Current perspectives of cardio-oncology: Epidemiology, adverse effects, pre-treatment screening and prevention strategies.

Cancer and cardiac diseases are the most prevalent causes of death in most developed countries. Due to the earlier detection and higher effectiveness of treatment, more patients survive the disease and have a long life expectancy. As the post-cancer population is growing, an increasing number of patients will be diagnosed with sequelae of those therapies, most often affecting the cardiovascular system. Although the risk of cancer recurrence decreases within years, the risk of cardiac complications-for example left ventricle (LV) systolic and diastolic dysfunction, arterial hypertension, arrhythmias, pericardial effusion and premature coronary artery disease remains elevated for decades after the completion of the therapy. The most common anticancer therapies that can cause adverse cardiovascular effects include chemotherapy-in particular anthracyclines, human epidermal growth receptor 2 targeted drugs and radiation therapy. A new field of research, cardio-oncology, addresses this increasing risk, screening, diagnosis and prevention. This review aims to present the most relevant reports regarding the adverse cardiac effects of oncological therapy, including the most prevalent types of cardiotoxicity, methods of pre-treatment screening and indications for prevention therapy.

Total impact of oxidative stress genes on cardiovascular events-a 7-year follow-up study.

Cardiovascular (CV) events are the number one cause of lifetime disability and deaths worldwide. It is well known that traditional risk factors do not fully correlate with clinical outcomes; therefore, searching for other markers that would explain CV events' occurrence seems essential. Of importance, one of the main factors at the origin of CV events is oxidative stress, causing inflammation and atherosclerotic plaque instability. Therefore, the present study was conducted to evaluate eight carefully selected genetic polymorphisms related to oxidative stress as risk modifiers for CV events. A cohort of 1020 patients with coronary atherosclerosis was analysed in a 7-year follow-up observational study. The following end points were assessed: CV death, myocardial infarction (MI) and a combined end point of CV death/MI/stroke. Our results show that single polymorphisms are not significant cardiovascular disease risk factors, but genetic risk score (GRS), defined as the accumulation of our eight studied polymorphisms, was significantly associated with the three. Specifically, low GRS was associated with a higher risk of CV death, MI and CV death/MI/stroke. In conclusion, when regarding CV events, GRS investigated here can become clinically meaningful and undoubtedly adds to the knowledge in stratifying the risk of CV events.

Speckle-tracking echocardiographic evaluation of the right ventricle in patients with ischemic left ventricular dysfunction.

BACKGROUND: The comprehensive assessment of right ventricular (RV) performance is of paramount importance because it is has been recognized as a strong prognostic factor in a variety of clinical settings. The aim herein was to evaluate the usefulness of RV longitudinal strain imaging by speckle-tracking echocardiography (STE) in daily clinical practice, especially in the context of RV systolic function and its changes after acute coronary syndrome (ACS). METHODS: This prospective study enrolled 63 patients with ischemic injury (left ventricular ejection fraction [LVEF] ≤ 45%). Additionally, a subgroup was created: patients with ACS treated with successful percutaneous coronary intervention. The clinical and echocardiographic parameters, including STE, were analyzed. RESULTS: Significant correlations for both RV free-wall (RVFWSL) and four-chamber (RV4CSL) longitudinal strain evaluated by STE with New York Heart Association class, LVEF, E/E' ratio, as well as conventional parameters of RV function were found. RVFWSL was able to detect subtle RV functional abnormalities, unreachable for traditional indices. RV recovery after ACS was not related to higher LVEF but better contractility of the interventricular septum (IVS) assessed by STE. CONCLUSIONS: Right ventricular strain proved to be a useful two-dimensional echocardiographic method to detect impaired RV performance, which showed a significant relationship with clinical and other echocardiographic indices. The IVS played a vital role in RV recovery among ACS survivors.

Association of Genes Related to Oxidative Stress with the Extent of Coronary Atherosclerosis.

