Preclinical Diastolic Dysfunction Research Articles

The role of polycystic ovary syndrome in preclinical left ventricular diastolic dysfunction: an echocardiographic approach: a systematic review and meta-analysis.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of childbearing age, causing hormonal imbalances, reproductive issues, and metabolic disturbances. Women with PCOS have an increased risk of cardiovascular disease due to insulin resistance, obesity, and hyperandrogenism. Detecting impaired left ventricular (LV) function is important in managing this condition. Echocardiography, a non-invasive imaging technique, can effectively detect LV dysfunction. The goal of this systematic review was to assess whether there are any variations in echocardiographic measures between women with PCOS and those without the condition in order to determine the potential impact of PCOS on LV function. This review followed the PRISMA reporting guidelines. A thorough search of databases including PubMed, Scopus, Web of Science, and Cochrane was conducted. The quality of the selected studies was assessed using the Joanna Briggs Institute appraisal instruments. After applying strict eligibility criteria, data were extracted and organized in Microsoft Excel sheets. Review Manager (RevMan) software was used for the analysis. Analysis of 29 studies revealed significant differences in echocardiographic measures related to diastolic function between women with PCOS and healthy controls. However, there were no significant differences in measures of systolic function. These findings indicate that PCOS may be linked to impaired LV function, thereby increasing the risk of cardiovascular disease. Further research is necessary to better understand this association and its clinical implications. Early detection and management of PCOS could potentially help prevent cardiovascular complications in affected women.

Impact of body mass index on worsening of diastolic function and impairment of left atrial strain in the general female urban population: a subanalysis of the Berlin female risk evaluation echocardiography follow-up study.

The association of body mass index (BMI) with diastolic dysfunction (DD) is well described in the literature. However, there is conflicting evidence and long-term follow-up data regarding effects of BMI on preclinical DD and left atrial (LA) function are scarce, highlighting the importance of early detection tools, such as myocardial strain. The aim of our study was to prospectively analyze the impact of clinical and demographic parameters, especially of BMI, on worsening of diastolic function and left atrial strain (LAS) in an urban population of women with a low prevalence of cardiovascular risk factors. An extensive clinical and echocardiographic assessment comprising the analysis of phasic LAS using two-dimensional speckle-tracking echocardiography (2D STE) was performed in 258 participants of the Berlin Female Risk Evaluation (BEFRI) trial between October 2019 and December 2020 after a mean follow-up period of 6.8 years. We compared clinical and echocardiographic parameters stratifying women by BMI < or ≥25 kg/m2, and we analyzed the impact of demographic characteristics on the worsening of DD and LA mechanics in the longer-term follow-up using univariate and multivariate regression analyses. 248 women were suitable for echocardiographic analysis of LAS using 2D STE. After a mean follow-up time of 6.8 years, LA reservoir strain (LASr) and LA conduit strain (LAScd) were significantly reduced in participants with a BMI ≥25 kg/m2 compared with women with a BMI <25 kg/m2 at baseline (30 ± 8% vs. 38 ± 9%, p < 0.0001; -14 ± 7% vs. -22 ± 8%, p < 0.0001). 28% of the overweighted women presented a deterioration of diastolic function at the time of follow-up in contrast with only 7% of the group with a BMI <25 kg/m2 (p < 0.0001). BMI remained significantly associated with LAS reductions after adjustment for other risk factors in multivariate regression analyses. Overweight and obesity are related to impaired LAS and to a worsening of diastolic function after a long-term follow-up in a cohort of randomly selected women.

Right ventricular and right atrial free wall deformation predicitive value in transformation of preclinical diastolic disfunction to heart failure with preserved ejection fraction.

Aim To study echocardiographic parameters of heart chamber strain in patients with left ventricular (LV) preclinical diastolic dysfunction (PDD) for determining predictors of the PDD transition to heart failure with preserved LV ejection fraction (HFpEF).Material and methods The study included 113 patients (including 69 women) with metabolic syndrome and LV PDD (mean age, 65±7 years). The control group consisted of 40 healthy individuals (mean age, 63.0±6.0 years, including 59% women). Metabolic syndrome was diagnosed in consistency with criteria of NCEP-ATP III 2001. PDD was diagnosed based on the absence of heart failure symptoms, normal level of brain natriuretic peptide, and the presence of at least three of the following echocardiographic criteria at rest or after diastolic stress-echocardiography (stress-echoCG): left atrial volume index (LAVI) &gt;34 ml / m2; the ratio of peak early transmitral filling velocity (E) to average lateral and medial mitral annular velocity (e'), Е / е' &gt;14, е' &lt;8.5, and peak tricuspid regurgitation velocity &gt;2.8 m /s. EchoCG that determined LV longitudinal strain (LS), right ventricular (RV) LS, right atrial (RA) LS, and left atrial (LA) LS was performed every year during the 3-year follow-up.Results During the follow-up period, 31 patients developed HFpEF. 19 of them reported symptoms while in the other 12 patients, HFpEF was detected by diastolic stress-echoCG. Patients with HFpEF had significantly lower absolute values of RV LS, LA LS, and RA LS (-27.8±2.9 in the PDD group vs. -23.8±3.2 in the HFpEF group; р&lt;0.03; 38.2±9.1 vs. 28.6±10.2; р&lt;0.03; and 46.2±10.4 vs. 31.6±8.3; р&lt;0.03, respectively). RV LS and RA LS were the strongest independent predictors for PDD transformation into HFpEF (odds ratio, OR, 2.7; 95 % confidence interval, CI, 1.48-2.91; р&lt;0.001 and OR 2.6; 95 % CI: 1.40-2.75; р&lt;0.001, respectively).Conclusion PDD is not a separate clinical nosology but rather an initial stage in the pathogenesis of HFpEF. Approximately ⅓ of PDD patients develop HFpEF. RV LS and RA LS are considered predictors of HFpEF. The duration of PDD is apparently an important factor that provides the development of HFpEF.

