Changes In Cardiac Parameters Research Articles

Changes in blood metabolomes as potential biomarkers for severity and prognosis in doxorubicin-induced heart failure: a study in HER2-positive and HER2-negative breast cancer patients

Abstract Background The use of doxorubicin for breast cancer treatment is often limited due to cardiotoxicity. Doxorubicin was shown to cause the alterations of cardiac metabolome levels in doxorubicin-treated rats. Interestingly, these changes were robustly associated with the development of doxorubicin-induced heart failure. Unfortunately, measurements of cardiac metabolome levels are rarely possible in humans. Hence, non-invasive biomarkers as representatives of doxorubicin-induced heart failure are required in clinical research and practice. Human epidermal growth factor receptor 2 (HER2) is a point of interest in breast cancer treatment. HER2 is associated with tumor aggressiveness. However, it was observed that HER2 protected against systemic oxidative stress and dilated cardiomyopathy. Therefore, we hypothesized that the alterations of blood metabolome levels and cardiac functions following doxorubicin treatment were different between HER2-positive and HER2-negative breast cancer patients. Purpose We determined the potential roles of changes in blood metabolomes as severity and prognostic markers of doxorubicin-induced heart failure. In addition, the changes in blood metabolomes and cardiac parameters following doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients were compared. Methods HER2-positive (n=37) and HER2-negative (n=37) breast cancer patients were enrolled. Echocardiography, heart rate variability, and blood collection were performed at baseline and 2 weeks after completion of doxorubicin treatment in all patients, as well as at 3 months after completion of doxorubicin treatment in HER2-negative breast cancer patients. Blood obtained at all 3 time points was processed for measuring cardiac injury markers. Blood obtained at baseline and 2 weeks after completion of doxorubicin treatment was also processed for measuring oxidative stress in peripheral blood mononuclear cells using flow cytometry and 85 metabolome levels in plasma using mass spectrometry-based targeted metabolomics. Results Cardiac injury and systolic dysfunction at 2 weeks after completion of doxorubicin treatment were comparable between HER2-positive and HER2-negative breast cancer patients. However, only HER2-negative breast cancer patients exhibited increased systemic oxidative stress and cardiac autonomic dysfunction at this time point. Moreover, 33 and 29 blood metabolomes were altered at 2 weeks after completion of doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients, respectively (Figure). Interestingly, the changes in most of these metabolomes were correlated with the changes in cardiac parameters, both at 2 weeks and 3 months after completion of doxorubicin treatment (Figure). Conclusions The changes in blood metabolomes following doxorubicin treatment were dependent on HER2 status, which might be served as severity and prognostic markers of doxorubicin-induced heart failure.

Changes in blood metabolomes as potential markers for severity and prognosis in doxorubicin-induced cardiotoxicity: a study in HER2-positive and HER2-negative breast cancer patients.

We aimed to compare the changes in blood metabolomes and cardiac parameters following doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients. Additionally, the potential roles of changes in blood metabolomes as severity and prognostic markers of doxorubicin-induced cardiotoxicity were determined. HER2-positive (n = 37) and HER2-negative (n = 37) breast cancer patients were enrolled. Cardiac function assessment and blood collection were performed at baseline and 2weeks after completion of doxorubicin treatment in all patients, as well as at three months after completion of doxorubicin treatment in HER2-negative breast cancer patients. Blood obtained at all three-time points was processed for measuring cardiac injury biomarkers. Blood obtained at baseline and 2weeks after completion of doxorubicin treatment were also processed for measuring systemic oxidative stress and 85 metabolome levels. Cardiac injury and systolic dysfunction 2weeks after completion of doxorubicin treatment were comparable between these two groups of patients. However, only HER2-negative breast cancer patients exhibited increased systemic oxidative stress and cardiac autonomic dysfunction at this time point. Moreover, 33 and 29 blood metabolomes were altered at 2weeks after completion of doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients, respectively. The changes in most of these metabolomes were correlated with the changes in cardiac parameters, both at 2weeks and 3months after completion of doxorubicin treatment. The changes in blood metabolomes following doxorubicin treatment were dependent on HER2 status, and these changes might serve as severity and prognostic markers of doxorubicin-induced cardiotoxicity. The study was conducted under ethical approval from the Institutional Review Board of the Faculty of Medicine, Chiang Mai University (Registration number: MED-2563-07001; Date: April 28, 2020). The study also complied with the Declaration of Helsinki.

Evidence of Bariatric Surgery Benefits Cardiac Function in Non-HFpEF Patients with Obesity: a Meta-Analysis.

