Abstract 17177: Furosemide Promotes Myocardial Fibrosis in Swine Heart Failure

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Nisha Plavelil ◽  
Mark C Haigney ◽  
Robert E Goldstein ◽  
Michael Klein ◽  
Matie Shou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Myocardial Fibrosis ◽  
Left Ventricular ◽  
Swine Model ◽  
Signaling Proteins ◽  
Ecm Remodeling ◽  
Animal Care ◽  
Pai 1 ◽  
Fractional Shortening

Introduction: Although frequently used in heart failure (HF), long-term furosemide exacerbates HF in a swine model. This paradoxical phenomenon may reflect furosemide-induced alterations in signaling proteins of the extracellular matrix (ECM) to increase fibrosis. Examination of the ECM may clarify how treatments like furosemide enhance the progression of HF. Hypothesis: The administration of furosemide increased inflammation and fibrosis of the heart, leading to accelerated HF deterioration in a swine model. Methods: After Institutional Animal Care and Use Committee (IACUC) approval, Yorkshire swine (N=10, 5 = furosemide, 5 = saline) were paced 3 to 5 weeks at 200 beats per minute to induce HF (left ventricular fractional shortening <16% on echocardiogram). Animals were treated with furosemide (1 mg/kg intramuscularly) or saline. Western Blot and histology with Masson’s trichrome stain were performed on transmural LV myocardium to quantify critical determinants of fibrosis. ANOVA with Tukey HSD correction and descriptive statistics were performed using SPSS with significance by α of 0.05; mean ± SEM. Results: The overall increase in ECM fibrosis in HF was clearly demonstrated on Masson’s trichrome histology associated with significant, uniform increase in signaling pathways leading to fibrosis associated with furosemide use. SMAD 2-HF Furosemide to Control (p<.05): HF Furosemide 0.266 ±.05, HF Saline 0.183±.02, Control 0.163±.01 ERK-all (p<.05): HF Furosemide 0.312±.02, HF Saline 0.209±.01,Control 0.149±.01 GDF-15-HF Furosemide to Control (p<.05): HF Furosemide 0.095 ±.00, HF Saline 0.073±.01, Control 0.062±.01 MMP-14-all (p<.05): HF Furosemide 0.451±.02, HF Saline 0.374±.03,Control 0.231±.02 TIMP-1-all (p<.05): HF Furosemide 0.184±.01, HF Saline 0.0135±.03,Control 0.033±.01 PAI-1-all (p<.05): HF Furosemide 0.105±.01, HF Saline 0.046±.01,Control 0.043±.00 Conclusions: Histologic and biochemical analysis showed worsening HF in furosemide-treated paced swine was associated with consistent increases in fibrosis and indices of adverse ECM remodeling. The diuretic intended to reduce water retention during HF appeared to enhance myocardial fibrosis, paradoxically accelerating pathological processes responsible for HF.

scholarly journals Systolic blood pressure and outcome in patients admitted with acute heart failure: a pooled analysis from 4 randomized clinical trials

2021 ◽  
Vol 10 (Supplement_1) ◽  
Author(s):  
J Grand ◽  
K Miger ◽  
A Sajadieh ◽  
L Kober ◽  
C Torp-Pedersen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Composite Endpoint ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Term Outcome ◽  
Ventricular Ejection Fraction ◽  
Long Term Outcome ◽  
All Cause Mortality ◽  
Short And Long Term