The Cardiorenal Effects of Chronic Phosphodiesterase-V Inhibition in Preclinical Diastolic Dysfunction (Stage B Heart Failure)

ObjectiveTo determine whether chronic phosphodiesterase-V (PDEV) inhibition with tadalafil will improve urinary sodium excretion, glomerular filtration rate (GFR), plasma cyclic guanosine 3’, 5’-monophosphate (cGMP), and urinary cGMP excretion in response to volume expansion (VE) in patients with preclinical diastolic dysfunction (PDD) or stage B heart failure. BackgroundPDD is defined as abnormal diastolic function with normal systolic function, without clinical heart failure. PDD is predictive of development of heart failure and all-cause mortality. Impaired renal function and attenuated cGMP response to VE are hallmarks of PDD. MethodsA double-blind, placebo-controlled, proof-of-concept study was conducted to compare 12 weeks of tadalafil 20 mg daily (n = 14) vs placebo (n = 7). Subjects underwent 2 study visits 12 weeks apart. Renal, neurohormonal and echocardiographic assessments were performed before and after intravascular VE (normal saline 0.25 mL/kg/min for 1 hour). ResultsBaseline characteristics were similar. There was no increase in GFR, plasma cGMP or urinary cGMP excretion in response to VE in either group at visit 1. At visit 2, tadalafil did not result in significant change in GFR but increased plasma cGMP and urinary cGMP excretion at baseline. In response to VE, tadalafil resulted in increased urine flow, urinary sodium excretion, GFR (7.00 [-1.0, 26.3] vs -9.00 [-24.5, 2.0] mL/min/1.73m2; P = 0.02) and plasma cGMP (0.50 [-0.1, 0.7] vs -0.25 [-0.6, -0.1] pmol/mL; P = 0.02). It did not improve urinary cGMP excretion after VE. ConclusionIn PDD, chronic PDEV inhibition with tadalafil improved renal response to VE through increased urine flow, urinary sodium excretion, GFR, and plasma cGMP. Further studies are required to determine whether this enhanced renal response can mitigate progression to clinical heart failure.

Inactive Matrix Gla Protein in Relation to Renal and Cardiac Functions and Cardiac Valvular Calcification Among Type 2 Diabetes Patients.

Matrix Gla protein (MGP) is a robust innate suppressor of the detrimental process of vascular calcification in the human body. The interrelationship between circulating MGP levels and renal and cardiac dysfunction, besides echocardiographic calcification score (ECS) was investigated in a sample of type 2 diabetes (T2D) patients. The study included 130 subjects. They were 95 patients with T2D and 35 age- and sex-matched healthy controls. Patients were further subdivided into 52 T2D patients without DKD (eGFR ⩾ 60 ml/minute/1.73 m²) and 43 T2D persons with DKD (eGFR > 60 ml/minute/1.73 m²). Serum MGP levels, determined by ELISA, renal function tests, lipid profile, and echocardiography were studied in all participants. Significantly elevated circulating inactive MGP level was noted in individuals having T2D compared to controls. It correlated negatively with eGFR and left ventricular (LV) diastolic and systolic functions and positively with indices of LV hypertrophy. ECS was significantly increased in both T2D groups compared to controls and in DKD group compared to the diabetic group without DKD. A significant positive correlation was observed between inactive MGP and ECS. Serum inactive MGP may contribute to the development of DKD and to the associated process of cardiac valvular calcification. It may be a beneficial diagnostic marker for early prediction of cardiac calcification and preclinical LV systolic and diastolic dysfunction in T2D patients, especially in those complicated with DKD.