Nowadays, increasing clinical evidence on metabolic and weight-loss effects of bariatric surgery on improving cardiac structure in obese patients, but its application in improving the cardiac function of HF (heart failure) patients remains controversial. The objective of this meta-analysis was to assess the effects of BS on cardiac function by quantifying the changes of LVEF (left ventricular ejection fraction) and NYHA (New York Heart Association classification) after operations in non-HFpEF (heart failure and preserved ejection fraction) patients. Articles were searched using PubMed and Embase from inception to December 9, 2022, and the Minors scale was used for quality assessments. The included patients should be non-HFpEF and clinically severely obese, and their pre-operative and post-operative values of LVEF or NYHA should be reported. Nine studies involving 146 patients were eventually included with a final result showing that the cardiac functional parameters were improved in non-HFpEF patients. After a weighted mean follow-up time of 15.8months, the mean NYHA decreased by 0.59 (I2 = 0; 95% CI 0.27 ~ 0.92; p = 0.003), and the mean LVEF increased by 7.49% (I2 = 0; 95% CI - 9.99 ~ - 4.99; p < 0.00001). Bariatric surgery offers beneficial cardiac effects on non-HFpEF patients with obesity but failed to show a significant improvement in the pooled analysis for the changes of cardiac parameters. The improving degree may be related to the baseline BMI, the extent of BMI loss, and the baseline age. Future studies should focus on finding out the influencing factors of effectivenesses and defining the suitable crowd.

Response of cardiac pulse parameters in humans at various inclinations via 360° rotating platform for simulated microgravity perspective

On the Earth, the human body is designed and adapted to function under uniform gravitational acceleration. However, exposure to microgravity or weightlessness as experienced by astronauts in space causes significant alterations in the functioning of the human cardiovascular system. Due to limitations in using real microgravity platforms, researchers opted for various ground-based microgravity analogs including head-down tilt (HDT) at fixed inclination. However, in the present study, an investigation of response of various cardiac parameters and their circulatory adaptation in 18 healthy male subjects was undertaken by using an indigenously developed 360° rotating platform. Cardiac pulse was recorded from 0° to 360° in steps of 30° inclination using piezoelectric pulse sensor (MLT1010) and associated cardiac parameters were analyzed. The results showed significant changes in the pulse shape while an interesting oscillating pattern was observed in associated cardiac parameters when rotated from 0° to 360°. The response of cardiac parameters became normal after returning to supine posture indicating the ability of the cardiovascular system to reversibly adapt to the postural changes. The observed changes in cardiac parameters at an inclination of 270°, in particular, were found to be comparable with spaceflight studies. Based on the obtained results and the proposed extended version of fluid redistribution mechanism, we herewith hypothesize that the rotation of a subject to head down tilt inclination (270°) along with other inclinations could represent a better microgravity analog for understanding the cumulative cardiac response of astronauts in space, particularly for short duration space missions.

Hyperuricaemia Does Not Interfere with Aortopathy in a Murine Model of Marfan Syndrome.

Redox stress is involved in the aortic aneurysm pathogenesis in Marfan syndrome (MFS). We recently reported that allopurinol, a xanthine oxidoreductase inhibitor, blocked aortopathy in a MFS mouse model acting as an antioxidant without altering uric acid (UA) plasma levels. Hyperuricaemia is ambiguously associated with cardiovascular injuries as UA, having antioxidant or pro-oxidant properties depending on the concentration and accumulation site. We aimed to evaluate whether hyperuricaemia causes harm or relief in MFS aortopathy pathogenesis. Two-month-old male wild-type (WT) and MFS mice (Fbn1C1041G/+) were injected intraperitoneally for several weeks with potassium oxonate (PO), an inhibitor of uricase (an enzyme that catabolises UA to allantoin). Plasma UA and allantoin levels were measured via several techniques, aortic root diameter and cardiac parameters by ultrasonography, aortic wall structure by histopathology, and pNRF2 and 3-NT levels by immunofluorescence. PO induced a significant increase in UA in blood plasma both in WT and MFS mice, reaching a peak at three and four months of age but decaying at six months. Hyperuricaemic MFS mice showed no change in the characteristic aortic aneurysm progression or aortic wall disarray evidenced by large elastic laminae ruptures. There were no changes in cardiac parameters or the redox stress-induced nuclear translocation of pNRF2 in the aortic tunica media. Altogether, the results suggest that hyperuricaemia interferes neither with aortopathy nor cardiopathy in MFS mice.