Oxidative stress is believed to play a critical role in atherosclerosis initiation and progression. In line with this, in a group of 1099 subjects, we determined eight single nucleotide polymorphisms (SNPs) related to oxidative stress (PON1 c.575A>G, MPO c.-463G>A, SOD2 c.47T>C, GCLM c.-590C>T, NOS3 c.894G>T, NOS3 c.-786T>C, CYBA c.214C>T, and CYBA c.-932A>G) and assessed the extent of atherosclerosis in coronary arteries based on Gensini score. An increased risk of having a Gensini score in the higher half of the distribution was observed for the PON1 c.575G allele (odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.004-1.617, p = 0.046). Next, the genetic risk score (GRS) for the additive effect of the total number of pro-oxidative alleles was assessed. We noted an increase in the risk of having a Gensini score above the median with the maximum number of risk alleles (OR = 2.47, 95% CI: 1.19-5.23, p = 0.014). A univariate Spearman's test revealed significant correlation between the total number of pro-oxidant alleles (GRS) and the Gensini score (ρ = 0.068, p = 0.03). In conclusion, the PON1 c.575A>G variant and the high number of risk alleles (GRS) were independent risk factors for a high Gensini score. We suggest, however, that GRS might occur as a more valuable component in adding a predictive value to the genetic background of atherosclerosis.

NADPH Oxidase Gene Polymorphism is Associated with Mortality and Cardiovascular Events in 7-Year Follow-Up.

The CYBA gene encodes the regulatory subunit of NADPH oxidase, which maintains the redox state within cells and in the blood vessels. That led us to investigate the course of coronary artery disease (CAD) with regards to CYBA polymorphisms. Thus, we recruited 1197 subjects with coronary atherosclerosis and observed them during 7-year follow-up. Three CYBA polymorphisms: c.214C>T (rs4673), c.-932G>A (rs9932581), and c.*24G>A (1049255) were studied for an association with death, major adverse cardiovascular events (MACE) and an elective percutaneous coronary intervention or coronary artery bypass grafting (PCI/CABG). We found an association between the CYBA c.214C>T polymorphism and two end points: death and PCI/CABG. CYBA c.214TT genotype was associated with a lower risk of death than C allele (9.5% vs. 21%, p < 0.05) and a higher risk of PCI/CABG than C allele (69.3% vs. 51.7%, p < 0.01). This suggests that the CYBA c.214TT genotype may be a protective factor against death OR = 0.47 (95%CI 0.28-0.82; p < 0.01), while also being a risk factor for an elective PCI/CABG OR = 2.36 (95%CI 1.15-4.82; p < 0.05). Thus, we hypothesize that among patients with coronary atherosclerosis, the CYBA c.214TT genotype contributes to atherosclerotic plaque stability by altering the course of CAD towards chronic coronary syndrome, thereby lowering the incidence of fatal CAD-related events.

Genetic risk factors influence nighttime blood pressure and related cardiovascular complications in patients with coronary heart disease.

Genetic predisposition of elevated nighttime blood pressure (BP) in patients with coronary heart disease is unknown. We evaluated genetic predisposition and the relationship between elevated nighttime BP and cardiovascular complications over a median of 8.6 years of observation of hypertensive subjects with coronary atherosclerosis confirmed by coronary angiography. Genetic Risk Score (GRS19) was constructed to evaluate the additive effect of single-nucleotide polymorphisms for daytime and nighttime BP. The Receiver Operating Characteristic was used for determination of cutoff points for daytime BP (systolic BP (SBP) 133 mm Hg and diastolic BP (DBP) 77 mm Hg) and nighttime BP (SBP 122 mm Hg and DBP 73 mm Hg). The curves of cumulative incidence revealed an increased risk of major advanced cardiovascular events in subjects with elevated nighttime BP compared with those without elevated nighttime BP during the follow-up period. Subjects with normal daytime and elevated nighttime BP exhibited increased GRS19 compared with those with normal daytime and nighttime BPs (8.6±3.0 vs. 7.9±3.0, P<0.01). After adjustment for cardiovascular risk factors, GRS19 determined nighttime SBP (ß 0.4, 95% confidence interval (CI) 0.3-0.5, P<0.01). Our study confirmed that elevated nighttime SBP was genetically determined and related to an increased risk of major adverse coronary events in patients with confirmed coronary atherosclerosis.