Diastolic Dysfunction in Asymptomatic Type 2 Diabetic Patients Having Preserved Systolic Function

Objective: To determine frequency of diastolic dysfunction in asymptomatic type 2 diabetic patients by employing twodimensional (2D) echocardiography as a measurement method.&#x0D; Study Design: It was an Analytical Cross sectional study.&#x0D; Place and Duration of Study: Rawalpindi Institute of Cardiology, Rawalpindi Pakistan, from Jul 2021 to Nov 2021&#x0D; Methodology: Patients, already diagnosed as diabetics for more than 5 years and on dietary control or on medications,presenting to the outpatient department of the hospital were enrolled. They were subjected to a 2D echocardiography in left lateral position. We excluded patients with valvular heart disease, ischemia, congestive heart failure, cardiomyopathy of any aetiology, renal failure, pulmonary illness, anemia, hemoglobinopathies, prior myocardial infarctions in any region, smokers,and hypertension. Diastolic dysfunction was evaluated as per the guidelines of American society of Echocardiography.&#x0D; Results: Overall (n=150) patients were calculated with reference to 11% prevalence of LVDD by sample size calculator, being the part of study who were fulfilling the inclusion criteria. There were 102(68.0%) male and 48(32.0%) female patients; mean age was 45.02±6.07 years. Mean duration of diabetes mellitus in years was 6.93±2.53 with ranges from 5 to 16 years. Patients on oral hypoglycemic were 121(80.7%), on insulin were 5(3.3%), on dietary control were 12(8%) and on mixed treatment were 12(8%). There were 58 (38.7%) patients who had diastolic dysfunction present on echocardiogram. Effect modifiers of durationof diabetes (p=0.2) did not show significant association; however, Age (p=0.001) and Gender (p=0.038) significantly associated with Diastolic Dysfunction.&#x0D; Conclusions: One of the simple and noninvasive approaches to diagnose diastolic dysfunction is doing 2D echocardiography which can identify large percentage of diabetic subjects having pre-clinical diastolic dysfunction. Thus, by on time detection we can initiate treatment and retard the progression of diastolic dysfunction.

Association of Glycosylated Haemoglobin (HbA1c) Level With Left Ventricular Diastolic Dysfunction in Patients With Type 2 Diabetes.

Background Some literature has shown a high prevalence of pre-clinical diastolic dysfunction in subjects with type 2 diabetes mellitus. The current study was carried out to determine the association of glycosylated hemoglobin (HbA1c) levels with left ventricular diastolic dysfunction (LVDD) in patients with type 2 diabetes. Methods An observational cross-sectional study was conducted in a tertiary health care center in Jharkhand.A total of 100 subjects diagnosed with type 2 diabetes mellitus who gave informed consent and fulfilled the inclusion and exclusion criteria were studied in our center from April 2019 to September 2020. Logistic regression was carried out to determine the association of potential variables with outcomes. Multivariable logistic regression analysis was conducted to determine the independent effects of variables for LVDD prediction. Results The mean HbA1c of the population with LVDD was found to be higher (11.07 ± 3.66%) as compared to the population with normal LVDD (9.11 ± 2.95%), which was found statistically significant (probability value (P) =0.004). This signifies that a higher level of HbA1c in a patient with diabetes will have a higher incidence of LVDD. On applying multivariate analysis to determine the independent effect of variables for LVDD, HbA1C was found to be significant with an odds ratio (OR) of 1.26, 95% CI 1.08-1.48. The duration of diabetes was also found to be significant with OR 1.48 and CI 95 % (1.20-1.82) P <0.001. On plotting the receiver operating characteristic curve (ROC), the area under the ROC curve to predict the left ventricular function with the model was 0.8137. Conclusions Patients who have higher HbA1C are linked to a higher risk of left ventricular diastolic dysfunction in patients with type 2 diabetes. The combination of diabetes and left ventricular dysfunction can lead to increase morbidity and mortality in those patients in whom it is not identified timely and appropriate measures are not taken.Our work emphasizes the requirement of screening intermittently symptomless diabetic patients for diastolic dysfunction through a Doppler echocardiography so that timely action can be taken.

Incidence of Preclinical Heart Failure in a Community Population.

BackgroundA high prevalence of preclinical heart failure (HF) (Stages A and B) has previously been shown. The aim of this study was to explore factors associated with the incidence of preclinical HF in a community population.Methods and ResultsRetrospective review of 393 healthy community individuals aged ≥45 years from the Olmsted County Heart Function Study that returned for 2 visits, 4 years apart. At visit 2, individuals that remained normal were compared with those that developed preclinical HF. By the second visit, 191 (49%) developed preclinical HF (12.1 cases per 100 person‐years of follow‐up); 65 (34%) Stage A and 126 (66%) Stage B. Those that developed preclinical HF (n=191) were older (P=0.004), had a higher body mass index (P<0.001), and increased left ventricular mass index (P=0.006). When evaluated separately, increased body mass index was seen with development of Stage A (P<0.001) or Stage B (P=0.009). Echocardiographic markers of diastolic function were statistically different in those that developed Stage A [higher E/e’ (P<0.001), lower e’ (P<0.001)] and Stage B [higher left atrial volume index (P<0.001), higher E/e’ (P<0.001), lower e’ (P<0.001)]. NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) was higher at visit 2 in those that developed Stage A or B (P<0.001 for both). Hypertension (57%), obesity (34%), and hyperlipidemia (25%) were common in the development of Stage A. Of patients who developed Stage B, 71% (n=84) had moderate or severe diastolic dysfunction.ConclusionsThere is a high incidence of preclinical HF in a community population. Development of Stage A was driven by hypertension and obesity, while preclinical diastolic dysfunction was seen commonly in those that developed Stage B.