Radiation-Induced Acute Cardiotoxicity in Women with Left Sided Breast Cancer: Results from a Phase II Prospective Clinical Trial

<h3>Purpose/Objective(s)</h3> Women with left sided breast cancer (BC) who receive adjuvant radiotherapy (RT) have increased risk of subsequent cardiac events, which may be mitigated by maintaining mean heart dose (MHD) below a threshold of 3 Gy. We hypothesized that early MRI evaluation of cardiac functional changes can identify acute cardiac insult and predict for the risk of long-term cardiac complications. Here we report the findings of a phase II prospective clinical trial evaluating RT-related LV structure and function using cardiac MRI in women with left sided BC treated with adjuvant RT. <h3>Materials/Methods</h3> Patients with left sided BC were enrolled into a single institutional phase II study. After informed consent, patients were allocated for breast RT with free breathing (FB) or with deep inspiratory breath hold (DIBH) delivery, if the predicted MHD was ≤3 Gy (≤ 5 Gy, if also regional nodal RT) or > 3 Gy (> 5 Gy, if regional nodal RT), respectively, on initial FB planning. Cardiac MRI was performed at baseline (pre-RT), and at 16 and 52 weeks. Cardiac toxicity was defined as change in the indexed LV end diastolic volume (LVEDVi), LV ejection fraction (LVEF), indexed LV end systolic volume (LVESVi) and indexed LV mass (LV MASSi). Estimation of multiple serum cardiac biomarkers were also done at the three time points. Continuous variables were expressed as mean ± standard deviation, and ANOVA analysis was used to identify correlation between changes in cardiac parameters from baseline to 16 and 52 weeks, when compared to cardiac radiation dosimetric data. <h3>Results</h3> Of the 69 participants, 25 received RT with FB technique. 44 received RT with DIBH, of which 23 also had received adjuvant chemotherapy (CT) prior to RT. For the FB, DIBH (no CT), and DIBH (with CT) cohorts, MHD was 1.70 ± 0.93 Gy, 1.93 ± 1.30 Gy, and 2.26 ± 1.15 Gy and mean LV dose was 2.47 ± 1.48 Gy, 3.18 ± 1.93 Gy, and 3.23 ± 1.82 Gy, respectively. Evaluation of LVEDVi, LVEF, LVESVi, and LV MASSi showed no statistical difference between the 3 treatment arms. No statistical correlation was noted between LVEF changes (≥ 5% and ≥ 10% from baseline) and the cardiac dosimetric data; all p values > 0.1. Prior CT did not measurably impact cardiac function. <h3>Conclusion</h3> In this prospective study, no significant post-RT cardiac events were demonstrable by functional imaging. This supports the significance of maintaining MHD ≤ 3 Gy to minimize or prevent RT related cardiac toxicity in women with left sided BC. Our observation warrants further investigation in a large prospective setting to evaluate late cardiac events. Analysis of serum cardiac biomarkers is currently ongoing.

Serial Cardiovascular Magnetic Resonance Studies Prior to and After mRNA-Based COVID-19 Booster Vaccination to Assess Booster-Associated Cardiac Effects.

BackgroundmRNA-based COVID-19 vaccination is associated with rare but sometimes serious cases of acute peri-/myocarditis. It is still not well known whether a 3rd booster-vaccination is also associated with functional and/or structural changes regarding cardiac status. The aim of this study was to assess the possible occurrence of peri-/myocarditis in healthy volunteers and to analyze subclinical changes in functional and/or structural cardiac parameters following a mRNA-based booster-vaccination.Methods and ResultsHealthy volunteers aged 18–50 years (n = 41; m = 23, f = 18) were enrolled for a CMR-based serial screening before and after 3rd booster-vaccination at a single center in Germany. Each study visit comprised a multi-parametric CMR scan, blood analyses with cardiac markers, markers of inflammation and SARS-CoV-2-IgG antibody titers, resting ECGs and a questionnaire regarding clinical symptoms. CMR examinations were performed before (median 3 days) and after (median 6 days) 3rd booster-vaccination. There was no significant change in cardiac parameters, CRP or D-dimer after vaccination, but a significant rise in the SARS-CoV-2-IgG titer (p < 0.001), with a significantly higher increase in females compared to males (p = 0.044). No changes regarding CMR parameters including global native T1- and T2-mapping values of the myocardium were observed. A single case of a vaccination-associated mild pericardial inflammation was detected by T2-weighted CMR images.ConclusionThere were no functional or structural changes in the myocardium after booster-vaccination in our cohort of 41 healthy subjects. However, subclinical pericarditis was observed in one case and could only be depicted by multiparametric CMR.

