laboratory analyzes, serum levels of FGF 23, soluble Klotho, iPTH, 1,25-dihydroxyvitamin D3; pulse wave velocity (PWV); left ventricular (LV) mass by ultrasound; and VCs score by Adragao method were measured.ResultsVC was found in 60% and LV concentric or eccentric hypertrophy in 50% patients. Dialysis vintage (OR 1.025, 95%CI 1.007–1.044, p=0.006) FGF23 (OR 1.006, 95% CI 0.992–1.012, p=0.029) and serum magnesium (OR 0.000, 95%CI 0.000–0.214, p=0.04) were associated with VC. Changes in myocardial geometry was associated with male sex (beta=-0.273, 95% CI -23.967 1.513, p=0.027), iPTH (beta 0.029, 95%CI -0.059–0.001, p=0.027) and vitamin D treatment (beta 25.49, 95%CI 11.325–39.667, p=0.001). Also, patients with the more widespread VC had the highest LV remodeling categories. PWV was associated patient’s age, cholesterol, diastolic blood pressure, LV mass (positively) and serum calcium (negatively), indicating potential link with atherosclerotic risk.ConclusionsDespite to different risk factors for VC and myocardial remodeling, obtained results could indicate that risk factors intertwine in long-term treatment of HD patients and therefore careful and continuous correction of mineral metabolism disorders is undoubtedly of the utmost importance.

A study of echocardiographic changes in patients of thalassemia major

Background: Thalassemia major is a chronic hematological disorder. Regular blood transfusion is the only modality of long-term survival for these patients. This leads to iron overload, the heart being the most severely affected organ. The gold standard for detecting myocardial iron deposition is cardiac MRI. However, very few patients can afford this investigation. Hence, authors carried out this study to find out whether early iron overload can be detected by echocardiography which is a simple and less expensive tool. The objective of this study was to document echocardiographic changes of cardiac iron overload in patients of thalassemia major even before appearance of symptoms.Methods: A comparative cohort study conducted from January 2018 to October 2018 in the Department of Paediatrics of SSG Hospital, and Government Medical College, Vadodara. The case group consisted of 35 patients of Thalassemia major. 35 age and sex matched normal children were selected as controls. Relevant blood investigations were performed in cases. 2-Dimensional M-Mode Echocardiography was performed in both patients and controls. Thalassemia major patients were compared to normal healthy children for various parameters in echocardiography indicating the systolic and diastolic function. Proportion and percentage were calculated for descriptive analysis. Independent t-Test was applied between two groups to find out significance level.Results: For all parameters except End systolic volume and fractional shortening, p values were less than 0.05 which is significant. 85% (30/35) had increase in interventricular septal dimensions (IVSD), 97%(34/35) had increase in posterior wall dimensions (PWD), 82%(29/35) had increased left ventricular internal diameter diastole(LVIDD), 88%(31/35) had increased left ventricular internal diameter systole (LVIDS), 80%(28/35) had increased E/A RATIO .Ejection fraction was affected in 77%(27/35).This shows that patients of thalassemia major have significant cardiac dysfunction; possibly because of cardiac iron overload.Conclusions: Echocardiography is an effective tool for screening cardiac iron overload in patients of thalassemia major and should be done periodically in all patients.

Urinary Peptidomic Biomarker for Personalized Prevention and Treatment of Diastolic Left Ventricular Dysfunction.

Diastolic heart failure (DHF) is characterized by slow left ventricular (LV) relaxation, increased LV stiffness, interstitial deposition of collagen, and a modified extracellular matrix proteins. Among Europeans, the frequency of asymptomatic diastolic LV dysfunction (DD) is 25%. This constitutes a large pool of people at high risk of DHF. The goal of this review was to describe the discovery and the initial validation of new multidimensional urinary peptidomic biomarkers (UPB) indicative of DD, mainly consisting of collagen fragments, and to describe a roadmap for their introduction into clinical practice. The availability of new drugs creates a window of opportunity for mounting a randomized clinical trial consolidating the clinical applicability of UPB to screen for DD. If successfully completed, such trial will benefit ≈25% of all people older than 50 years and open a large market for a UPB diagnostic tool and the drug tested. Moreover, sequenced peptides making up UPB will generate novel insights in the pathophysiology of DD and facilitate personalized treatment of patients with DHF for whom prevention came too late. If proven cost‐effective, the clinical application of UPB will contribute to the sustainability of health care in aging population in epidemiologic transition.

Unmasking of oestrogen-dependent changes in left ventricular structure and function in aged female rats: a potential model for pre-heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is seen more frequently in older women; risk factors include age, hypertension and excess weight. No female animal models of early stage remodelling (pre-HFpEF) have examined the effects that the convergence of such factors have on cardiac structure and function. In this study, we demonstrate that ageing can lead to the development of mild chamber remodelling, diffuse fibrosis and loss of diastolic function. The loss of oestrogens further aggravates such changes by leading to a notable drop in cardiac output (while preserving normal ejection fraction) in the presence of diffuse fibrosis that is more predominant in endocardium and is accompanied by papillary fibrosis. Excess weight did not markedly aggravate such findings. This animal model recapitulates many of the features recognized in older, female HFpEF patients and thus, may serve to examine the effects of candidate therapeutic agents. Two-thirds of patients with heart failure with preserved ejection fraction (HFpEF) are older women, and risk factors include hypertension and excess weight/obesity. Pathophysiological factors that drive early disease development (before heart failure ensues) remain obscure and female animal models are lacking. The study evaluated the intersecting roles of ageing, oestrogen depletion and excess weight on altering cardiac structure/function. Female, 18-month-old, Fischer F344 rats were divided into an aged group, aged + ovariectomy (OVX) and aged + ovariectomy + 10% fructose (OVF) in drinking water (n=8-16/group) to induce weight gain. Left ventricular (LV) structure/function was monitored by echocardiography. At 22months of age, animals were anaesthetized and catheter-based haemodynamics evaluated, followed by histological measures of chamber morphometry and collagen density. All aged animals developed hypertension. OVF animals increased body weight. Echocardiography only detected mild chamber remodelling with ageing while intraventricular pressure-volume loop analysis showed significant (P<0.05) decreases vs. ageing in stroke volume (13% OVX and 15% for OVF), stroke work (34% and 52%) and cardiac output (29% and 27%), and increases in relaxation time (10% OVX) with preserved ejection fraction. Histology indicated papillary and interstitial fibrosis with ageing, which was higher in the endocardium of OVX and OVF groups. With ageing, ovariectomy leads to the loss of diastolic and global LV function while preserving ejection fraction. This model recapitulates many cardiovascular features present in HFpEF patients and may help understand the roles that ageing and oestrogen depletion play in early (pre-HFpEF) disease development.