Effects of phosphodiesterase V inhibition alone and in combination with BNP on cardiovascular and renal response to volume load in human preclinical diastolic dysfunction.

Preclinical diastolic dysfunction (PDD) results in impaired cardiorenal response to volume load (VL) which may contribute to the progression to clinical heart failure with preserved ejection fraction (HFpEF). The objective was to evaluate if phosphodiesterase V inhibition (PDEVI) alone or combination PDEVI plus B‐type natriuretic peptide (BNP) administration will correct the impaired cardiorenal response to VL in PDD. A randomized double‐blinded placebo‐controlled cross‐over study was conducted in 20 subjects with PDD, defined as left ventricular ejection fraction (LVEF) >50% with moderate or severe diastolic dysfunction by Doppler echocardiography and without HF diagnosis or symptoms. Effects of PDEVI with oral tadalafil alone and tadalafil plus subcutaneous (SC) BNP, administered prior to acute volume loading, were assessed. Tadalafil alone did not result in improvement in cardiac response to VL, as measured by LVEF, LV end diastolic volume, left atrial volume (LAV), or right ventricular systolic pressure (RVSP). Tadalafil plus SC BNP resulted in improved cardiac response to VL, with increased LVEF (4.1 vs. 1.8%, p = 0.08) and heart rate (4.3 vs. 1.6 bpm, p = 0.08), and reductions in both LAV (−4.3 ± 10.4 vs. 2.8 ± 6.6 ml, p = 0.03) and RVSP (−4.0 ± 3.0 vs. 2.1 ± 6.0 mmHg, p < 0.01) versus tadalafil alone. Plasma and urinary cyclic guanosine monophosphate (cGMP) excretion levels were higher (11.3 ± 12.3 vs. 1.7 ± 3.8 pmol/ml, 1851.0 ± 1386.4 vs. 173.4 ± 517.9 pmol/min, p < 0.01) with tadalafil plus SC BNP versus tadalafil alone. There was no improvement in renal response as measured by GFR, renal plasma flow, sodium excretion, and urine flow with tadalafil plus SC BNP compared to tadalafil alone. In subjects with PDD, tadalafil alone resulted in no improvement in cardiac adaptation, while tadalafil and SC BNP resulted in enhanced cardiac adaptation to VL.Trial RegistrationClinicalTrials.gov NCT01544998.

Possibilities of speckle-tracking echocardiography in diagnostic of diastolic dysfunction at the preclinical stage in obese patients

Abstract Funding Acknowledgements Type of funding sources: None. Currently, it is shown that the prevalence of diastolic dysfunction is extremely high. However, with the help of traditional echocardiography (ECG) indicators, it is not possible to detect diastolic dysfunction at the preclinical stage. Therefore, it is important to search for new non-invasive methods for the diagnostic of myocardial fibrosis, as an equivalent of diastolic dysfunction, at an early stage to prevent progression in HF. Objective to study the relationship of left ventricular (LV) mechanics with the level of serum markers of myocardial fibrosis in patients with epicardial obesity (EO). Materials and methods The study included 110 men with general obesity. According to the results of echocardiography (ECG), patients were divided into 2 groups: EO (+) with epicardial fat thickness (tEAT) ≥7 mm (n = 70); EO (-) with tEAT &amp;lt; 7 mm (n = 40) without diastolic dysfunction according to the results of ECG. Profibrotic markers in blood serum (MMP-3, collagen I, collagen III, TGF – β, VEGFA, PICP) were determined in all patients using enzyme immunoassay. Using speckle-tracking echocardiography, the mechanics of LV were studied (twist LV, peak twist ratio LV, time to peak twist of LV, peak untwist ratio LV, time to peak untwist of LV). The exclusion criteria were the presence of coronary pathology, arterial hypertension, and type 2 diabetes mellitus. Results In the group of patients with EO ( + ) statistically significant increase the level of all studied profibrotic markers was revealed. According to the results of speckle-tracking ECG in the EO (+) group an increase peak untwist ratio LV to -128.31 (-142.0; -118.0) deg/s-1 (p = 0.002) and an increase time to peak untwist of LV of 476.44 (510.0; 411.0) msec was determined in comparison with the EO ( - ) group (p = 0.03). A weak statistically significant effect of tEAT on the peak untwist ratio LV in EO (+) group was revealed (r = 0.24; p = 0.04). In addition, there was a significant relationship between peak untwist ratio LV and markers of myocardial fibrosis MMP-3 (r = 0,21; p = 0.04) and collagen type III (r = 0,26; p = 0.03). Conclusion Given the presence of increasing serum levels of profibrotic factors, we can assume that in patients with EO, there is preclinical diastolic dysfunction LV, identification of which is possible with the help of determining peak untwist ratio LV, time to peak untwist of LV.

