Women's cardiovascular health - the cardio-oncologic jigsaw.

Improvements in cancer care have led to an exponential increase in cancer survival. This is particularly the case for breast cancer, where 5-year survival in Australia exceeds 90%. Cardiovascular disease (CVD) has emerged as one of the competing causes of morbidity and mortality among cancer survivors, both as a complication of cancer therapies and because the risk factors for cancer are shared with those for CVD. In this review we cover the key aspects of cardiovascular care for women throughout their cancer journey: the need for baseline cardiovascular risk assessment and management, a crucial component of the cardiovascular care; the importance of long-term surveillance for ongoing maintenance of cardiovascular health; and strong evidence for the beneficial effects of physical exercise to improve both cancer and cardiovascular outcomes. There is general disparity in cardiovascular outcomes for women, which is further exacerbated when both CVD and cancer co-exist. Collaboration between oncology and cardiac services, with an emergence of the whole field of cardio-oncology, allows for expedited investigation and treatment for these patients. This collaboration as well as a holistic approach to patient care and key role of patients' general practitioners are essential to ensure long-term health of people living with, during and beyond cancer.

European Society of Cardiology quality indicators for the prevention and management of cancer therapy-related cardiovascular toxicity in cancer treatment.

AIMS: To develop quality indicators (QIs) for the evaluation of the prevention and management of cancer therapy-related cardiovascular toxicity. METHODS AND RESULTS: We followed the European Society of Cardiology (ESC) methodology for QI development which comprises (i) identifying the key domains of care for the prevention and management of cancer therapy-related cardiovascular toxicity in patients on cancer treatment, (ii) performing a systematic review of the literature to develop candidate QIs, and (iii) selecting of the final set of QIs using a modified Delphi process. Work was undertaken in parallel with the writing of the 2022 ESC Guidelines on Cardio-Oncology and in collaboration with the European Haematology Association, the European Society for Therapeutic Radiology and Oncology and the International Cardio-Oncology Society. In total, 5 main and 9 secondary QIs were selected across five domains of care: (i) Structural framework, (ii) Baseline cardiovascular risk assessment, (iii) Cancer therapy related cardiovascular toxicity, (iv) Predictors of outcomes, and (v) Monitoring of cardiovascular complications during cancer therapy. CONCLUSION: We present the ESC Cardio-Oncology QIs with their development process and provide an overview of the scientific rationale for their selection. These indicators are aimed at quantifying and improving the adherence to guideline-recommended clinical practice and improving patient outcomes.

Cardiotoxicity of Radiation Therapy: Mechanisms, Management, and Mitigation.

OPINION STATEMENT: Radiation therapy is a key component of modern-day cancer therapy and can reduce the rates of recurrence and death from cancer. However, it can increase risk of cardiovascular (CV) events, and our understanding of the timeline associated with that risk is shorter than previously thought. Risk mitigation strategies, such as different positioning techniques, and breath hold acquisitions as well as baseline cardiovascular risk stratification that can be undertaken at the time of radiotherapy planning should be implemented, particularly for patients receiving chest radiation therapy. Primary and secondary prevention of cardiovascular disease (CVD), as appropriate, should be used before, during, and after radiation treatment in order to minimize the risks. Opportunistic screening for subclinical coronary disease provides an attractive possibility for primary/secondary CVD prevention and thus mitigation of long-term CV risk. More data on long-term clinical usefulness of this strategy and development of appropriate management pathways would further strengthen the evidence for the implementation of such screening. Clear guidelines in initial cardiovascular screening and cardiac aftercare following radiotherapy need to be formulated in order to integrate these measures into everyday clinical practice and policy and subsequently improve post-treatment morbidity and mortality for these patients.

The nitric oxide redox sibling nitroxyl partially circumvents impairment of platelet nitric oxide responsiveness.

