Primary prevention of chronic anthracycline cardiotoxicity with ACE inhibitor is temporarily effective in rabbits, but benefits wane in post-treatment follow-up

Angiotensin-converting enzyme inhibitors (ACEis) have been used to treat anthracycline-induced cardiac dysfunction, and they appear beneficial for secondary prevention in high-risk patients. However, it remains unclear whether they truly prevent anthracycline-induced cardiac damage and provide long-lasting cardioprotection. This study aimed to examine the cardioprotective effects of perindopril on chronic anthracycline cardiotoxicity in a rabbit model previously validated with the cardioprotective agent dexrazoxane with focus on post-treatment follow-up (FU). Chronic cardiotoxicity was induced by daunorubicin (3 mg/kg/week for 10 weeks). Perindopril (0.05 mg/kg/day) was administered before and throughout chronic daunorubicin treatment. After the completion of treatment, significant benefits were observed in perindopril co-treated animals, particularly full prevention of daunorubicin-induced mortality and prevention or significant reductions in cardiac dysfunction, plasma cardiac troponin T levels, morphological damage, and most of the myocardial molecular alterations. However, these benefits significantly waned during 3 weeks of drug-free FU, which was not salvageable by administering a higher perindopril dose. In the longer (10-week) FU period, further worsening of left ventricular function and morphological damage occurred together with heart failure-related mortality. Continued perindopril treatment in the FU period did not reverse this trend but prevented heart failure-related mortality and reduced the severity of the progression of cardiac damage. These findings contrasted with the robust long-lasting protection observed previously for dexrazoxane in the same model. Hence, in this study, perindopril provided only temporary control of anthracycline cardiotoxicity development, which may be associated with the lack of effects on anthracycline-induced and topoisomerase II beta-dependent DNA damage responses in the heart.

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Prodrug of ICRF-193 provides promising protective effects against chronic anthracycline cardiotoxicity on a rabbit model in vivo

Clinical Science ◽

10.1042/cs20210311 ◽

2021 ◽

Author(s):

Petra Kollárová-Brázdová ◽

Olga Lencova-Popelova ◽

Galina Karabanovich ◽

Júlia Kocúrová-Lengvarská ◽

Jan Kubes ◽

...

Keyword(s):

Rabbit Model ◽

Left Ventricular ◽

Water Soluble ◽

Drug Candidate ◽

Protective Effects ◽

Cardiac Damage ◽

Anthracycline Cardiotoxicity ◽

Lv Dysfunction ◽

Full Protection

The anthracycline (ANT) anticancer drugs such as doxorubicin or daunorubicin (DAU) can cause serious myocardial injury and chronic cardiac dysfunction in cancer survivors. A bisdioxopiperazine agent dexrazoxane has been developed as a cardioprotective drug to prevent these adverse events, but it is uncertain whether it is the best representative of the class. This study used a rabbit model of chronic ANT cardiotoxicity to examine another bisdioxopiperazine compound called GK-667, a water-soluble prodrug of ICRF-193, as a potential cardioprotectant. The cardiotoxicity was induced by DAU (3 mg/kg, i.v. weekly, 10 weeks), and GK-667 (1 or 5 mg/kg, i.v.) was administered before each DAU dose. The treatment with GK-667 was well tolerated and provided full protection against DAU-induced mortality and left ventricular (LV) dysfunction (determined by echocardiography and LV catheterization). Markers of cardiac damage/dysfunction revealed minor cardiac damage in the group co-treated with GK-667 in the lower dose, whereas almost full protection was achieved with the higher dose. This was associated with similar prevention of DAU-induced dysregulation of redox and calcium homeostasis proteins. GK-667 dose-dependently prevented p53-mediated DNA damage response in the LV myocardium not only in the chronic experiment but also after single DAU administration. These effects appear essential for cardioprotection, presumably because of the topoisomerase IIβ inhibition provided by its active metabolite ICRF-193. In addition, GK-667 administration did not alter the plasma pharmacokinetics of DAU and its main metabolite daunorubicinol in rabbits in vivo. Hence, GK-667 merits further investigation as a promising drug candidate for cardioprotection against chronic ANT cardiotoxicity.

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P1640Longitudinal patterns of NT-proBNP, troponin T and CRP in relation to the dynamics of echocardiographic parameters in heart failure patients

European Heart Journal ◽

10.1093/eurheartj/ehz748.0399 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

D Klimczak-Tomaniak ◽

V Van Den Berg ◽

M Strachinaru ◽

K M Akkerhuis ◽

S Baart ◽

...