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Danish Heart Foundation Background In acute heart failure (AHF), low systolic blood pressure (SBP) has been associated with poor outcome. Less is known of the risk related to normal versus elevated SBP and interaction with left ventricular ejection fraction. Purpose The aim of the present study was to assess the association between baseline SBP and short- and long-term outcome in a large cohort of AHF-patients. Methods A pooled cohort of four randomized controlled trials investigating the vasodilator serelaxin versus placebo in patients admitted with AHF and an SBP from 125 to 180 mmHg. Endpoints were 180-day all-cause mortality and a short-term composite endpoint (worsening heart failure, all-cause mortality or hospital readmission for HF through Day 14). Left ventricular ejection fraction (LVEF) was categorized into HFrEF (&lt;40%) and HFpEF (= &gt;40%). Multivariable Cox regression was used and adjusted for age, sex, baseline body mass index, HFrEF, serum estimated glomerular filtration rate, allocated treatment (placebo/serelaxin), diabetes mellitus, ischemic heart disease, and atrial fibrillation/flutter. Measurements and Main Results A total of 10.533 patients with a mean age of 73 (±12) years and median SBP of 140 (130-150) mmHg were included within mean 8.2 hours from admission. LVEF was assessed in 8493 (81%), and of these, 4294 (51%) had HFrEF. Increasing SBP as a continuous variable was inversely associated with 180-day mortality (HRadjusted: 0.93 [0.88-0.98], p = 0.004 per 10 mmHg increase) and with the composite endpoint (HRadjusted: 0.90 [0.85-0.95], p &lt; 0.0001 per 10 mmHg increase). A significant interaction was observed regarding LVEF, revealing that SBP was not associated with mortality in patients with HFpEF  (HRadjusted: 1.01 [0.94-1.09], p = 0.83 per 10 mmHg increase), but SBP was associated with increased mortality in HFrEF (HRadjusted: 0.80 [0.73-0.88], p &lt; 0.001 per 10 mmHg increase) (Figure). Conclusions Elevated SBP is independently associated with favorable short- and long-term outcome in AHF-patients. The association between SBP and mortality was, however, not present in patients with preserved LVEF. Abstract Figure. Survival plots by SBP and LVEF

scholarly journals The link between left ventricular extracellular volume determined by T1 myocardial mapping and gut microbiota composition in individuals with heart failure and preserved ejection fraction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.N Kaburova ◽  
O.M Drapkina ◽  
S.M Uydin ◽  
M.V Vishnyakova ◽  
M.S Pokrovskaya ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Gut Microbiota ◽  
Myocardial Fibrosis ◽  
Volume Fraction ◽  
Extracellular Volume ◽  
Left Ventricular ◽  
Diffuse Myocardial Fibrosis ◽  
Rrna Gene ◽  
Preserved Ejection Fraction

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) represents a major challenge in modern cardiology. As described previously, in HFpEF comorbidities promote a systemic inflammatory state, leading to diffuse myocardial fibrosis resulting in myocardial stiffening. Gut dysbiosis which is considered as the novel source of chronic systemic inflammation has been actively investigated as the risk factor for the development and aggravation of cardiovascular diseases including heart failure. Cardiac magnetic resonance T1-mapping is a novel tool, which allows noninvasive quantification of the extracellular space and diffuse myocardial fibrosis. Moreover, the extracellular volume (ECV) fraction can be calculated, providing information on the relative expansion of the extracellular matrix, thus being a noninvasive alternative to myocardial biopsy studies. Purpose The research was aimed at investigating the correlation between the left ventricular ECV and gut microbial genera in patients with HFpEF. Methods 42 patients with confirmed HF-pEF (mediana and interquartile range of age 67 [64; 72] years, 47% men, body mass index &lt;35 kg/m2 with no history of myocardial infarction or diabetes mellitus) were enrolled in the study. The patients underwent transthoracic echocardiography with Doppler study, HF-pEF was confirmed according to the recent ESC guidelines (based on E/e' ratio, N-terminal pro-B type natriuretic peptide &gt;125 pg/ml and symptoms of heart failure). The intestinal microbiome was investigated using high-throughput sequencing of bacterial 16S rRNA gene. As the last step of research T1-myocardial mapping with the modified look-locker inversion-recovery protocol (MOLLI) sequence at 1.5 Tesla was performed to assess left ventricular extracellular volume fraction. Results The mean±std in ECV was 31.02±4.4%. The relative abundance (%) of the most prevalent phyla in gut microbiota was 48±22.5 for Firmicutes, 47.4±22.8 for Bacteroidetes and 1.5 [1.5; 2.5] for Proteobacteria. The analysis showed significant negative correlations between ECV and the following bacterial genera: Faecalibacterium (r=−0.35), Blautia (r=−0.43), Lachnoclostridium (r=−0.32). Moreover ECV positively correlated with Holdemania (r=0.4), Victivallis (r=0.38), Dehalobacterium (r=0.38), Enterococcus (r=0.33) and Catabacter (r=0.32). All correlation values with p&lt;0.05. Conclusion We discovered both negative and positive significant correlations between ECV – the non-invasive marker of myocardial fibrosis and several bacterial genera, which may have negative impact on myocardial remodeling in HF-pEF. Funding Acknowledgement Type of funding source: None

