Cardiomyocyte Damage: Ferroptosis Relation to Ischemia-Reperfusion Injury and Future Treatment Options.

About half a century ago, Eugene Braunwald, a father of modern cardiology, shared a revolutionary belief that "time is muscle", which predetermined never-ending effort to preserve the unaffected myocardium. In connection to that, researchers are constantly trying to better comprehend the ongoing changes of the ischemic myocardium. As the latest studies show, metabolic changes after acute myocardial infarction (AMI) are inconsistent and depend on many constituents, which leads to many limitations and lack of unification. Nevertheless, one of the promising novel mechanistic approaches related to iron metabolism now plays an invaluable role in the ischemic heart research field. The heart, because of its high levels of oxygen consumption, is one of the most susceptible organs to iron-induced damage. In the past few years, a relatively new form of programmed cell death, called ferroptosis, has been gaining much attention in the context of myocardial infarction. This review will try to summarize the main novel metabolic pathways and show the pivotal limitations of the affected myocardium metabolomics.

Fatal pulmonary tumour thrombotic microangiopathy in patient with ovarian adenocarcinoma: review and a case report.

BACKGROUND: Pulmonary tumour thrombotic microangiopathy (PTTM) is a fatal disease in which tumour cells embolize to the pulmonary vasculature leading to pulmonary hypertension and right heart failure. Early diagnosis is essential for timely treatment which can reduce intimal pulmonary vascular proliferation and prolong survival, improve the symptoms. Due to rare occurrences and no clear diagnostic guidelines the disorder usually is found post-mortem. We present a review of this rare disease and a case of post-mortem diagnosed pulmonary tumour thrombotic microangiopathy in a young female. CASE PRESENTATION: 51 years old woman presented with progressively worsening dyspnea, right ventricular failure signs and symptoms. Computerized tomography denied pulmonary embolism. 2D transthoracic echocardiography demonstrated right ventricle dilatation and dysfunction, severely increased systolic pulmonary pressure. Right heart catheterization revealed pre-capillary pulmonary hypertension with mean pulmonary artery pressure of 78 mmHg, pulmonary wedge pressure of 15 mmHg, reduced cardiac output to 1.78 L/min with a calculated pulmonary vascular resistance of 35 Wood units, and extremely low oxygen saturation (26%) in pulmonary artery. Because of worsening ascites, pelvic magnetic resonance imaging was performed, tumours in both ovaries were diagnosed. Due to the high operative risk, detailed tumour diagnosis surgically was not established. The patient developed progressive cardiorespiratory failure, unresponsive to optimal heart failure drug treatment. A postmortem morphology analyses revealed tumorous masses in pre-capillary lung vessels, right ventricle hypertrophy, ovary adenocarcinoma. CONCLUSIONS: An early diagnosis of PTTM is essential. Most cases are lethal due to respiratory failure progressing rapidly. Patients with a history of malignancy, symptoms and signs implying of PH should be considered of having PTTM. If detected early enough, combination of chemotherapy with specific PH therapy is believed to be beneficial in reducing intimal proliferation and prolonging survival, along with improving the symptoms.

Anaemia in Heart Failure Patients, Associated with Angiotensin - Renin - Aldosterone System Altering Medications.

Heart failure (HF) remains one of the most common diseases and one of the major causes of death worldwide. HF is often associated with other chronic diseases, most commonly with anemia. Anemia increases patients' mortality and lowers their quality of life. There are a few pathophysiological mechanisms that explain anemia in patients with HF - hemodilution, absolute or functional iron deficiency, activation of the inflammatory cascade, chronic kidney disease, and impaired erythropoietin production and activity. Moreover, congestive HF is often treated with angiotensin-converting enzyme inhibitors and aldosterone receptors blockers, which could be linked to the development of anemia.

The Difference of Cholesterol, Platelet and Cortisol Levels in Patients Diagnosed with Chronic Heart Failure with Reduced Ejection Fraction Groups According to Neutrophil Count.