Keyword(s):

Heart Failure ◽

The Netherlands ◽

Troponin T ◽

Left Ventricular ◽

Serum Biomarkers ◽

Clinical Event ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Echocardiographic Parameters

Abstract Introduction Linking temporal biomarker evolutions to changes within myocardial structure and function could provide additional insights into the mechanisms that underlie associations between blood biomarkers and clinical outcome, which have been reported in previous studies. Purpose We aimed to investigate whether serum biomarkers reflect the functional state of the heart in a longitudinal setting. We examined the relationship between serial simultaneous measurements of echocardiographic parameters and serum biomarkers C-reactive protein (CRP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin t (hs-TnT) in chronic heart failure (CHF) patients. Materials and methods In total, 117 CHF patients enrolled in a prospective observational study underwent serial measurement of hs-TnT, NT-proBNP and CRP, accompanied by echocardiographic evaluation at six-month intervals until the end of 30-month follow-up or until an adverse clinical event (HF hospitalization, left ventricular assist device implantation, cardiac transplantation, cardiac death) occurred. Linear mixed effects (LME) models were used for data-analysis. Results Mean age was 58±11 years, 80% were male, 76% in NYHA class I or II and all had reduced left ventricular ejection fraction (LVEF). Median follow-up was 2.2 years [IQR: 1.5–2.6]. We performed up to 6 follow-up evaluations with 55% of patients having at least 3 evaluations performed. A model containing all three biomarkers revealed a significant, independent association between NT-proBNP and all the echocardiographic parameters, including LVEF (Beta coefficient per doubling of NT-proBNP [95% CI]: −0.12 [−0.16; −0.07] log2 (%EF), p<0.0001); mitral E/e' (0.17 [0.09; 0.24] log2 (change in ratio), p<0.0001); mitral E/A (0.22 [0.13; 0.30] log2 (change in ratio), p<0.0001); TAPSE (−0.06 [−0.11; −0.02] log2(mm), p=0.008), tricuspid regurgitation gradient (0.13 [0.07; 0.20] log2(mmHg), p=0.0001) as well as left ventricular and left atrial dimensions (p<0.001). Hs-TnT and CRP showed significant associations with some echocardiographic parameters after adjustment for clinical covariates, but associations lost significance after correction for the other biomarkers. Figure 1. Associations between repeatedly measured NT-proBNP and repeatedly measured echocardiographic parameters (Panel A). Temporal evolution of echocardiographic parameters (B) and biomarker levels (C). Conclusion Serum NT-proBNP independently reflects temporal changes in echocardiographic parameters of systolic and diastolic function, left ventricular filling pressure, estimated pulmonary pressure and chamber diameters. Our results support further studies on NT-proBNP as a surrogate marker for hemodynamic congestion and herewith support its potential value for therapy guidance. Acknowledgement/Funding The Bio-SHiFT study was supported by the Jaap Schouten Foundation (Rotterdam, the Netherlands) and the Noordwest Academie (Alkmaar, the Netherlands).

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Abstract 811: Natural History and Expanded Clinical Profile of Stress (Tako-Tsubo) Cardiomyopathy in United States Women

Circulation ◽

10.1161/circ.118.suppl_18.s_615-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Scott W Sharkey ◽

Denise C Windenburg ◽

Robert G Hauser ◽

John R Lesser ◽

Barry J Maron

Keyword(s):

United States ◽

Heart Failure ◽

Cardiac Arrest ◽

Troponin T ◽

Tertiary Care ◽

Left Ventricular ◽

Stressful Events ◽

Clinical Profile ◽

Hospital Death

Stress cardiomyopathy (SC) is a newly reported condition of older women, triggered by emotionally and physically stressful events, characterized by acute heart failure with a distinctive angiographic profile, and regarded as a reversible process. To date, extended follow-up of SC patients is largely unavailable. We have assembled a substantial consecutive group of patients with SC to assess short and long-term clinical consequences of this condition. Between 2001–2008, we prospectively identified and followed (mean 2.0 years, range 0–6.7) 113 consecutive women with SC at a tertiary care United States hospital. Patients were female, aged 32–92 years (mean 68±13), and 16 (14%) were < 55 years. In 105 (93%) a triggering stressful event (emotional in 50, acute illness in 55) was identified; however, in 8 patients (7%) no such event preceded SC. The ECG showed ST-segment elevation in 58(51%) patients and ejection fraction (EF) was 31±11%. Troponin was elevated in 109 (96%); peak troponin (T) was 0.64±0.76 ng/ml. Of the 113 patients, 110(97%) survived the acute event: 3 patients (3%) died in-hospital (cardiogenic shock in 2; subarachnoid hemorrhage in 1). Other complications included: cardiac arrest 2 (2%), hypotension requiring inotropic drug and/or intra-aortic balloon pump in 22 (19%), pulmonary or cerebral embolism in 3 (3%), left ventricular (LV) or right ventricular thrombus in 7 (6%) and LV outflow obstruction in 13 (12%). CMR findings included absent delayed hyperenhancement (gadolinium) in 82/83 (99%), normal LV apical contraction in 46%, RV akinesia in 22%, and pleural effusions due to heart failure in 46%. At follow-up, EF returned to normal in all patients, but one or more SC events recurred in 7 (6%) patients (complicated by non-fatal cardiac arrest in 1), of whom 3 were taking beta-blockers. Post-hospital death occurred in 15 (13%) patients of which 14 were noncardiac and 1 of unknown cause. Among this large cohort of women, some SC events occurred atypically either without a stress trigger or in younger premenopausal patients. SC also led to death in the acute phase or to later non-fatal recurrences of SC or cardiac arrest in about 10%. Therefore, the clinical profile of SC is much broader than previously regarded.