Importance of antioxidant and antiapoptotic effects of β-receptor blockers in heart failure therapy

2004 ◽  
Vol 287 (3) ◽  
pp. H1003-H1012 ◽  
Author(s):  
Keisuke Kawai ◽  
Fuzhong Qin ◽  
Junya Shite ◽  
Weike Mao ◽  
Shuji Fukuoka ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Diastolic Pressure ◽  
Cardiac Pacing ◽  
Left Ventricular ◽  
Beneficial Effects ◽  
Myocyte Apoptosis ◽  
Adrenergic Blocking ◽  
Fractional Shortening

The present study was carried out to determine whether beneficial effects of carvedilol in congestive heart failure (CHF) are mediated via its β-adrenergic blocking, antioxidant, and/or α-adrenergic blocking action. Rabbits with heart failure induced by rapid cardiac pacing were randomized to receive subcutaneous carvedilol, metoprolol, propranolol plus doxazosin, or placebo pellets for 8 wk and compared with sham-operated rabbits without pacing. We found rapid cardiac pacing produced clinical heart failure, left ventricular dilation, and decline of left ventricular fractional shortening. This was associated with an increase in left ventricular end-diastolic pressure, decrease in left ventricular first derivative of left ventricular pressure, and myocyte hypertrophy. Tissue oxidative stress measured by GSH/GSSG was increased in the heart with increased oxidation product of mitochondrial DNA, 8-oxo-7,8-dihydro-2′-deoxyguanosine, increase of Bax, decrease of Bcl-2, and increase of apoptotic myocytes as measured by anti-single-stranded DNA monoclonal antibody. Administration of carvedilol and metoprolol, which had no effect in sham animals, attenuated cardiac ventricular remodeling, cardiac hypertrophy, oxidative stress, and myocyte apoptosis in CHF. In contrast, propranolol plus doxazosin, which has less antioxidant effects, produced smaller effects on left ventricular function and myocyte apoptosis. In all animals, GSH/GSSG correlated significantly with changes of left ventricular end-diastolic dimension ( r = −0.678, P < 0.0001), fractional shortening ( r = 0.706, P < 0.0001), and apoptotic myocytes ( r = −0.473, P = 0.0001). Thus our findings suggest antioxidant and antiapoptotic actions of carvedilol and metoprolol are important determinants of clinical beneficial effects of β-receptors in the treatment of CHF.

Long-term levosimendan treatment improves systolic function and myocardial relaxation in mice with cardiomyocyte-specific disruption of the Serca2 gene

2013 ◽  
Vol 115 (10) ◽  
pp. 1572-1580 ◽  
Author(s):  
Vigdis Hillestad ◽  
Frank Kramer ◽  
Stefan Golz ◽  
Andreas Knorr ◽  
Kristin B. Andersson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cardiac Function ◽  
Diastolic Dysfunction ◽  
Systolic Function ◽  
Cytosolic Calcium ◽  
Left Ventricular ◽  
Pressure Measurements ◽  
Human Heart Failure