Background and Objectives: It is known that neutrophils are involved in the pro-inflammatory processes and thus, can have a great impact on the pathophysiology of heart failure (HF). Moreover, hypercholesterolemia heightens neutrophil production, thereby accelerating cardiovascular inflammation. However, there is a lack of information about the relation of low inflammation to the state of stress, hypercholesterolemia, and pro-thrombotic statement in patients with chronic HF. Therefore, we aimed to determine whether platelet, cholesterol and cortisol levels differ in a different inflammatory condition groups according to the neutrophil count in patients diagnosed with CHF with reduced ejection fraction (CHFrEF), and whether there is a correlation between those readings. Materials and Methods: The average of neutrophil count was 4.37 × 109 L; therefore, 180 patients were separated into two groups: one with relatively a higher inflammatory environment (neutrophil count ≥ 4.37 × 109 L (n = 97)) and one with a relatively lower inflammatory environment (neutrophil count < 4.38 × 109 L (n = 83)). We also determined the levels of lymphocytes, monocytes, platelet count (PLT), mean platelet volume (MPV), platelet aggregation, the levels of cortisol and cholesterol and the concentrations of C reactive protein (CRP) and fibrinogen. Results: We found that CRP, fibrinogen and cortisol concentrations were statistically significantly higher in the group with higher neutrophil counts. However, there were no differences among cholesterol concentration and other markers of platelet function between the groups. We also showed that PLT, leukocyte and monocyte counts were higher in the group with a higher neutrophil count, and the PLT correlated with other cell type count and CRP. In addition, the neutrophil count correlated with concentrations of fibrinogen, evening cortisol and CRP. Conclusions: Cortisol, fibrinogen and CRP levels, PLT and monocyte counts were higher in the CHFrEF patient group with higher neutrophil counts. The cholesterol levels and platelet function readings did not differ between the groups. The neutrophil count correlated with evening cortisol concentration.

Platelet Activity and Its Correlation with Inflammation and Cell Count Readings in Chronic Heart Failure Patients with Reduced Ejection Fraction.

Background and objectives: There has been an increasing interest in the role of inflammation in thrombosis complications in chronic heart failure (HF) patients. The incidence of thrombosis in HF has been shown to be the highest in patients classified as NYHA IV (New York Heart association). It is stated that inflammation is regulated by platelet-induced activation of blood leukocytes. We aimed to compare the platelet and cell count readings in chronic HF with reduced ejection fraction (HFrEF) patients according to NYHA functional class and to evaluate the correlation between those readings. Materials and methods: A total of 185 patients were examined. The results of heart echoscopy (TEE) testing; fibrinogen, N-terminal pro b-type natriuretic peptide (NT-proBNP), C reactive protein (CRP), and cortisol concentrations; complete blood counts; and a 6 min walking test were assessed and platelet aggregation was determined. Results: Mean platelet volume (MPV) increased with deterioration of a patient's state (p < 0.005). Lymphocyte count and percentage were the lowest in the NYHA IV group (p < 0.005). Neutrophil and monocyte percentage and count were the highest (p < 0.045) in the NYHA IV group. Adenosine diphosphate (ADP)- and ADR-induced platelet aggregation was higher in the NYHA III group compared to NYHA II and I groups (p < 0.023). NYHA functional class correlated with mean platelet volume (MPV) (r = 0.311, p = 0.0001), lymphocyte count (r = -0.186, p = 0.026), monocyte count (p = 0.172, p = 0.041), and percentage (r = 0.212, p = 0.011). CRP concentration correlated with NT-proBNP (r = 0.203, p = 0.005). MPV correlated with fibrinogen concentration (r = 0.244, p = 0.004). Conclusions: (1) MPV could be considered as an additional reading reflecting a patient's condition, however the use of MPV to identify patients at risk of hypercoagulable state should be evaluated in more extensive studies; (2) increased neutrophil and monocyte counts could indicate a higher inflammatory state in chronic HFrEF.

The Effect of Oxidant Hypochlorous Acid on Platelet Aggregation and Dityrosine Concentration in Chronic Heart Failure Patients and Healthy Controls.

Background and objective: One of the reasons for thrombosis in chronic heart failure (CHF) might be reactive forms of oxygen activating platelets. The aim of this study was to evaluate the effect of oxidant hypochlorous acid (HOCl) on platelet aggregation and dityrosine concentration in CHF patients and healthy controls. Materials and Methods: CHF patients (n 67) and healthy (n 31) were investigated. Heart echoscopy, 6-min walking test, complete blood count, platelet aggregation, and dityrosine concentration were performed. Platelet aggregation and dityrosine concentration were measured in plasma samples after incubation with different HOCl concentrations (0.15, 0.0778, and 0.0389 mmol/L). Results: Platelet aggregation without oxidant was lower (p = 0.049) in CHF patients than in controls. The spontaneous platelet aggregation with oxidant added was higher in CHF patients (p = 0.004). Dityrosine concentration was also higher (p = 0.032) in CHF patients. Platelet aggregation was the highest in samples with the highest oxidant concentration in both healthy controls (p = 0.0006) and in CHF patients (p = 0.036). Platelet aggregation was higher in NYHA III group in comparison to NYHA II group (p = 0.0014). Concentration of dityrosine was significantly higher in CHF samples (p = 0.032). The highest concentration of dityrosine was obtained in NYHA IV group samples (p 0.05). Intensity of platelet aggregation, analyzed with ADP, was correlated with LV EF (r 0.42, p = 0.007). Dityrosine concentration was correlated with NYHA functional class (r 0.27, p 0.05). Conclusions: The increase in platelet aggregation in CHF and healthy controls shows the oxidant effect on platelets. The increase in dityrosine concentration in higher NYHA functional classes shows a higher oxidative stress in patients with worse condition.