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Titin-Related Dilated Cardiomyopathy: The Clinical Trajectory and the Role of Circulating Biomarkers in the Clinical Assessment

Diagnostics ◽

10.3390/diagnostics12010013 ◽

2021 ◽

Vol 12 (1) ◽

pp. 13

Author(s):

Przemysław Chmielewski ◽

Grażyna Truszkowska ◽

Ilona Kowalik ◽

Małgorzata Rydzanicz ◽

Ewa Michalak ◽

...

Keyword(s):

Heart Failure ◽

Risk Assessment ◽

Dilated Cardiomyopathy ◽

Troponin T ◽

Left Ventricular Systolic Dysfunction ◽

Multivariable Analysis ◽

Disease Onset ◽

Left Ventricular ◽

Cardiac Biomarkers

Titin truncating variants (TTNtv) are known as the leading cause of inherited dilated cardiomyopathy (DCM). Nevertheless, it is unclear whether circulating cardiac biomarkers are helpful in detection and risk assessment. We sought to assess 1) early indicators of cardiotitinopathy including the serum biomarkers high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in clinically stable patients, and 2) predictors of outcome among TTNtv carriers. Our single-center cohort consisted of 108 TTNtv carriers (including 70 DCM patients) from 43 families. Clinical, laboratory and follow-up data were analyzed. The earliest abnormality was left ventricular dysfunction, present in 8, 26 and 47% of patients in the second, third and fourth decade of life, respectively. It was followed by symptoms of heart failure, linked to NT-proBNP elevation and severe left ventricular systolic dysfunction, and later by arrhythmias. Hs-cTnT serum levels were increased in the late stage of the disease only. During the median follow-up of 5.2 years, both malignant ventricular arrhythmia (MVA) and end-stage heart failure (esHF) occurred in 12% of TTNtv carriers. In multivariable analysis, NT-proBNP level ≥650 pg/mL was the best predictor of both composite endpoints (MVA and esHF) and of MVA alone. In conclusion, echocardiographic abnormalities are the first detectable anomalies in the course of cardiotitinopathies. The assessment of circulating cardiac biomarkers is not useful in the detection of the disease onset but may be helpful in risk assessment.

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Early detection of anthracycline cardiotoxicity in a rabbit model: left ventricle filling pattern versus troponin T determination

Physiological Research ◽

10.33549/physiolres.931025 ◽

2007 ◽

pp. 535-545

Author(s):

M Štěrba ◽

T Šimůnek ◽

O Popelová ◽

A Potáčová ◽

M Adamcová ◽

...

Keyword(s):

Early Detection ◽

Plasma Levels ◽

Troponin T ◽

Rabbit Model ◽

Left Ventricular ◽

Anthracycline Cardiotoxicity ◽

Anticancer Chemotherapy ◽

Filling Pattern ◽

Significant Impairment ◽

And Control

Anthracycline cardiotoxicity represents a serious risk of anticancer chemotherapy. The aim of the present pilot study was to compare the potential of both the left ventricular (LV) filling pattern evaluation and cardiac troponin T (cTnT) plasma levels determination for the early detection of daunorubicin-induced cardiotoxicity in rabbits. The echocardiographic measurements of transmitral LV inflow as well as cTnT determinations were performed weekly for 10 weeks in daunorubicin (3 mg/kg weekly) and control groups (n=5, each). Surprisingly, no significant changes in LV-filling pattern were observed through the study, most likely due to the xylazine-containing anesthesia, necessary for appropriate resolving of the E and A waves. In contrast to the echographic measurement, the dP/dt(min) index obtained invasively at the end of the study revealed a significant impairment in LV relaxation, which was further supported by observed disturbances in myocardial collagen content and calcium homeostasis. However, at the same time cTnT plasma levels were progressively rising in the daunorubicin-treated animals from the fifth week (0.024+/-0.008 microg/l) until the end of the experiment (0.186+/-0.055 microg/l). Therefore, in contrast to complicated non-invasive evaluation of diastolic function, cTnT is shown to be an early and sensitive marker of anthracycline-induced cardiotoxicity in the rabbit model.