Impaired platelet responsiveness to nitric oxide (NO resistance) is a common characteristic of many cardiovascular disease states and represents an independent risk factor for cardiac events and mortality. NO resistance reflects both scavenging of NO by superoxide (O2(-)), and impairment of the NO receptor, soluble guanylate cyclase (sGC). There is thus an urgent need for circumvention of NO resistance in order to improve clinical outcomes. Nitroxyl (HNO), like NO, produces vasodilator and anti-aggregatory effects, largely via sGC activation, but is not inactivated by O2(-). We tested the hypothesis that HNO circumvents NO resistance in human platelets. In 57 subjects with or without ischemic heart disease, platelet responses to the HNO donor isopropylamine NONOate (IPA/NO) and the NO donor sodium nitroprusside (SNP) were compared. While SNP (10µM) induced 29±3% (p<0.001) inhibition of platelet aggregation, IPA/NO (10µM) caused 75±4% inhibition (p<0.001). In NO-resistant subjects (n=28), the IPA/NO:SNP response ratio was markedly increased (p<0.01), consistent with partial circumvention of NO resistance. Similarly, cGMP accumulation in platelets was greater (p<0.001) with IPA/NO than with SNP stimulation. The NO scavenger carboxy-PTIO (CPTIO, 200µM) inhibited SNP and IPA/NO responses by 92±7% and 17±4% respectively (p<0.001 for differential inhibition), suggesting that effects of IPA/NO are only partially NO-mediated. ODQ (10µM) inhibited IPA/NO responses by 36±8% (p<0.001), consistent with a contribution of sGC/haem to IPA/NO inhibition of aggregation. There was no significant relationship between whole blood ROS content and IPA/NO responses. Thus the HNO donor IPA/NO substantially circumvents platelet NO resistance while acting, at least partially, as a haem-mediated sGC activator.

Prevention of aortic valve stenosis: a realistic therapeutic target?

Aortic valve stenosis (AS) is the most common form of valvular heart disease in the Western world, affecting ~40% of the population over the age of 80; to date the only established treatment is valve replacement. However, AS progression occurs over many years, and is associated from its earliest stages with increased risk of coronary events. Recent insight into the pathophysiology of AS has included central roles for angiotensin II, for diminished nitric oxide effect at the level of valve endothelium and matrix, and for inflammatory activation/redox stress culminating in activation of pro-calcific stimuli. Despite the presence of atheroma within the stenotic valve, hyperlipidemia per se does not play a critic role in the development of obstructive disease. We review emerging options for pharmacotherapy of AS, including in particular retardation of disease progression. The various clinical evaluations of lipid-reducing therapy have been uniformly unsuccessful in slowing AS progression. However, recent studies in animal models and retrospective evaluations in humans suggest that ACE inhibitors and/or angiotensin receptor blockers may be effective in this regard. Furthermore, agents normally utilized to treat osteoporosis also offer promise in retarding AS. Given the considerable morbidity, mortality and health care costs associated with AS, such therapeutic developments should be expedited.

Determinants of insulin responsiveness in young women: Impact of polycystic ovarian syndrome, nitric oxide, and vitamin D.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with incremental risk of atherosclerosis and possibly of cardiovascular events. Insulin resistance (IR) occurs frequently in PCOS subjects, which might be one of the mechanisms involved in engendering such risk. We sought to evaluate whether the impact of other factors potentially associated both with PCOS and with IR might differentially modulate degree of IR in women with and without PCOS. METHODS AND RESULTS: We measured body mass index (BMI), hs-CRP, plasma concentrations of asymmetric dimethylarginine (ADMA), vitamin D (25(OH)D3) levels and platelet responsiveness to nitric oxide donor sodium nitroprusside (NO responsiveness) in 47 young women (n=27 with PCOS and n=20 weight-matched controls) without metabolic syndrome, hypertension or overt cardiovascular disease. We performed univariate and multivariate regression analyses to establish correlates of the quantitative insulin-sensitivity check index (QUICKI), as a marker of IR. On univariate analysis, plasma 25(OH)D3 levels and low NO responsiveness tended to be direct correlates with QUICKI in the entire subject group. BMI, hs-CRP, and ADMA levels were significant inverse correlates of QUICKI in PCOS subjects, but not in subjects without PCOS. On multivariate analysis, NO responsiveness, and 25(OH)D3 levels, but not PCOS per se were significant correlates of QUICKI. CONCLUSIONS: In the entire cohort of young women, low NO responsiveness and vitamin D deficiency are associated with low QUICKI, while elevated ADMA, inflammatory activation and obesity are selectively associated with low QUICKI in PCOS subjects; this may contribute to the increased cardiovascular risk associated with this syndrome.

The endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) predicts LV mass independent of afterload.