Echocardiographic evaluation of right ventricular systolic function: The traditional and innovative approach.

Estimation of right ventricular (RV) performance still remains technically challenging due to its anatomical and functional distinctiveness. The current guidelines for the echocardiographic quantification of RV function recommend using multiple indices to describe the RV in a thorough and comprehensive manner, such as RV index of myocardial performance, tricuspid annular plane systolic excursion, fractional area change, Doppler tissue imaging-derived tricuspid lateral annular systolic velocity (S'-wave), three-dimensional RV ejection fraction (3D RVEF), RV longitudinal strain (RVLS)/strain rate by speckle- tracking echocardiography (STE). Among these, the last one mentioned here is an innovative and a particularly promising tool that yields more precise information about complex regional and global RV mechanics. STE was initially designed to evaluate left ventricular function, but recently it has been introduced to assess RV performance, which is difficult due to its unique structure and physiology. Many studies have shown that both free wall and 6-segment RVLS present a stronger correlation with the RVEF assessed by cardiac magnetic resonance than conventional parameters and seem to be more sensitive in detecting myocardial dysfunction at an earlier, subclinical stage.

Elevated ambulatory systolic-diastolic pressure regression index is genetically determined in hypertensive patients with coronary heart disease.

OBJECTIVES: Ambulatory systolic-diastolic pressure regression index (ASDPRI) as a composite marker of cardiovascular (CV) properties is related to CV complications. However, genetic determinants of ASDPRI are not known. The aim of this study is to report the relationship between certain single nucleotide polymorphisms (SNP) and ASDPRI in hypertensive patients with CAD confirmed by coronary angiography. METHODS: A total of 1345 hypertensive subjects with CAD were included. SNPs were selected from genome-wide association studies. SNPs were reported to be associated with coronary artery disease risk. There were significant differences in 24 h and daytime and nighttime ASDPRIs for PHCTR1, LPA and ADAMTS7 polymorphisms. Genetic risk score (GRS18) was constructed to evaluate additive effect of 18 SNPs for ASDPRI. RESULTS: Analysis of covariance revealed a significant relationship between the PPAB2B (ß - 0.85; 95 CI -1.85--0.16, p < 0.02), WDR12 (ß - 1.31; 95 CI -2.19--0.43, p < 0.01) polymorphisms and nighttime ASDPRI dipping. Analysis of covariance revealed a significant relationship between GRS 18 and 24-h ASDPRI (ß 0.34; 95 CI 0.16-0.31, p < 0.01). CONCLUSIONS: In conclusion, ADAMTS7 and LPA polymorphisms are related to 24-h ASDPRI but PPAB2B and WDR12 gene polymorphisms are associated with nighttime ASDPRI dipping. A total of 24-h ASDPRI is determined by GRS18.

Diurnal blood pressure profile and coronary atherosclerosis extent are related to cardiovascular complications.

The aim of this study was to assess the relationship between 24 h blood pressure (BP) profile, extent of significant coronary artery stenosis, confirmed by coronary angiography, and cardiovascular events in patients with coronary artery disease. Coronary angiographies were performed for all included subjects and significant coronary artery stenosis was considered as ≥ 50% stenosis by atherosclerotic plaque. Twenty-four-hour ambulatory BP monitoring was performed. Major advanced cardiovascular events (MACE) included revascularization, cardiovascular mortality, total mortality, acute coronary syndromes and stroke. BP analysis revealed higher night-time systolic blood pressure (SBP) values in patients with three or more significant coronary artery stenoses than in those without significant stenosis (120.7 ± 16.4 vs 116.7 ± 14.3 mmHg, p < 0.001), lower night-time SBP dip in patients with three or more significant coronary artery stenoses than in those without significant stenosis (5.7 ± 3.2 vs 7.4 ± 6.8 mmHg, p < 0.001) and lower night-time diastolic blood pressure dip in patients with three or more significant stenoses than in patients without significant stenosis (9.4 ± 7.4 vs 11.9 ± 7.4 mmHg, p < 0.001). Night-time SBP values, night-time/daytime SBP dip and extent of significant coronary artery stenosis were risk factors for MACE, revascularization and cardiovascular mortality. In conclusion, the study shows that advanced coronary artery disease is related to blunted night-time BP dipping and cardiovascular complications.