Early Passive Leg Movement Prevents Against the Development of Heart Failure With Preserved Ejection Fraction in Rats.

Exercising was reported by several studies to bring great benefits to heart failure with preserved ejection fraction (HFpEF), which reduced the hospitalization and the mortality of heart failure. However, the underlying mechanism of exercising on HFpEF remains unclear. In the present study, we designed and constructed a device that can perform early passive leg movement (ePLM) in rats and further observed whether treatment of ePLM exerts protective effects on HFpEF of rats. Rats were fed with high salt feed to establish an animal model of pre-clinical diastolic dysfunction (PDD), which would eventually develop into HFpEF, and then treated rats with ePLM. We conducted several experiments to evaluate the conditions of heart and blood vessel. The results show that diastolic functions of heart and blood vessel in rats were significantly improved by treatment of ePLM. We also found that pathological injuries of heart and blood vessel were ameliorated after treatment of ePLM. Moreover, treatment of ePLM decreased the protein levels of Collagen type I, Collagen type III, MMP2, and MMP9 in heart and blood vessel, indicating that cardiac and vascular fibrosis were reduced apparently by treatment of ePLM. Further investigation suggested that treatment of ePLM probably inhibit the activation of TGF-β1/Smad3 signaling pathway as well as promote the activation of Akt/eNOS signaling pathway in high salt diet induced HFpEF. In conclusion, treatment of ePLM alleviated high salt diet induced HFpEF by inhibiting fibrosis via suppressing TGF-β1/Smad3 signaling pathway as well as activating Akt/eNOS signaling pathway, implicating treatment of ePLM as a promising novel non-pharmacological approach for HFpEF.

Early diagnosis of myocardial fibrosis in patients with epicardial obesity

It has been proven that about half of patients with heart failure (HF) have a preserved the left ventricle (LV) ejection fraction (EF), which complicates early detection of HF. Currently, there is a search for non-invasive methods for diagnosing myocardial fibrosis at the preclinical heart failure to prevent its progression and the appearance of clinical symptoms.Aim. To study the relationship of LV mechanics with the level of serum myocardial fibrosis markers in patients with epicardial obesity (EO).Material and methods. The study included 110 men with general obesity. Depending on echocardiographic data, the patients were divided into 2 groups: EO (+) with epicardial fat thickness (EFT) ≥7 mm (n=70); EO (-) with EFT &lt;7 mm (n=40). All patients were studied for serum profibrotic markers (MMP-3, collagen I, collagen III, TGF-β, VEGFA, PICP) using enzyme-linked immunosorbent assay. Speckle-tracking echocardiography was used to study LV mechanics (LV twisting, LV twisting rate, time to peak twist, LV untwisting rate, time to peak untwist). The exclusion criteria were the presence of coronary artery disease, hypertension, type 2 diabetes.Results. In the group of patients with EO (+), a significant increase in the level of all studied profibrotic markers was revealed. According to the results of speckletracking echocardiography in the EO (+) group, an increase in the LV untwisting rate to -128,31 (-142,0; -118,0) deg/s-1 (p=0,002) and an increase in the time to peak untwist to 476,44 (510,0; 411,0) ms compared to the EO (-) group (p=0,03). A weak significant effect of EFT on LV untwisting rate was revealed in the EO (+) group (r=0,24; p=0,04). In addition, a significant relationship was found between the LV untwisting rate and markers of myocardial fibrosis: MMP-3 (r=0,21; p=0,04) and type III collagen (r=0,26; p=0,03).Conclusion. Thus, the obtained data suggest that patients with EO have signs of preclinical LV diastolic dysfunction, which are characterized by an increase in LV untwisting rate and level of serum profibrotic factors.

Metformin in non-diabetic patients with metabolic syndrome and diastolic dysfunction: the MET-DIME randomized trial.