BACKGROUND: Nitric oxide (NO) is a modulator of left ventricular hypertrophy (LVH) and myocardial relaxation. The impact of NO availability on development of LVH has never been demonstrated in humans. We tested the hypotheses that elevation of asymmetric dimethylarginine (ADMA) concentrations (biochemical marker of decreased NO generation), and impairment of vascular responsiveness to NO donor GTN, would each predict the presence of LVH and associated LV diastolic dysfunction in a normal aging population. METHODS AND RESULTS: In 74 subjects aged 68±6 years, LV volumes and mass indexed to height(2.7) (LVMI) were calculated from cardiac MRI. Despite the absence of clinically-defined LVH, there was a relationship (r=0.29; p=0.01) between systolic BP and LVMI. Both elevation of ADMA levels to the highest quartile or impairment of GTN responsiveness (determined by applanation tonometry) to the lowest quartile were determinants of LVMI independent of systolic BP (p=0.01 and p=0.03, respectively). Filling pressure (E/E' ratio from echocardiography) was increased in patients with impaired vascular NO responsiveness (p<0.05) irrespective of LVMI. ADMA remained a significant determinant of LVMI on multivariate analysis. CONCLUSIONS: These data imply that NO bioavailability within the myocardium modulates earliest stages of LVH development and facilitates development of diastolic dysfunction at a given LV mass.

[The influence of sodium nitrite on the osmoresistance of Chinese hamster cells].

We have previously demonstrated that incubation of V-79 cells in the medium containing the nitric oxide donor, NaNO2, increases cell resistance to damaging effect of gamma-rays, UV radiation and hyperthermia. In the present study, we investigated the effects of the nitric oxide donor on the sensitivity of V-79 cells to changes in osmomolarity of the medium by adding different amounts of sodium chloride or water. We found that pretreatment of the cells with NaNO2 resulted in a significant increase in the number of growing cells in 48 h after the treatment. The osmomolarity-dependent morphological changes in cultured cells were also substantially diminished following NaNO2 treatment. This effect could be observed under both hyper- and hypoosmosis, and was dependent on concentration of sodium chloride in hypertonic medium (being maximal under 0.17 M NaCl) and on the amount of water in hypotonic medium (being maximal under 1.1 times the dilution with water). In the experiments with increased osmomolarity, we found that the observed increase in the number of growing cells following NaNO2 treatment was accompanied with a significant increase of the mitotic index. These findings indicate that nitric oxide increases cell resistance to the damaging effects of osmotic shock in the way which is similar to the protective effect of these molecules against radiation and hyperthermia. Similarities in the effects of NaNO2 under different conditions leading to cell damage suggest that nitric oxide might serve as the universal factor participating in recovery of damaged cells and mediating increased cellular resistance to the damaging conditions.

[The influence of nitric oxide inductor (NaNO2) on the sensitivity of Chinese hamster cells to hyperthermia].

Formerly we reported the reduction of sensitivity to gamma- and UV-radiation in Chinese hamster cells of line 90 under the influence of nitric oxide inductor (NaNO2). Of interest was to learn if it possible to reduce the influence of hyperthermia on cells by means of NO inductor. A 1 h long incubation with this NO donor demonstrated an increased survival of cells heated up to 45 degrees C, and a decreased frequency of chromosomal aberrations in these. Employment of cycloheximide (CHE), an inhibitor of protein synthesis, and administration of CHE together with nitric oxide donor (NaNO2), equally increased the cell survival at hyperthermia. These and relevant literature data suggest that the demonstrated effect of exogenous NO may be associated with HSP70 protein. The noticed decrease in the number of chromosomal aberrations in heated cells under the influence of NO donor may play an important role in its modifying effect on cells at hyperthermia.

[Effect of nitric oxide donor (NaNO2) on the stability of non-transformed and malignant cells to ultraviolet and gamma-radiation]. / Vliianie donora oksida azota (NaNO2) na ustoichivost' netransformirovannykh i zlokachestvenno pererozhdennykh kletok k ultrafioletovomu i gamma-izlucheniiam.

A decreased sensitivity of the Chinese hamster cells (line V-79) to gamma-radiation under the influence of nitric oxide induction was shown elsewhere. This effect is connected hypothetically with post-radiation reparation of DNA. The investigation of the nitric oxide donor effect on sensitivity of these to UV-radiation is of interest, because this radiation is an important ecological factor of the environment. The question of retention of nitric oxide positive effect on UV and gamma-radiation sensitivity in malignant HeLa cells is no less actual, because these cells significantly differ from normal cells of line V-79. We demonstrated that the donor of nitric oxide enhances stability of the Chinese hamster cells (line V-79) to UV-radiation, as well as to gamma-radiation independently of the time of cell incubation with sodium oxide donor before or after irradiation. The inefficiency of nitric oxide as a factor increasing UV-stability of cells was shown for malignant HeLa cells. A 1 h long incubation of these cells with NO-donor before gamma-irradiation decreased the number of chromosome aberrations, and conversely, the addition of this agent to the HeLa cell culture after gamma-irradiation did not change the radiostability. It may be inferred that distinctions in behaviour of nitric oxide in cultures of V-79 and HeLa cells using UV-radiation may be explained by transformation of the latter special features of their damage, and by the following reparation.