A Higher Mean Heart Radiation Dose Induces Higher Frequency of Multiple Cardiac Changes

Radiotherapy (RT) induces late changes in all cardiac structures. Most studies of early changes focus on individual parameters. Data from eighty early-stage breast cancer patients at baseline, post-RT and three-year follow-up visit were assessed prospectively. Changes in ten cardiac parameters were collected including electrocardiogram (ECG), echocardiography, and biomarkers. A percentage of abnormal changes was calculated. The mean heart radiation dose (Dmean) was independently associated with the increased incidence of changes post-RT (β=0.403, p<0.001) and at the three-year follow-up (β=0.353, p=0.001). Each 1-Gray increase in Dmean increased the cardiac changes by 3.7% (95%CI=1.9-5.6%) after RT and 3.1% (95%CI=1.3, 4.9%) at the three-year follow-up. A higher cardiac radiation dose was independently associated with a higher incidence of changes in cardiac parameters. Multiparameter changes imply that the early phase after RT is already characterized by several overlapping cardiac changes.

Echocardiographic Changes in Patients with End-Stage Renal Disease at Initiation of Dialysis

Introduction: Echocardiography is a simple and established method of evaluating cardiac functions, assessing left ventricle geometry, and systolic and diastolic functions. Patients with chronic kidney disease have a tremendous burden of cardiovascular disease (CVD), and patients with end-stage renal disease (ESRD) are at a greater risk of CVD and deaths.Materials and Methods: In this study, 245 incident dialysis patients were included, and none of the patient was on erythropoietin. All the patients were aged &gt;18 years. Patients with ESRD, already on maintenance dialysis, were not included in this study. Patient’s data such as demographic details, comorbidities, laboratory values, echocardiographic changes, management, and outcome were recorded.Results: Out of 245 patients, 165 (67.3%) were males and 80 (32.6%) females. The mean age of the patients was 49.7 years. Left ventricular hypertrophy (LVH) was observed in 188 (76.7%), mild left ventricular dysfunction (LVD) in 25.7%, moderate LVD in 23.67%, severe LVD in 8.5%, global hypokinesia in 33.8%, valvular heart disease in 26.5%, regional wall motion abnormality in 4.4%, and pericardial effusion in 1.6% patients. Echocardiographic changes, such as LVD, LVH, and global hypokinesia, were observed in greater number in hypertensive group com-pared to normotensive group (P &lt; 0.05). On regression analysis adjusted for age and gender, we found that hypertension and anemia (&lt;10 g/dL) were associated with LVH. Further, hypertension and anemia (Hb &lt; 10 g/dL) were associated with LVD. Similarly, anemia (Hb &lt; 10 g/dL) was associated with global hypokinesia and valvular heart disease. LVD was associated with death in our study.Conclusion: Echocardiography is a noninvasive diagnostic test which detects early changes in cardiac parameters. All ESRD patients with hypertension and anemia at the time of initiation of renal replacement therapy must undergo echocardiography screening.

Myocardial changes on 3T cardiovascular magnetic resonance imaging in response to haemodialysis with fluid removal

BackgroundMapping of left ventricular (LV) native T1 is a promising non-invasive, non-contrast imaging biomarker. Native myocardial T1 times are prolonged in patients requiring dialysis, but there are concerns that the dialysis process and fluctuating fluid status may confound results in this population. We aimed to assess the changes in cardiac parameters on 3T cardiovascular magnetic resonance (CMR) before and after haemodialysis, with a specific focus on native T1 mapping.MethodsThis is a single centre, prospective observational study in which maintenance haemodialysis patients underwent CMR before and after dialysis (both scans within 24 h). Weight measurement, bio-impedance body composition monitoring, haemodialysis details and fluid intake were recorded. CMR protocol included cine imaging and mapping native T1 and T2.ResultsTwenty-six participants (16 male, 65 ± 9 years) were included in the analysis. The median net ultrafiltration volume on dialysis was 2.3 L (IQR 1.8, 2.5), resulting in a median weight reduction at post-dialysis scan of 1.35 kg (IQR 1.0, 1.9), with a median reduction in over-hydration (as measured by bioimpedance) of 0.75 L (IQR 0.5, 1.4). Significant reductions were observed in LV end-diastolic volume (− 25 ml, p = 0.002), LV stroke volume (− 13 ml, p = 0.007), global T1 (21 ms, p = 0.02), global T2 (− 1.2 ms, p = 0.02) following dialysis. There was no change in LV mass (p = 0.35), LV ejection fraction (p = 0.13) or global longitudinal strain (p = 0.22). On linear regression there was no association between baseline over-hydration (as defined by bioimpedance) and global native T1 or global T2, nor was there an association between the change in over-hydration and the change in these parameters.ConclusionsAcute changes in cardiac volumes and myocardial native T1 are detectable on 3T CMR following haemodialysis with fluid removal. The reduction in global T1 suggests that the abnormal native T1 observed in patients on haemodialysis is not entirely due to myocardial fibrosis.

Effect of bariatric surgery on cardiac structure and function in obese patients: Role of the renin-angiotensin system.