Metabolic syndrome (MetS) affects one out of 3 adults in the western world and is associated with preclinical diastolic dysfunction that impairs functional capacity and quality of life (QoL). This randomized trial was designed to evaluate if the addition of metformin to the standard treatment of non-diabetic patients with MetS improves diastolic dysfunction. Prospective, randomized, open-label, blinded-endpoint trial. Fifty-four non-diabetic adults with MetS and diastolic dysfunction were randomized to lifestyle counseling or lifestyle counseling plus metformin (target dose 1000 mg bid). The primary endpoint was the change in mean e' velocity (assessed at baseline, 6, 12 and 24 months). Secondary endpoints were improvements in insulin resistance, functional capacity and QoL. Linear mixed effects modeling was used for longitudinal data analysis using modified intention-to-treat (mITT) and per-protocol (PP) approaches. Forty-nine patients were included in the mITT analysis (mean age = 51.8 ± 6.4; 55% males). Metformin treatment was associated with a significant decrease in HOMA-IR. There was a significantly different mean change in e' velocity during the study period between trial arms, both in the mITT (at 24 months, change of +0.67 ± 1.90 cm/s in metformin arm vs. -0.33 ± 1.50 cm/s in control arm) and PP populations (+0.80 ± 1.99 cm/s in metformin arm vs. -0.37 ± 1.52 cm/s in control arm), using a random intercept linear mixed model. There were no significant differences in peak oxygen uptake and SF-36 scores between trial arms. Treatment with metformin of non-diabetic MetS patients with diastolic dysfunction, on top of lifestyle counseling, is associated with improved diastolic function.

Metformin in non-diabetic patients with metabolic syndrome and diastolic dysfunction: the MET-DIME randomized trial

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Merck Background Metabolic syndrome (MetS) affects one out of 3 adults in the western world and is associated with preclinical diastolic dysfunction that impairs functional capacity and quality of life (QoL). Purpose This randomized trial was designed to evaluate if the addition of metformin to the standard treatment of non-diabetic patients with MetS improves diastolic dysfunction. Methods Prospective, randomized, open-label, blinded-endpoint trial. Fifty-four non-diabetic adults with MetS and diastolic dysfunction were randomized to lifestyle counseling or lifestyle counseling plus metformin (target dose 1000 mg bid). The primary endpoint was the change in mean e’ velocity (assessed at baseline, 6, 12 and 24 months). Secondary endpoints were improvements in insulin resistance, functional capacity and QoL. Linear mixed effects modelling was used for longitudinal data analysis using modified intention-to-treat (mITT) and per-protocol (PP) approaches. Results Forty-nine patients were included in the mITT analysis (mean age = 51.8 ± 6.4; 55% males). Metformin treatment was associated with a significant decrease in HOMA-IR. There was a significantly different mean change in e’ velocity during the study period between trial arms, both in the mITT (at 24 months, change of +0.67 ± 1.90cm/s in metformin arm vs. -0.33 ± 1.50cm/s in control arm) and PP populations (+0.80 ± 1.99cm/s in metformin arm vs. -0.37 ± 1.52cm/s in control arm), using a random intercept linear mixed model. There were no significant differences in peak oxygen uptake and SF-36 scores between trial arms. Conclusion Treatment with metformin of non-diabetic MetS patients with diastolic dysfunction, on top of lifestyle counseling, is associated with improved diastolic function. Abstract Figure.

Relationships between kidney dysfunction and left ventricular diastolic dysfunction: a hospital-based retrospective study.

Preclinical left ventricular diastolic dysfunction (LVDD) is a high-risk state for heart failure. Kidney dysfunction is a known risk factor for heart failure, but its association with asymptomatic LVDD is not well-known. A hospital-based retrospective cohort study was conducted on patients who underwent echocardiogram between 2006 and 2016 to assess the association between baseline kidney function and LVDD on echocardiogram. E/e' ratio was defined as the ratio of peak velocity of early diastolic left ventricular inflow (E) to mitral annular velocity (e'). The primary outcome was time to development of LVDD, which was defined as E/e' ratio > 14. The changes in the E/e' ratio and other echocardiographic parameters were assessed using a mixed effects model. Among 1167 patients, the mean age was 61 years, and the mean baseline E/e' ratio and ejection fraction were 9.6 and 69%, respectively. During a median follow-up of 3.2 years, 231 (19.8%) people developed LVDD. According to eGFR (mL/min/1.73m2), the risk for LVDD based on hazard ratio [95% confidence interval (95% CI)] was 1.20 (0.82, 1.75) for 60 to < 90, 1.42 (0.87, 2.31) for 45 to < 60, and 2.57 (1.61, 4.09) for < 45 (P trend < 0.001). The adjusted risks (95% CI) for annual change in E/e' ratio was 0.09 (0.03, 0.14) overall and 0.28 (0.11, 0.45) in the lowest eGFR group; the trend in changes in annual E/e' ratio by baseline eGFR was significant (P trend = 0.01). Relatively low kidney function was related with the risks for LVDD. Long-term cohort studies are warranted to confirm the association between LVDD and symptomatic heart failure in patients with kidney dysfunction.