Relationship between selected DNA polymorphisms and coronary artery disease complications.

BACKGROUND: Coronary heart disease (CHD) development is complex in origin, with contributions from well-defined lifestyle and not well-determined genetic risk factors. The aim of this study is to report the relationship between certain SNPs and the risk of cardiovascular (CV) complications in patients with CAD confirmed by coronary angiography. METHODS: In the present study, 1345 subjects with CHD were included. The median follow-up period was 8.6years. 19 SNPs were investigated for any association with Major Advanced CV Events (MACE), Acute Coronary Syndromes (ACS) and Revascularizations. We modeled the 19 SNPs as a multilocus genetic risk score (GRS19). RESULTS: During follow-up period, 245 participants died; 114 due to CV causes. A fatal or non-fatal CV event occurred in 882 participants including 214 ACS, 578 revascularizations and 90 strokes. The alleles of the following SNPs: rs1746048 (CXCL12), rs9818870 (MRAS) and rs17114036 (PPAP2B) were associated with a higher risk of MACE and the alleles of SNPs rs1746048 (CXCL12) and rs1122608 (LDLR) were associated with a higher risk of revascularization. The alleles of rs12190287 (MRAS), rs121902287 (TCF21) and rs2259816 (HNF1a) were associated with a higher risk of ACS. Despite the lack of relationship between significant CAD and GRS19, in the top quartile of GRS19 there was significant relationship between GRS19 and combined endpoint, MACE, ACS, and revascularization. CONCLUSIONS: Conclusions. The SNPs of CXCL12 and LDLR were associated with risk of revascularization and CXCL12, LPA, MRAS, and PPAP2B were associated with the risk of MACE. GRS19 determines CV complications in CAD patients with the highest genetic risk score values.

The Relationship Between Gene Polymorphisms and Dipping Profile in Patients With Coronary Heart Disease.

BACKGROUND: The aim of this study is to report the relationship between certain single-nucleotide polymorphisms (SNPs) and blunted nighttime blood pressure (BP) fall in patients with coronary artery disease confirmed by coronary angiography. METHODS: According to the percentage decrease in mean systolic BP (SBP) and diastolic BP (DBP) during the nighttime period, subjects were classified as dippers or nondippers (nighttime relative SBP or DBP decline ≥10% and <10%, respectively). Genetic risk score (GRS18) was constructed to evaluate additive effect of 18 SNPs for nondipping status. RESULTS: In the present study, 1,345 subjects with coronary heart disease (CHD) were included. During follow-up period (median 8.3 years, interquartile range 5.3-9.0 years), there were 245 all-cause deaths (18.2%) including 114 cardiovascular deaths (8.5%). There were significant differences in the number of revascularizations between nondippers SBP and DBP and dippers SBP and DBP (48.0% vs. 36.4%, P < 0.01). SNPs of the genes, MIA3, MRAS, PCSK9, SMG6, and ZC3HC1, were related to a higher risk of nondipping SBP and DBP status. CONCLUSIONS: In the present study, polymorphisms of genes related to CHD (MIA3, MRAS, PCSK9, SMG6, and ZC3HC1) were associated with nondipping SBP and DBP profile, and GRS18 was associated with nondipping status. In addition, this profile was related to a higher risk of revascularization.

Superiority of waist circumference and body mass index in cardiovascular risk assessment in hypertensive patients with coronary heart disease.