The predictive value of left ventricular myocardium mechanics evaluation in asymptomatic patients with aortic regurgitation and preserved left ventricular ejection fraction. A long-term speckle-tracking echocardiographic study.

BACKGROUND: The management of asymptomatic patients with aortic regurgitation (AR) and preserved left ventricular (LV) ejection fraction (LVEF) remains challenging. The purpose of the study was to assess the early changes of LV mechanics by 2D speckle-tracking echocardiography (2D-STE) in order to predict a decrease in LVEF. METHODS: Sixty-seven patients (age, 47 ± 15 years) with asymptomatic moderate (n = 27) and severe AR (n = 40) with preserved LVEF were prospectively followed for about 5 years. Sixty healthy age-matched controls were included in the study. Standard echocardiography and 2D-STE were performed at the baseline and follow-up. The primary endpoint was a deterioration of the LVEF (≤50%). RESULTS: At baseline, global LV longitudinal peak systolic strain (GLS) and strain rate (GLSRs) were decreased in patients with severe AR compared to controls (-18.9 ± 2.4 vs 20.0 ± 2.1%; -1.05 ± 0.19 vs -1.18 ± 0.15 1/s, P < .05, respectively). In the moderate AR group, GLS was not different from that of the control group, but GLSRs was significantly lower than in controls. The primary endpoint was reached in 12 patients with severe AR, while this was not observed in patients with moderate AR. In multivariate analysis, GLS was an independent predictor of LVEF. According to ROC curve analysis, probability of primary endpoint occurrence was significantly greater in patients with GLS values ≥-18.5% (AUC: 0.89, P < .01). CONCLUSIONS: The reduction of LV longitudinal deformation is a sign of early subclinical LV dysfunction. GLS is a prognostic predictor of LV dysfunction and may be potentially useful for optimal timing of surgery for patients with significant AR.

Pharmacological treatment changes of chronic heart failure during cardiac resynchronization therapy: A 1-year follow-up study.

BACKGROUND: Cardiac resynchronization therapy (CRT) is associated with improved morbidity and mortality in patients with chronic heart failure (HF) on optimal medical therapy. We aimed to evaluate changes of medical therapy during CRT and its influence on the CRT response. METHODS: We evaluated 85 HF patients' pharmacological treatment changes during 1-year follow-up of CRT. Statistical analysis was performed using IBM SPSS statistical software (SPSS v.21.0 for Mac OS X). RESULTS: Beta-blockers (BAB) were used in 81.2% of patients before CRT, and consumption increased after CRT implantation (96.5% at 1-year follow-up visit) (p<0.002). Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) consumption and dose didn't significantly change statistically during the study. 55.3% of patients were taking spironolactone before CRT, and this number increased at discharge till 76.5% (p<0.001) and till 70.6% (p=0.01) at 1-year follow-up visit. The average dose of spironolactone during the study significantly decreased statistically. The use of diuretics was higher after CRT device implantation, compared with the period before CRT 80% to 84.7% (p<0.001), but torasemide dose hadn't significantly changed statistically and remained almost the same. Cardiovascular medication consumption was significantly lower before CRT, compared with discharge (p<0.001) and follow-up (p<0.001) periods. However, no statistically significant relation between pharmacological treatment and echocardiographic response was found. CONCLUSIONS: The present study confirmed that pharmacological treatment has changed during the period before and after CRT. But no statistically significant relation between pharmacological treatment and echocardiographic response was found.

Predictors of positive response to cardiac resynchronization therapy.

BACKGROUND: Approximately 30% of patients treated with cardiac resynchronization therapy (CRT) do not achieve favourable response. The purpose of the present study was to identify echocardiographic and clinical predictors of a positive response to CRT. METHODS: The study included 82 consecutive heart failure (HF) patients in New York Heart Association (NYHA) functional class III or IV with left bundle branch block (LBBB), QRS duration ≥ 120 ms and left ventricular ejection fraction (LVEF) ≤ 35%. Statistical analysis was performed using IBM SPSS statistical software (SPSS v.21.0 for Mac OS X). A p value < 0.05 was considered statistically significant. RESULTS: Echocardiographic response was established in 81.6% and clinical response was achieved in 82.9% of patients. Significant univariate predictors of favourable echocardiographic response after 12 months were smaller left ventricular end-diastolic diameter (LVEDD) (odds ratio [OR] 0.89; 95% confidence interval [CI] 0.82 - 0.97, p = 0.01), and smaller left ventricular end-systolic diameter (LVESD) (OR 0.91; 95% CI 0.85 - 0.98, p = 0.01). Lower uric acid concentration was associated with better echocardiographic response (OR 0.99; 95% CI 0.99 - 1.0, p = 0.01). Non-ischemic HF etiology (OR 4.89; 95% CI 1.39 - 17.15, p = 0.01) independently predicted positive clinical response. Multiple stepwise regression analysis demonstrated that LVEDD lower than 75 mm (OR 5.60; 95% confidence interval [CI] 1.36 - 18.61, p = 0.01) was the strongest independent predictor of favourable echocardiographic response. CONCLUSIONS: Smaller left ventricular end-diastolic and end-systolic diameters and lower serum uric acid concentration were associated with better response to CRT. Left ventricular end-diastolic diameter and non-ischemic heart failure etiology were the strongest independent predictors of positive response to CRT.