Echocardiographic alterations have been described in obesity, but their modifications after bariatric surgery (BS) and mechanisms are little known, mostly in normotensive patients. We aimed to analyze cardiac changes 1 year post‐BS and to explore possible mechanisms. A cohort of patients with severe obesity (58% normotensives) were prospectively recruited and examined before surgery and after 12 months. Clinical and echocardiographic data, 24 h BP, renin‐angiotensin‐aldosterone system (RAAS) components, cytokines, and inflammatory markers were analyzed at these two time points. Overall reduction in body weight was mean (IQR) = 30.0% (25.9–33.8). There were statistically significant decreases in left ventricle mass index2.7(LVMI)2.7, septum thickness (ST), posterior wall thickness (PWT), relative wall thickness (RWT), and E/e’, both in the whole cohort and in patients without RAAS blockers (p ≤ .04 for all). Plasma renin activity (PRA) decreased from (median, IQR) = 0.8 (0.3;1.35) to 0.4 (0.2;0.93) ng/ml/h, plasma aldosterone from 92 (58.6;126) to 68.1 (56.2;83.4) ng/dl, and angiotensin‐converting enzyme (ACE)‐2 activity from 7.7 (5.7;11.8) to 6.8 (5.3;11.2) RFU/µl/h, p < .05. The body weight loss correlated with a decrease in both 24 h SBP and 24 h DBP (Pearson's coefficient 0.353, p = .022 and 0.384, p = .012, respectively). Variation (Δ) of body weight correlated with ΔE/e’ (Pearson's coeff. 0.414, p = .008) and with Δ lateral e’ (Pearson's coeff. = −0.363, p = .018). Generalized linear models showed that ΔPRA was an independent variable for the final (12‐months post‐BS) LVMI2.7 (p = .028). No other changes in cardiac parameters correlated with ΔBP. In addition to the respective baseline value, final values of PWT and RWT were dependent on 12‐month Δ of PRA, ACE, and ACE/ACE2 (p < .03 for all). We conclude that there are cardiac changes post‐BS in patients with severe obesity, normotensives included. Structural changes appear to be related to modifications in the renin‐angiotensin axis.

Effect of VTILVOT variation rate on the assessment of fluid responsiveness in septic shock patients.

This study aimed to assess the predictive value of velocity time integral (VTI) of the left ventricular outflow tract (LVOT) on volume expansion test (VET) as an indicator of volume responsiveness in septic shock patients. Septic shock patients undergoing mechanical ventilation were recruited. The hemodynamic parameters before and after VE were monitored by pulse indicated continuous cardiac output (PiCCO) and echocardiography. Heart rate, cardiac index (CI), mean arterial pressure (MAP), central venous pressure, stroke volume variation (SVV), CI and variation of pulse pressure (PPV), and the changes in cardiac parameters (Dheart rate, Dmean arterial pressure, Dcentral venous pressure, DSVV, DCI, and DPPV) were determined. The relationships of hemodynamic parameters and their changes with DVTI were further evaluated with Pearson relation analysis. The value of these parameters in fluid responsiveness prediction was evaluated by using the receiver operating characteristic (ROC) curve analysis. Results showed that 44 VETs were performed in 44 septic shock patients with responsiveness in 24 patients and non-responsiveness in 20. The CI increased by ≥ 15% in responsive patients, but by<15% in non-responsive patients after VET. There were significant differences in the SVV and PPV after VET between responsive and non-responsive groups. DSVV, DPPV, and DCI were positively related to DVTI. The area under ROC curve (AUC) for SVV in fluid responsiveness prediction was 0.80, and the sensitivity and specificity of SVV were 66.5% and 95%, respectively, when the cut-off value was 24.8%. The AUC for PPV in fluid responsiveness prediction was 0.843, and the sensitivity and specificity of PPV were 83.3% and 75%, respectively, when the cut-off value was 25.8%. The AUC for DVTILVOT in fluid responsiveness prediction was 0.956, and the sensitivity and specificity were 87.5% and 95%, respectively, when the cut-off value was 15.9%. In conclusion, DVTILVOT is effective to predict fluid responsiveness after VET in mechanical ventilation patients with septic shock. It may serve as a new, noninvasive and functional hemodynamic parameter with the same accuracy to SVV.

Sequential nephron blockade with combined diuretics improves diastolic function in patients with resistant hypertension.