INTRODUCTION: It has been reported in coronary heart disease (CHD) patients that mortality is inversely associated with body mass index (BMI), and directly associated with waist circumference (WC). The purpose of this study was to examine the association of the general obesity parameter (BMI) and the adipose tissue discriminator (WC) with cardiovascular (CV) risk in patients with CHD established by coronary angiography. OBJECTIVES: 1345 subjects with CHD were included in the PROGNOSIS (Prognostic Value of Ambulatory Blood Pressure Monitoring in Patients with Coronary Artery Disease Confirmed by Angiography) study. PATIENTS AND METHODS: A multivariate Cox proportional regression model adjusted for potential confounders was used to assess the relative risk of total and CV mortality according to the parameters of general obesity (BMI) and adipose tissue distribution (WC).The mean age of subjects was 63.2 ± 9.2 years, and 57% were men. Results. There was direct relationship between WC and both total mortality [hazard ratio, HR = 1.03 (95% CI 1.01-1.10), p < 0.01] and CV mortality [HR = 1.03 (95% CI 1.01-1.07), p < 0.03], but an inverse relationship between BMI and both total mortality [HR = 0.91 (95% CI 0.86-0.98), p < 0.03] and CV mortality [HR = 0.97 (95% CI 0.87-0.99), p < 0.05]. After combining WC with BMI, the group of subjects with BMI < 25 kg/m(2) and WC ≥ 104 cm had the highest rates of both total and CV mortality of all CHD patients. CONCLUSIONS: Assessment based on a combination of WC and BMI is superior to assessment based on a separate estimation of these parameters in both total and CV mortality risk evaluation.

Mortality in hypertensive patients with coronary heart disease depends on chronopharmacotherapy and dipping status.

BACKGROUND: The goal of our study was to assess the influence of hypertension chronopharmacotherapy on diurnal blood pressure (BP) profile and mortality. METHODS: Subjects with established coronary heart disease (CHD) (n = 1345, mean age 63.2 ± 9.2 years) were included. RESULTS: Non-dipping status was related to a lack of nighttime hypertensive drug administration (OR 3.87, 95% CI 3.00-4.98). In a Cox proportional hazards regression model, non-dipping status (HR 1.17, 95% CI 1.02-1.47) and non-nighttime antihypertensive drug administration (HR 1.13, 95% CI 1.01-1.45) were predictors of all-cause mortality. CONCLUSIONS: The non-dipping profile of CHD patients and increased mortality were related to a lack of antihypertensive drug administration at bedtime.

Is daytime blood pressure adequate in cardiovascular risk assessment in patients with coronary atherosclerosis?

OBJECTIVES: The goal of our study was to estimate the impact of abnormal night-time blood pressure (BP) on cardiovascular (CV) mortality in hypertensive patients with significant atherosclerosis established in coronary angiography. METHOD: We enrolled 891 patients, 63.7 ± 9.4 years of age. They were divided into patients with normal daytime BP values, and patients with abnormal daytime BP values. During a follow-up period of 4.7 years in total, all-cause mortality and both CV and non-CV mortality were assessed. RESULTS: In the group with normal daytime BP, a clinic BP value ≥ 140/90 mmHg was observed in 25.7% (n = 161) of patients, and a night-time BP value ≥ 120/70 mmHg was observed in 37.8% (n = 236) of patients. In the group of patients with normal daytime BP in comparison with those with abnormal daytime BP, there was lower CV mortality (5.6% vs 9.8%, p < 0.02). Abnormal daytime BP was associated with a hazard ratio of CV mortality of 1.80 (95% CI 1.08-3.00, p < 0.02), and abnormal night-time BP with a hazard ratio of 1.63 (95% CI 1.03-2.66, p < 0.04). CONCLUSION: Assessment of both daytime and night-time BP is essential and superior over clinic BP in CV risk evaluation in patients with coronary artery disease confirmed in coronary angiography.

Severity of coronary atherosclerosis and stroke incidence in 7-year follow-up.