Global constructive work and left atrial reservoir function is reduced in patients with heart failure with preserved ejection fraction compared with patients with preclinical diastolic dysfunction

Abstract Heart failure with preserved ejection fraction (HFpEF) remains an unresolved issue with morbidity and mortality comparable with that of reduced EF HF. Diastolic dysfunction (DD) is the hallmark of HFpEF but it is unclear why some patients do not develop symptoms and remain in preclinical DD (PDD) stage with the same degree of DD as patients with HFpEF. We assumed that patients with HFpEF might have more deteriorated global myocardial work (GW) and left atrial reservoir longitudinal strain (LALS) parameters compared with PDD patients. Methods 210 patients (150 female, mean age 71±5 years) of which 118 with PDD and 92 with HFpEF were enrolled in this study. PDD was diagnosed if patients had normal NT-proBNP values, and at least 3 of the following echocardiographic criteria at rest or after diastolic stress echocardiography: end-systolic left atrial volume index (LAVi) &amp;gt;34 ml/m2, LV E/e' &amp;gt;13, average LV e' &amp;gt;8.5, and systolic pulmonary artery pressure &amp;gt;30 mmHg. GW index (GWI) was obtained from pressure-strain loops composed from speckle tracking analysis indexed to brachial systolic blood pressure, global constructive work (GCW) was measured as the sum of positive work due to myocardial shortening during systole and negative work due to lengthening during isovolumic relaxation, global wasted work (GWW) was calculated as energy loss by myocardial lengthening in systole and shortening in isovolumic relaxation, and GW efficiency (GWE) as the percentage ratio of constructive work to the sum of constructive work and wasted work. LALS was measured by speckle tracking echocardiography as average value of two basal segments in apical 4 chamber view along LAVi and 4D LV mass index (LVMi) offline by experienced echocardiographer who was unaware of the study aims. Results Patients with PDD and HFpEF have comparable values of LAVi, LVMi, GWI, GWW, and GWE (LAVi 38.4±3.9 ml/m2 vs 39.1±4.1 ml/m2, p=NS; LVMi 82.8±11.4 g/m2 vs 83.5±10.2 g/m2, p=NS; PDD GWI 2389±154 mmHg% vs 2368±139 mmHg%, p=NS; GWW 62±5 mmHg% vs 65±4 mmHg%, p=NS; GWE PDD 89±9% vs 87±11%, p=NS). LALS and GCW were significantly reduced in patients with HFpEF compared with PDD patients (LALS 21.3±7% vs 29±5%, p&amp;lt;0.01; GCW 1964±112 mmHg% vs 2259±164 mmHg%, p&amp;lt;0.01). Conclusion Patients with HFpEF have reduced LALS and GCW compared with PDD patients. Both parameters are indicative for LA and LV myocardial fibrotic burden respectively which might be one of the probable explanations of PDD transition to HFpEF. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Committee of Science at Ministry of Education of Republic of Armenia

Leg raise can detect exercise-induced pulmonary arterial wedge pressure elevation

Abstract Background Exercise-induced elevation of pulmonary arterial wedge pressure (PAWP) may show preclinical or exercise-induced left ventricular diastolic dysfunction. Invasive hemodynamic assessment during provocative maneuvers, like exercise and volume challenge, in these patients allows greater sensitivity to diagnose or exclude HFpEF. The aim of this study was to examine how the leg raise, which is a simple way to increase preload, can detect exercise-induced PAWP elevation. Methods Four hundred seventy-nine patients (60±14y.o, mean pulmonary arterial pressure (PAP) 19mmHg, PAWP 8mmHg, CTEPH /IPAH/CTD-PH/SOB unknown reason: 357/56/38/28pts) with near-normal PAP and normal PAWP at rest underwent symptom-limited exercise test using supine cycle ergometer with right heart catheter. Exercise-induced elevation in PAWP of over 20mmHg was defined as exercise-induced elevation group. Results ΔPAWP (after leg raise - rest) in the exercise-induced elevation group was significantly higher (6.0±4.1 vs. 2.7±3.9mmHg, p&amp;lt;0.001, in the older (age≥60y.o) group (n=276); 3.4±3.5 vs. 1.9±3.4mmHg, p&amp;lt;0.001, in the younger (age&amp;lt;60y.o) group (n=203)) than that in the non-elevation group after legs raise for cycle ergometer exercise. The area under the ROC curve for ΔPAWP was 0.72 (95% CI: 0.65–0.78) in the older and 0.64 (95% CI: 0.53–0.75) in the younger. In the older, the cut-off value for detect exercise-induced PAWP elevation of ΔPAWP was 4mmHg, with 72% sensitivity and 58% specificity. On the other hand, in the younger, the cut-off value was 3mmHg, with 69% sensitivity and 59% specificity. Conclusion Leg raise can easily detect occult left ventricular diastolic dysfunction. Funding Acknowledgement Type of funding source: None

Cardiac mechanics in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical entity associated with significant morbidity and mortality. Common comorbidities including hypertension, coronary artery disease, diabetes, chronic kidney disease, obesity, and increasing age predispose to preclinical diastolic dysfunction that often progresses to frank HFpEF. Clinical HFpEF is typically associated with some degree of diastolic dysfunction, but can occur in the absence of many conventional diastolic dysfunction indices. The exact biologic links between risk factors, structural changes, and clinical manifestations are not clearly apparent. Innovative approaches including deformation imaging have enabled deeper understanding of HFpEF cardiac mechanics beyond conventional metrics. Furthermore, predictive analytics through data-driven platforms have allowed for a deeper understanding of HFpEF phenotypes. This review focuses on the changes in cardiac mechanics that occur through preclinical myocardial dysfunction to clinically apparent HFpEF.