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Titin-Related Dilated Cardiomyopathy: The Sequence of Events and The Role of Circulating Biomarkers in The Clinical Assessment

10.21203/rs.3.rs-692235/v1 ◽

2021 ◽

Author(s):

Przemysław Chmielewski ◽

Grażyna Truszkowska ◽

Ilona Kowalik ◽

Małgorzata Rydzanicz ◽

Ewa Michalak ◽

...

Keyword(s):

Heart Failure ◽

Risk Assessment ◽

Dilated Cardiomyopathy ◽

Troponin T ◽

Left Ventricular Systolic Dysfunction ◽

Multivariable Analysis ◽

Left Ventricular ◽

Cardiac Biomarkers ◽

Sequence Of Events

Abstract Titin truncating variants (TTNtv) are known as the leading cause of inherited dilated cardiomyopathy (DCM). Nevertheless, the clinical course is not fully understood and it is unclear whether circulating cardiac biomarkers are helpful in the detection and risk assessment. We sought to assess: 1) early signs of cardiotitinopathy including serum biomarkers: high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in clinically stable patients, and 2) indicators of outcome among TTNtv carriers. Our single-centre cohort included 108 carriers (including 70 DCM patients) from 43 families. Clinical, laboratory and follow-up data were analyzed. The earliest abnormality was left ventricular dysfunction, present in 8, 26 and 47% of patients in the 2nd, 3rd and 4th decade of life, respectively. It was followed by symptoms of heart failure and elevation of NT-proBNP, linked to severe (persistent or transient) left ventricular systolic dysfunction, and later by arrhythmias, preceding both malignant ventricular arrhythmia (MVA) and end-stage heart failure (esHF). Hs-cTnT serum levels were increased in the late stage of the disease only. During the median follow-up of 5.2 years both MVA and esHF occurred in 12% of TTNtv carriers. In multivariable analysis, NT-proBNP level ≥650 pg/ml was the best predictor of both composite endpoint (MVA and esHF), and of MVA alone. We conclude that assessment of circulating cardiac biomarkers is not useful in the detection of cardiotitinopathies but may be helpful in the risk assessment.

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Longitudinal patterns of N-terminal pro B-type natriuretic peptide, troponin T, and C-reactive protein in relation to the dynamics of echocardiographic parameters in heart failure patients

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jez242 ◽

2019 ◽

Vol 21 (9) ◽

pp. 1005-1012 ◽

Cited By ~ 1

Author(s):

Dominika Klimczak-Tomaniak ◽

Victor J van den Berg ◽

Mihai Strachinaru ◽

K Martijn Akkerhuis ◽

Sara Baart ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Natriuretic Peptide ◽

Troponin T ◽

Relative Increase ◽

Left Ventricular ◽

C Reactive Protein ◽

Reactive Protein ◽

Echocardiographic Parameters

Abstract Aims To further elucidate the nature of the association between N-terminal pro-B type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-TnT), C-reactive protein (CRP), and clinical outcome, we examined the relationship between serial simultaneous measurements of echocardiographic parameters and these biomarkers in chronic heart failure (CHF) patients. Methods and results In 117 CHF patients with ejection fraction ≤50%, NT-proBNP, hs-TnT, and CRP were measured simultaneously with echocardiographic evaluation at 6-month intervals until the end of 30 months follow-up or until an adverse clinical event occurred. Linear mixed effects models were used for data-analysis. Median follow-up was 2.2 years (interquartile range 1.5–2.6). We performed up to six follow-up evaluations with 55% of patients having at least three evaluations performed. A model containing all three biomarkers revealed that doubling of NT-proBNP was associated with a decrease in left ventricular ejection fraction by 1.83 (95% confidence interval −2.63 to −1.03)%, P < 0.0001; relative increase in mitral E/e′ ratio by 12 (6–18)%, P < 0.0001; relative increase in mitral E/A ratio by 16 (9–23)%, P < 0.0001; decrease in tricuspid annular plane systolic excursion by 0.66 (−1.27 to −0.05) mm, P = 0.03; rise in tricuspid regurgitation peak systolic gradient by 2.74 (1.43–4.05) mmHg, P = 0.001; and increase in left ventricular and atrial dimensions, P < 0.05. Hs-TnT and CRP showed significant associations with some echocardiographic parameters after adjustment for clinical covariates, but after adjustment for the other biomarkers the associations were not significant. Conclusion Serum NT-proBNP independently reflects changes in echocardiographic parameters of systolic function, left ventricular filling pressures, estimated pulmonary pressure, and chamber dimensions. Our results support further studies on NT-proBNP as a surrogate marker for haemodynamic congestion and herewith support its potential value for therapy guidance.