Navigation and thermophotovoltaic activity by hornets at different light conditions: the influence of UVB blockers.

The aim of the present investigation was two-fold: a) to observe the homing of the Oriental hornet, Vespa orientalis (Hymenoptera, Vespinae) from different distances; and b) to study the photothermoelectric activity of hornet cuticle obtained from the subjects of goal (a) and kept frozen for a number of days prior to its testing. In both the above mentioned phases of the investigation, an attempt was made to assess how the covering of the hornets' cuticle with Ultra Violet B (UVB) blockers affects their activity as compared to the control. Flying hornets were observed to return to the nest from distances of up to 7 km, once they had learned the way back. However, covering of the cuticle with UVB blockers increases the percentage of 'non-returners' to nearly 100%. Covering the cuticle completely or partly with a number of UVB blockers (except for Sisley) proves lethal for the hornets within 24 hours. A statistical model on homing is proposed of the effect of range, of covering with UVB blockers and covering ocelli with Tippex. In the wing of the hornet there is increase in the electric current with rise in the temperature and decrease in the current upon drop of the temperature, but light has no effect on this alar (wing) current. Contrariwise, the body cuticle of the hornet responds to both temperature and illumination in terms of its electric current. Coating of the cuticle with UVB blockers causes in the wing (under all conditions of illumination) and in the cuticle (only in the dark) a moderation in the amplitude of the photothermoelectric current.

Thermophotovoltaic (TPV) properties of hornet cuticle as dependent on relative humidity.

This paper deals with the thermophotovoltaic (TPV) properties of the cuticle of the Oriental hornet as assessed over time under different regimens of relative humidity (RH). The tests were run at two levels of RH, namely, 30% vs. 90%. Each experiment entailed measuring the cuticular voltage and current in the dark as compared to under illumination (white light = 700 Lux), and at a temperature range of 20-30 degrees C. It was found that increase in the RH level boosts the current values by 2-3 orders of magnitude; contrariwise, the voltage values rise by about three times with drop in the RH. At high RH, the changes in current become rhythmical and each cycle of warming-cooling assumes a distinctly cyclic pattern. Under illumination, the current decreases, the polarity reverses and the resistance increases. The obtained results are describable by a model of electric conductance upon a surface, in this case the hornet cuticle; the findings are also discussed and compared with similar phenomena recorded from other substances possessing the properties of organic semiconductors.

[Increased efficacy of radiation protection against fission neutrons using unithiol]. / Povyshenie éffektivnosti khimicheskoi zashchity ot neitronov deleniia s pomoshch'iu unitiola.

It was found that the combination of unithiol (Sodium salt of 2,3-dimercapto-1-propansulfonic acid) with cystamine and AET diminished their toxicity. The optimum ratio for the antitoxic effect is 0.5 molar equivalent of unithiol per radioprotective 1.0 equivalent of thiol. Animals withstand big doses of protectors well, that gives an opportunity to use increased amounts of cystamine and AET. In the experiments with circular irradiation of male (CBA x C57B1)F1 mice weighing 18-22 g with fission neutrons (the neutron mean energy was 0.85 MeV, the contribution of gamma-quanta to the total was 25%, dose rate was 14 cGy/min) it was shown that the combination of unithiol with cystamine and AET enhances their radioprotective effect: the DRF of cystamine (150 mg/kg)--1.1, and the DRF of the combination of cystamine (300 mg/kg) with unithiol (152 mg/kg)--1.2; the DRF of AET (150 mg/kg)--1.2, the DRF of the combination of AET (300 mg/kg) with unithiol--1.4. Thus, the enhancement of dose of the radioprotectors, which was made possible as a result of their combination with unithiol, leads to enhancement of efficacy of chemical protection against fission neutron irradiation as much as 10-20%. Efficacy of AET is found to be comparable to efficacy of this protector in conditions of X-rays irradiation.

[Effect of unithiol on cystamine toxicity in dogs]. / Vliianie unitiola na toksicheskie éffekty tsistamina u sobak.

In experiments with dogs it was shown that administration of unithiol before administration of cystamine decreases toxic effect of the last: period of excitation induced by cystamine is shortened, the time of emetic reaction decreases and expression of the emetic reaction to this preparation is diminished, the recorded EKG changes of conditions of heart decrease.