In human heart failure (HF), reduced cardiac function has, at least partly, been ascribed to altered calcium homeostasis in cardiomyocytes. The effects of the calcium sensitizer levosimendan on diastolic dysfunction caused by reduced removal of calcium from cytosol in early diastole are not well known. In this study, we investigated the effect of long-term levosimendan treatment in a murine model of HF where the sarco(endo)plasmatic reticulum ATPase ( Serca) gene is specifically disrupted in the cardiomyocytes, leading to reduced removal of cytosolic calcium. After induction of Serca2 gene disruption, these mice develop marked diastolic dysfunction as well as impaired contractility. SERCA2 knockout (SERCA2KO) mice were treated with levosimendan or vehicle from the time of KO induction. At the 7-wk end point, cardiac function was assessed by echocardiography and pressure measurements. Vehicle-treated SERCA2KO mice showed significantly diminished left-ventricular (LV) contractility, as shown by decreased ejection fraction, stroke volume, and cardiac output. LV pressure measurements revealed a marked increase in the time constant (τ) of isovolumetric pressure decay, showing impaired relaxation. Levosimendan treatment significantly improved all three systolic parameters. Moreover, a significant reduction in τ toward normalization indicated improved relaxation. Gene-expression analysis, however, revealed an increase in genes related to production of the ECM in animals treated with levosimendan. In conclusion, long-term levosimendan treatment improves both contractility and relaxation in a heart-failure model with marked diastolic dysfunction due to reduced calcium transients. However, altered gene expression related to fibrosis was observed.

Effect of Sacubitril/Valsartan Combined with Dapagliflozin on Long-Term Cardiac Mortality in Heart Failure with Reduced Ejection Fraction

Angiology ◽  
2021 ◽  
pp. 000331972110473
Author(s):  
Umut Karabulut ◽  
Kudret Keskin ◽  
Dilay Karabulut ◽  
Ece Yiğit ◽  
Zerrin Yiğit
Keyword(s):  
Heart Failure ◽  
Combination Therapy ◽  
Ejection Fraction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Cardiac Mortality ◽  
Ventricular Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Neprilysin Inhibitor

The angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan and sodium-glucose cotransporter-2 (SGLT-2) inhibitor dapagliflozin have been shown to reduce rehospitalization and cardiac mortality in patients with heart failure (HF) with reduced ejection fraction (HFrEF). We aimed to compare the long-term cardiac and all-cause mortality of ARNI and dapagliflozin combination therapy against ARNI monotherapy in patients with HFrEF. This retrospective study involved 244 patients with HF with New York Heart Association (NYHA) class II–IV symptoms and ejection fraction ≤40%. The patients were divided into 2 groups: ARNI monotherapy and ARNI+dapagliflozin. Median follow-up was 2.5 (.16–3.72) years. One hundred and seventy-five (71.7%) patients were male, and the mean age was 65.9 (SD, 10.2) years. Long-term cardiac mortality rates were significantly lower in the ARNI+dapagliflozin group (7.4%) than in the ARNI monotherapy group (19.5%) ( P = .01). Dapagliflozin [Hazard Ratio (HR) [95% Confidence Interval (CI)] = .29 [.10–.77]; P = .014] and left ventricular ejection fraction (LVEF) [HR (95% CI) = .89 (.85–.93); P < .001] were found to be independent predictors of cardiac mortality. Our study showed a significant reduction in cardiac mortality with ARNI and dapagliflozin combination therapy compared with ARNI monotherapy.

scholarly journals Long-term outcomes in patients with critical limb ischemia and heart failure with preserved or reduced ejection fraction

2017 ◽  
Vol 22 (4) ◽  
pp. 307-315 ◽  
Author(s):  
Kavita B Khaira ◽  
Ellen Brinza ◽  
Gagan D Singh ◽  
Ezra A Amsterdam ◽  
Stephen W Waldo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Critical Limb Ischemia ◽  
Limb Ischemia ◽  
Left Ventricular ◽  
Term Survival ◽  
Long Term Survival ◽  
Reduced Ejection Fraction ◽  
History Of