Sex-specific pattern of left ventricular hypertrophy and diastolic function in patients with type 2 diabetes mellitus

Few prospective studies have evaluated sex-specific pattern, natural progression of left ventricular (LV) remodelling, and diastolic dysfunction in patients with type 2 diabetes (T2DM). The aim of this study was to study the sex-specific prevalence, longitudinal changes of LV remodelling, and diastolic dysfunction in patients with T2DM. Further, the prognostic value of diastolic function in women and men was also evaluated. A total of 350 patients with T2DM (mean age 61 ± 11 years; women, 48.3%) was recruited. Detailed echocardiography was performed at baseline and after 25 months. A major adverse cardiovascular event (MACE) was defined as cardiovascular death, heart failure hospitalization, or myocardial infarction. Despite a similar age, prevalence of hypertension and body mass index, women had a higher prevalence of LV hypertrophy and diastolic dysfunction at baseline and follow-up compared with men. A total of 21 patients developed MACE (5 cardiovascular death, 9 hospitalization for heart failure, and 7 myocardial infarction) during a median follow-up of 56 months. Women with diastolic dysfunction had a higher incidence of MACE than those with normal diastolic function but this association was neutral in men. Multivariable Cox-regression analysis indicated that diastolic dysfunction was associated with MACE in women [hazard ratio = 6.30; 95% confidence interval (CI) = 1.06-37.54; P < 0.05] but not men (hazard ratio = 2.29, 95% CI = 0.67-7.89; P = 0.19). LV hypertrophy and diastolic dysfunction, both at baseline and follow-up, were more common in women than men. Pre-clinical diastolic dysfunction was independently associated with MACE only in women with T2DM but was neutral in men.

Cell‐based hormone therapy prevents diastolic dysfunction after estrogen loss in the Spontaneously Hypertensive Rat (SHR)

Introduction. Preclinical left ventricular diastolic dysfunction (LVDD) is a forerunner to heart failure with preserved ejection fraction, which is seen more often in older women than men of the same age. While hormone therapy plays an important role in the management of vasomotor and genitourinary symptoms experienced by many women during the menopausal transition, its efficacy with regard to maintenance of cardiac structure and function and prevention of LVDD disease progression with aging has not been tested due to the concern for off‐target health risks (e.g., cancer, blood clots). We developed a cell‐based hormone therapy (cHT) approach that recapitulates native cell–cell interactions between ovarian granulosa and theca cells in a 3D bioengineered construct to mimic the dynamic release of sex hormones into the circulation. Our first report in ovariectomized rats shows that ovarian constructs are able to ameliorate various somatic adverse effects of hormone deficiency (e.g. bone loss). To extend these findings to cardiac health, we sought to determine the efficacy of cHT in preserving cardiac diastolic function after estrogen loss using a hypertensive rodent model.Methods14 SHR females underwent bilateral ovariectomy (OVX) while 5 SHRs received sham surgery at 12 weeks of age; 8 weeks post‐surgery, OVX rats were randomized (n=4–5/group) to vehicle, cHT, or pharmacologic hormone therapy (pHT: E2 (10mg/kg/day) and P4 (2mg/kg/day) subcutaneous pellets) and compared to gonad‐intact rats treated with vehicle (VEH). Body weights and tail cuff systolic blood pressure (SBP) were measured biweekly. Following 10 weeks of treatment, rats were lightly anesthetized (isoflurane) for Doppler measures of diastolic function. Data were analyzed by one‐way ANOVA. P&lt;0.05 was significant.ResultsOVX rats, irrespective of treatment, had higher body weights when compared to sham (P&lt;0.001). Uterine atrophy by OVX was minimized by pHT and cHT, reflecting modest E2‐related effects (Figure A). SBP increased progressively over time (P&lt;0.01), without overt differences across treatment groups. Even so, both cHT and pHT prevented adverse OVX‐related effects on myocardial relaxation (e') and Doppler‐derived filling pressures (E/e') when compared to vehicle (Figures B, C).ConclusionThese data show that novel cell‐based hormone therapy is effective in preventing diastolic dysfunction from surgically‐induced menopause in the SHR. Additional studies are underway to determine cHT’s long‐term (6 months) treatment efficacy in middle‐to‐advanced aged OVX rats.Support or Funding InformationNIH AG061588Figure 1