AimsHypertension is a major contributor to cardiac diastolic dysfunction. Different therapeutics strategies have been proposed to control blood pressure (BP), but their independent impact on cardiac function remains undetermined. In patients with resistant hypertension, we compared the changes in cardiac parameters between two strategies based on sequential nephron blockade (NBD) with a combination of diuretics or sequential renin‐angiotensin system blockade (RASB).Methods and resultsAfter a 4‐week period where all patients received Irbesartan 300 mg/day + hydrochlorothiazide 12.5 mg/day + amlodipine 5 mg/day, 140 resistant hypertension patients (54.8 ± 11.1 years, 76% men, mean duration with hypertension: 13.1 ± 10.5 years, no previous history of heart failure or current symptoms of congestive heart failure) were randomized 1:1 to the NBD regimen or to the RASB regimen at week 0 (W0, baseline). Treatment intensity was increased at week 4, 8, or 10 if home BP was ≥135/85 mmHg, by sequentially adding 25 mg spironolactone, 20–40 mg furosemide, and 5 mg amiloride (NBD group) or 5–10 mg ramipril and 5–10 mg bisoprolol (RASB group). No other antihypertensive drug was allowed during the study. BP, BNP levels, and echocardiographic parameters were assessed at weeks 0 and 12.The baseline characteristics, laboratory parameters, and plasma hormones (BNP, renin, and aldosterone) and cardiac echocardiographic parameters did not significantly differ between the NBD and the RASB groups. Over 12 weeks, BNP levels significantly decreased in NBD but increased in RASB (mean [CI 95%] change in log‐transformed BNP levels: −43% [−67%; −23%] vs. +55% [46%; 62%] in NBD vs. RASB, respectively, P < 0.0001). Similarly, the proportion of patients presenting ≥2 echocardiographic criteria of diastolic dysfunction decreased between baseline and W12 from 31% to 3% in NBD but increased from 19% to 32% in RASB (P = 0.0048). As compared with RASB, NBD induced greater decrease in ambulatory systolic BP (P < 0.0001), pulse pressure (P < 0.0001), and systemic vascular resistance (P < 0.005). In multivariable linear regression analyses, NBD treatment was significantly associated with decreased BNP levels (adjusted ß: −46.41 ± 6.99, P < 0.0001) independent of age, gender, renal function, and changes in BPs or heart rate.ConclusionsIn patients with resistant hypertension, nephron blockade with a combination of diuretics significantly improves cardiac markers of diastolic dysfunction independently of BP lowering.

Cardiac remodeling secondary to chronic volume overload is attenuated by a novel MMP9/2 blocking antibody.

ObjectiveMonoclonal antibody derivatives are promising drugs for the treatment of various diseases due to their high matrix metalloproteinases (MMP) active site specificity. We studied the effects of a novel antibody, SDS3, which specifically recognizes the mature active site of MMP9/2 during ventricular remodeling progression in a mouse model of chronic volume overload (VO).MethodsVO was induced by creating an aortocaval fistula (ACF) in 10- to 12-week-old C57BL male mice. The VO-induced mice were treated with either vehicle control (PBS) or with SDS3 twice weekly by intraperitoneal (ip) injection. The relative changes in cardiac parameters between baseline (day 1) and end-point (day 30), were evaluated by echocardiography. The effects of SDS3 treatment on cardiac fibrosis, cardiomyocyte volume, and cardiac inflammation were tested by cardiac staining with Masson's trichrome, wheat Germ Agglutinin (WGA), and CD45, respectively. Serum levels of TNFα and IL-6 with and without SDS3 treatment were tested by ELISA.ResultsSDS3 significantly reduced cardiac dilatation, left ventricular (LV) mass, and cardiomyocyte hypertrophy compared to the vehicle treated animals. The antibody also reduced the heart-to-body weight ratio of the ACF animals to values comparable to those of the controls. Interestingly, the SDS3 group underwent significant reduction of cardiac inflammation and pro-inflammatory cytokine production, indicating a regulatory role for MMP9/2 in tissue remodeling, possibly by tumor necrosis factor alpha (TNFα) activation. In addition, significant changes in the expression of proteins related to mitochondrial function were observed in ACF animals, these changes were reversed following treatment with SDS3.ConclusionThe data suggest that MMP9/2 blockage with SDS3 attenuates myocardial remodeling associated with chronic VO by three potential pathways: downregulating the extracellular matrix proteolytic cleavage, reducing the cardiac inflammatory responses, and preserving the cardiac mitochondrial structure and function.

Model Reference Adaptive Control for Aortic Pressure Regulation in Ex Vivo Heart Perfusion

This brief proposes the first model reference adaptive control (MRAC) method for aortic pressure (AoP) regulation and maintaining the heart’s physiological aerobic metabolism in ex vivo heart perfusion (EVHP). A mathematical model of the EVHP was established to describe the hemodynamic behavior of EVHP and quantify the changes in cardiac parameters. A reference model consisting of a virtual proportional–integral–derivative (PID) controller and the EVHP model was employed to generate the reference trajectory of AoP. An adaptation algorithm tunes the control parameters based on the reference model and the isolated heart. Experiments were conducted using large animal hearts (50 ± 5 kg porcine) to validate the adaptive controller’s performance for stepwise and fast switching AoP references. The results confirmed the effectiveness of the proposed controller for regulating the AoP in isolated porcine hearts, in an accurate (mean error less than 2 mmHg) and fast (4–8 s of settling time) manner.