The impact of heart failure (HF) on long-term survival in patients with critical limb ischemia (CLI) has not been well described. Outcomes stratified by left ventricular ejection fraction (EF) are also unknown. A single center retrospective chart review was performed for patients who underwent treatment for CLI from 2006 to 2013. Baseline demographics, procedural data and outcomes were analyzed. HF diagnosis was based on appropriate signs and symptoms as well as results of non-invasive testing. Among 381 CLI patients, 120 (31%) had a history of HF and 261 (69%) had no history of heart failure (no-HF). Within the HF group, 74 (62%) had HF with preserved ejection fraction (HFpEF) and 46 (38%) had HF with reduced ejection fraction (HFrEF). The average EF for those with no-HF, HFpEF and HFrEF were 59±13% vs 56±9% vs 30±9%, respectively. The likelihood of having concomitant coronary artery disease (CAD) was lowest in the no-HF group (43%), higher in the HFpEF group (70%) and highest in the HFrEF group (83%) ( p=0.001). Five-year survival was on average twofold higher in the no-HF group (43%) compared to both the HFpEF (19%, p=0.001) and HFrEF groups (24%, p=0.001). Long-term survival rates did not differ between the two HF groups ( p=0.50). There was no difference in 5-year freedom from major amputation or freedom from major adverse limb events between the no-HF, HFpEF and HFrEF groups, respectively. Overall, the combination of CLI and HF is associated with poor 5-year survival, independent of the degree of left ventricular systolic dysfunction.

scholarly journals Time delay to peak left ventricular pressure rise identifies the substrate for dyssynchronous heart failure and detects disease modification with resynchronization- an observational clinical study

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
H Odland ◽  
T Holm ◽  
S Ross ◽  
LO Gammelsrud ◽  
R Cornelussen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Nyha Class ◽  
Pressure Rise ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Cardiac Resynchronization ◽  
Disease Modification ◽  
Volumetric Response

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Norwegian South East Health Authorities Introduction Identification of disease modification prior to implantation of Cardiac Resynchronization Therapy may help select the right patients, increase responder-rates and promote the utilization of CRT. We tested the hypothesis that shortening of time-to-peak left ventricular pressure rise (Td) with CRT is useful to predict long-term volumetric response (End-systolic volume (ESV) decrease &gt;15%) to CRT. Methods Forty-five heart failure patients admitted for CRT implantation with a class I/IIa indication according to current ESC/AHA guidelines were included in the study. Td was measured from onset QRS at baseline and from onset of pacing with CRT. Results Baseline characteristics were mean age 63 ± 10 years , 71% males, NYHA class 2.5, 87% LBBB, QRS duration 173 ± 15ms, EF biplane 31 ± 1%, ESV 144 ± 12mL and end-diastolic volume 2044 ± 14mL. At 6-months follow-up six patients increased ESV by 5 ± 8%, while 37 responders (85%) had a mean ESV decrease of 40 ± 2%.  Responders presented with a higher Td at baseline compared to non-responders (163 ± 4ms vs 119 ± 9ms, p &lt; 0.01). Td decreased to 156 ± 4ms (p = 0.02) with CRT in responders, while in non-responders Td increased to 147 ± 10ms (p &lt; 0.01) with CRT. A decrease in Td of less than +3.5ms from baseline accurately identified responders to therapy (AUC 0.98, p &lt; 0.01, sensitivity 97%, specificity 100%). AUC was 0.92 for baseline Td and a cut-off at 120ms yielded a sensitivity of 100% and specificity of 80% to identify volumetric responders. A linear relationship between the change in Td from baseline and ESV decrease on long term was found (β=-61, R = 0.58, P &lt; 0.01). Conclusions Td at baseline and the shortening of Td with CRT accurately identifies responders to CRT, with incremental value on top of current guidelines, in a population with already high response rates. Td carries the potential to become the marker for prediction of long-term volumetric response in CRT candidates. Abstract Figure.

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