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Cardiometabolic Biomarkers and Their Temporal Patterns Predict Poor Outcome in Chronic Heart Failure (Bio-SHiFT Study)

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-01241 ◽

2018 ◽

Vol 103 (11) ◽

pp. 3954-3964 ◽

Cited By ~ 7

Author(s):

Milos Brankovic ◽

K Martijn Akkerhuis ◽

Henk Mouthaan ◽

Jasper J Brugts ◽

Olivier C Manintveld ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Troponin T ◽

Temporal Patterns ◽

Left Ventricular ◽

Clinical Predictors ◽

Igf Binding Proteins ◽

Fatty Acid Binding ◽

End Point

Abstract Purpose Multiple hormonal and metabolic alterations occur in chronic heart failure (CHF), but their proper monitoring during clinically silent progression of CHF remains challenging. Hence, our objective was to explore whether temporal patterns of six emerging cardiometabolic biomarkers predict future adverse clinical events in stable patients with CHF. Methods In 263 patients with CHF, we determined the risk of a composite end point of heart failure hospitalization, cardiac death, left ventricular assist device implantation, and heart transplantation in relation to serially assessed blood biomarker levels and slopes (i.e., rate of biomarker change per year). During 2.2 years of follow-up, we repeatedly measured IGF binding proteins 1, 2, and 7 (IGFBP-1, IGFBP-2, IGFBP-7), adipose fatty acid binding protein 4 (FABP-4), resistin, and chemerin (567 samples in total). Results Serially measured IGFBP-1, IGFBP-2, IGFBP-7, and FABP-4 levels predicted the end point [univariable hazard ratio (95% CI) per 1-SD increase: 3.34 (2.43 to 4.87), 2.86 (2.10 to 3.92), 2.45 (1.91 to 3.13), and 2.46 (1.88 to 3.24), respectively]. Independently of the biomarkers’ levels, their slopes were also strong clinical predictors [per 0.1-SD increase: 1.20 (1.11 to 1.31), 1.27 (1.14 to 1.45), 1.23 (1.11 to 1.37), and 1.27 (1.12 to 1.48)]. All associations persisted after multivariable adjustment for patient baseline characteristics, baseline N-terminal pro-hormone brain natriuretic peptide and cardiac troponin T, and pharmacological treatment during follow-up. Main Conclusions The temporal patterns of IGFBP-1, IGFBP-2, IGFBP-7, and adipose FABP-4 predict adverse clinical outcomes during outpatient follow-up of patients with CHF and may be clinically relevant as they could help detect more aggressive CHF forms and assess patient prognosis, as well as ultimately aid in designing more effective biomarker-guided therapy.

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Oxidative stress and inflammation: determinants of anthracycline cardiotoxicity and possible therapeutic targets

Heart Failure Reviews ◽

10.1007/s10741-020-10063-9 ◽

2020 ◽

Author(s):

Iacopo Fabiani ◽

Alberto Aimo ◽

Chrysanthos Grigoratos ◽

Vincenzo Castiglione ◽

Francesco Gentile ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Imaging Techniques ◽

Significant Risk ◽

Left Ventricular ◽

Cardiac Damage ◽

Anthracycline Cardiotoxicity ◽

Screening Strategies ◽

Dose Dependent

AbstractChemotherapy with anthracycline-based regimens remains a cornerstone of treatment of many solid and blood tumors but is associated with a significant risk of cardiotoxicity, which can manifest as asymptomatic left ventricular dysfunction or overt heart failure. These effects are typically dose-dependent and cumulative and may require appropriate screening strategies and cardioprotective therapies in order to minimize changes to anticancer regimens or even their discontinuation. Our current understanding of cardiac damage by anthracyclines includes a central role of oxidative stress and inflammation. The identification of these processes through circulating biomarkers or imaging techniques might then be helpful for early diagnosis and risk stratification. Furthermore, therapeutic strategies relieving oxidative stress and inflammation hold promise to prevent heart failure development or at least to mitigate cardiac damage, although further evidence is needed on their efficacy, either alone or as part of combination therapies with neurohormonal antagonists, which are the current adopted standard.

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