1405Sequential nephron blockade with diuretics improves diastolic dysfunction in patients with resistant hypertension, a substudy a the PHARES trial

Abstract Introduction Hypertension is one of the major contributors to cardiac diastolic dysfunction as observed in patients with heart failure and preserved ejection fraction. Different therapeutics strategies have been proposed to control blood pressure (BP) but their independent impact on cardiac function remain undetermined. In patients referred to our center for uncontrolled hypertension, we compared changes in cardiac parameters between two strategies consisting of sequential nephron blockade with intensive diuretics (NBD) or sequential renin angiotensin blockade (RAB). Purpose To determine evolution of BNP levels and echocardiographic (TTE) parameters of diastolic dysfunction according to strategies to control BP. Methods After 4-weeks treatment with 300mg irbesartan + 12.5mg hydrochlorothiazide + 5mg amlodipine, 140 patients with uncontrolled hypertension were randomized to either complete nephron blockade with sequential introduction of 25mg spironolactone, 20 to 40mg furosemide and 5mg amiloride (NBD group, n=74) or complete RAAS blockade with 5 to 10mg ramipril and 5 to 10mg bisoprolol (RAB group, n=67). BNP levels and TTE parameters according to ESC guidelines were assessed at baseline and week 12. Results BNP levels were not significantly different in the two groups at baseline (mean±SD 30.1±37.0pg/mL in NBD versus 22.6±22.3pg/mL in RAB, p=0.147) but significantly decreased in NBD at week 12 (20.1±22.7pg/mL in NBD versus 55.2±60.4pg/mL in RAB, p&lt;0.0001). At week 12, only 9 (12%) patients in NBD presented BNP levels &gt;35pg/mL versus 37 (55%) in RAB (p&lt;0.001). Concordantly, TTE parameters such as left ventricular end-diastolic diameter (mean±SD, 49±4mm in NBD and 52±5mm in RAB, p=0,004) and left atrial area (16.9±3.6cm2 in NBD and 19.1±3.7cm2 in RAB, p=0,003) improved significantly in NBD group. The proportions of patients presenting ≥2 criteria of diastolic dysfunction according to ESC guidelines in NBD and RAB group respectively were 31.2% and 19.3% at baseline vs. 3.1% and 32.2% after 12 weeks (p=0.001). In a multivariate analysis, NBD treatment was significantly associated with a decline in BNP levels (p&lt;0.01) even after adjustment on daytime systolic BP lowering, heart rate, renal function, age and gender. Conclusion In patients with uncontrolled hypertension, intensive nephron blockade with sequential addition of diuretics improves markers of diastolic dysfunction independently of BP lowering.

Cardiovascular Responses to Selected Cranial Osteopathic Manipulations in Hypertensive Patients

Background and PurposeOsteopathic cranial manipulations (CM) have been used as a part of therapeutic management of hypertensive patients. However, our knowledge about physiological responses to CM in cardiac patients is limited. A quantitative relationship between applied CM and cardiovascular parameters has not been well established. The purpose of this study was to measure changes in heart rate, autonomic input to the heart by using the heart rate variability test, cardiac contractility by using impedance cardiography, and systemic blood pressure in response to selected CM, namely occipital‐atlantal decompression, occipital‐mastoid decompression, and compression of the fourth ventricle.MethodHypertensive 65–75 year old subjects, three men and two women, were involved in this study. Hypertension was controlled by an angiotensin‐converting enzyme inhibitor (3 subjects), calcium channels blocker (1 subject) and beta‐blocker (1 subject). Each subject participated in the experimental (CM) and control (sham) groups. A non‐invasive impedance cardiography method was used to measure changes in cardiac parameters before and after manipulations. Data were recorded and analyzed using BIOPAC Systems, Inc. equipment and software. Blood pressure was measured before and after manipulations by using a sphygmomanometer. All manipulations were performed by the same osteopathic physician.ResultsCranial and sham manipulations resulted in different responses by the subjects. CM produced a decrease in systolic (5%) and mean arterial (6%) pressures, and revealed a trend towards an increase in sympathetic and decrease in parasympathetic cardiac activity based on heart rate variability test. Sham manipulations did not affect blood pressure and were associated with a trend towards a decrease in sympathetic and increase in parasympathetic cardiac activity. No changes in cardiac contractility were recorded for CM and sham manipulations.Discussion and conclusionIt appears that cranial manipulations may enhance the antihypertensive effect of medication through the effect on autonomic nervous system. The physiological effect of CM on autonomic control of systemic hemodynamics needs further investigation.Support or Funding InformationThis project was funded by the TUN Research Grant AwardThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Methodological exploration of bone marrow stem cell therapy in acute myocardial infarction - how to achieve greater benefit on cardiac outcomes: A systematic review and meta-analysis.