The purpose of this prospective study was to investigate the association between the severity of coronary atherosclerosis in angiography and the risk of stroke in symptomatic coronary artery disease (CAD) patients without atrial fibrillation or atrial flutter. Associations between stroke and coronary artery disease were examined in 1,183 subjects without a history of stroke and who were referred for diagnostic coronary angiography. Association between stoke and coronary artery disease was determined using the COX proportional hazard regression model. During the follow-up period (mean 6.7 years), 50 strokes occurred. In the group with strokes there was a higher prevalence of multi-vessel coronary artery disease (62 vs. 46 %, p < 0.01). In the COX proportional hazard regression model, multi-vessel CAD was significantly associated with the stroke hazard ratio (HR) of 1.8 (CI 1.03-3.43), determined from a 7-year period of observation. Symptomatic patients with multi-vessel CAD are thus at a high risk of stroke development.

Heart rate and double product in relation to insulin resistance in patients with hypertension and coronary artery disease.

BACKGROUND: Elevated values of heart rate (HR) and insulin resistance (IR) reflect enhanced sympathetic nervous system activity and may be connected to the development of coronary artery disease (CAD) and diabetes. AIM: To evaluate the relationship between HR, blood pressure (BP), double product and IR in nondiabetic hypertensive patients with stable CAD. METHODS: There were 73 patients included in the study. Ambulatory BP monitoring was recorded in all patients by a Spacelabs 90207 device. Homeostasis model assessment (HOMA-IR) was used to estimate IR. Double product was calculated by multiplying systolic BP and HR. RESULTS: In the study population (mean age 67.1 ± 8.4 years, 52% males) there was a positive correlation between HOMAIR and 24-h double product (r = 0.35, p < 0.01) and body mass index (BMI) (r = 0.45, p < 0.001). The receiver operating characteristic analysis of 24-h double product and BMI as predictive markers of IR did not reveal statistical differences between AUC (0.72 ± 0.09 vs. 0.72 ± 0.08, 24-h double product and BMI, respectively, p = NS). The best cut-off points in predicting IR were 8,978 mm Hg/min for 24-h double product and 33.02 kg/m2 for BMI. There were differences between the non obese (n = 44, mean age 67.9 ± 9.2 years) and obese (n = 29, mean age 65.8 ± 6.9 years) groups in: serum insulin level (7.3 ± 2.3 µU/mL vs. 12.0 ± 7.3 µU/mL, p < 0.01), HOMA-IR (1.8 ± 0.7 µU/mL × mmol/L vs. 3.0 ± 2.0 µU/mL × mmol/L, p < 0.01), and day systolic BP (128.0 ± 10.8 mm Hg vs. 134.1 ± 10.1 mm Hg, p < 0.02). CONCLUSIONS: 24-h double product and BMI may be complementary parameters in the prediction of IR in hypertensive nondiabetics with CAD confirmed by percutaneous coronary interventions in history and/or at least one coronary artery stenosis ? 70% in elective coronary angiography.

Ambulatory systolic-diastolic pressure regression index predicts acute coronary syndromes.

OBJECTIVES: Ambulatory systolic-diastolic pressure regression index (ASDPRI) is a composite marker of cardiovascular properties. The study was conducted to investigate the relationship between ASDPRI and cardiovascular events in patients with significant coronary atherosclerosis confirmed in angiography. METHODS: Associations between ASDPRI and cardiovascular events were examined in 891 subjects referred for diagnostic coronary angiography. ASDPRI was calculated as 1 minus the slope of the linear relation between 24-h DBP and 24-h SBP. RESULTS: During follow-up (median 6.7 years), 135 acute coronary syndromes (ACS), including five deaths and 55 strokes occurred in the studied group. There was a higher 24-h ASDPRI in patients with ACS than in patients with no ACS (0.35 ± 01 vs 0.30 ± 0.1, p < 0.01); 24-h ASDPRI was the independent predictor for ACS (OR = 4.0; 95% CI 1.3-12.0). CONCLUSIONS: ASDPRI has an important role as a risk factor of ACS in patients with coronary atherosclerosis.