Clinical trials of intracoronary injection of bone marrow-derived stem cells (BMCs) in patients with acute myocardial infarction (AMI) have revealed promising but variable and modest results. One of the reasons underlying this situation may be the unstandardized preparation of BMCs. The aim of this study was to explore whether methodological differences affect the prognosis of acute myocardial infarction patients who received BMCs transplantation. MEDLINE was searched for randomized controlled trials providing AMI patients with intracoronary BMCs injection or a standard therapy. Changes in cardiac parameters and clinical outcomes were analyzed. Subgroup analyses were conducted according to different methodologies for cell preparation, including supplement for serum or plasma, use of heparin and cell washout. Non-use of serum or plasma in the cell suspension is associated with more reduction in infarct size (IS) and a lower risk of all-cause mortality. Heparin usage could diminish the benefit in reducing IS. All-cause mortality rose significantly without the cell washout procedure when heparin was used. Methodological differences in BMCs preparation as well as the use of heparin and serum/ plasma impact on the prognosis of AMI patients.

Disruption of dopamine D1/D2 receptor complex is involved in the function of haloperidol in cardiac H9c2 cells

AimsHaloperidol is an antipsychotic agent and acts as dopamine D2 receptor (D2R) antagonist, as a prototypical ligand of sigma1 receptors (Sig1R) and it increases expression of type 1 IP3 receptors (IP3R1). However, precise mechanism of haloperidol action on cardiomyocytes through dopaminergic signaling was not described yet. This study investigated a role of dopamine receptors in haloperidol-induced increase in IP3R1 and Sig1R, and compared physiological effect of melperone and haloperidol on basic heart parameters in rats. Materials and methodsWe used differentiated NG-108 cells and H9c2 cells. Gene expression, Western blot and immunofluorescence were used to evaluate haloperidol-induced differences; proximity ligation assay (PLA) and immunoprecipitation to determine interactions of D1/D2 receptors. To evaluate cardiac parameters, Wistar albino male rats were used. Key findingsWe have shown that antagonism of D2R with either haloperidol or melperone results in upregulation of both, IP3R1 and Sig1R, which is associated with increased D2R, but reduced D1R expression. Immunofluorescence, immunoprecipitation and PLA support formation of heteromeric D1/D2 complexes in H9c2 cells. Treatment with haloperidol (but not melperone) caused decrease in systolic and diastolic blood pressure and significant increase in heart rate. SignificanceBecause D1R/D2R complexes can engage Gq-like signaling in other experimental systems, these results are consistent with the possibility that disruption of D1R/D2R complex in H9c2 cells might cause a decrease in IP3R1 activity, which in turn may account for the increase expression of IP3R and Sig1R. D2R is probably not responsible for changes in cardiac parameters, since melperone did not have any effect.

Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy

Objectives: Cardiomyopathy is a major cause of death in both the hereditary form of transthyretin (TTR) amyloidosis and the sporadic late-age-onset transthyretin amyloidosis (ATTR wild-type (ATTRwt)). Clinically disease progression from time of diagnosis to death is usually quoted as 5- to 15-years. In prior studies, significant progression of cardiac parameters in patients with moderate to severe cardiomyopathy has been noted within a 12-month time span.Methods: The present study was designed to prospectively monitor changes in cardiac parameters, both structural and functional, in patients with ATTR cardiomyopathy while treated with a TTR specific antisense oligonucleotide (ASO; IONIS-TTR℞) designed to lower blood levels of the amyloid fibril precursor protein. To date 22 patients have been admitted to the study, 15 have completed 12 months on the drug and are the subject of this report.Results: Eight patients with hereditary ATTR amyloidosis and 7 patients with wild-type ATTR amyloidosis with moderate to severely advanced restrictive cardiomyopathy showed stabilization of disease as measured by left ventricular wall thickness, left ventricular mass (LVM), 6-min walk test (6MWT), and echocardiographic global systolic strain. IONIS-TTR℞ was well tolerated by all 15 subjects and showed a good safety profile.Conclusions: ASO treatment of patients with moderate to advanced ATTR cardiomyopathy shows indication of stabilization of disease progression and may therefore contribute to enhanced life expectancy.