The value of 99mTc-MIBI myocardial perfusion imaging in differentiation of heart failure conditioned by global left ventricular systolic impairment.

OBJECTIVE: The global left ventricular systolic impairment with left ventricular dilatation can manifest due to idiopathic dilated cardiomyopathy or ischemic heart disease and can present a similar clinical picture of severe heart failure. The aim of our investigation was to assess a differential diagnostic value of resting (99m)Tc-MIBI myocardial perfusion defects in evaluation of the etiology of heart failure. MATERIAL AND METHODS: The data of 2D echocardiography, coronary angiography, and myocardial gated single photon emission computed tomography with (99m)Tc-MIBI investigation were evaluated in 43 patients with global left ventricular systolic impairment, characterized by left ventricular end-diastolic diameter of > or =65 mm and ejection fraction of < or =40%. The idiopathic dilative cardiomyopathy was diagnosed in 26 patients (Group 1) and ischemic heart failure in 17 patients (Group 2). The area and the degree (severity) of myocardial perfusion defects (AMPD and DMPD) at rest in regions supplied by three coronary arteries were evaluated in all the patients. RESULTS: The area of perfusion defects in the left anterior descending (LAD) and right coronary artery (RCA) regions in dilative cardiomyopathy patients was smaller than in ischemic heart failure patients (1.43+/-0.9 vs 2.53+/-0.53, P=0.001, and 2.19+/-0.6 vs 2.82+/-0.56, P=0.02). The degree of perfusion defects was also less severe in the same circulation regions (1.39+/-0.93 vs 2.59+/-0.6, P=0.01, and 1.6+/-0.46 vs 2.71+/-0.15, P=0.001). We have designed a logistic regression model expressed by formula x=2.52AMPD(rca)+2.47AMPD(lad)+2.21DMPD(rca). Idiopathic dilative cardiomyopathy was predicted when x was < or =16 and ischemic heart failure when x was >16. The sensitivity in predicting idiopathic dilative cardiomyopathy was 94.44%, and the specificity was 88.24%. CONCLUSION: The difference in the area and degree of (99m)Tc-MIBI myocardial perfusion defects at rest in patients with heart failure caused by idiopathic dilative cardiomyopathy or ischemic heart failure is measurable and has a predictive value for differentiation of the etiology of global left ventricular systolic impairment.

The prevalence of the metabolic syndrome components and their combinations in men and women with acute ischemic syndromes.

During the last decade, it has been shown that the metabolic syndrome and its different components--arterial hypertension (AH), abdominal obesity (AO), diabetes mellitus (DM), atherogenic hypertriglyceridemia (HTG), and/or low concentration of high-density lipoprotein cholesterol (HDL-C))--increase the risk of cardiovascular diseases. There is increasing evidence that the incidence of the metabolic syndrome and the distribution of its components in combinations in the general male and female population differ. The aim of our study was to determine the incidence of the metabolic syndrome in men and women with acute ischemic syndromes and to evaluate the distribution of the metabolic syndrome component combinations in the presence of the metabolic syndrome. Contingent and methods. The study included 2756 patients (1670 males and 1086 females) with acute ischemic syndromes (1997 with myocardial infarction and 759 with unstable angina pectoris), in whom all five components of the metabolic syndrome were assessed. Women were significantly older than men (68.1+/-9.5 vs. 60.2+/-11.8 years, P<0.001). The metabolic syndrome was found (according to modified NCEP III) in 1641 (59.5%) patients (in 70.2% of females and in 52.6% of males, P<0.001). The most common components in both men and women were AH and AO (94.0% vs. 95.9% and 86.4% vs. 84.5%, respectively). HTG was significantly more common in men than in women (80.0% vs. 73.0%, P<0.001), while decreased HDL-C concentration was more common in women (82.8% and 59.2%, P<0.001). The DM component, detected in more than one-third of patients with acute ischemic syndromes, was significantly more common in women than in men (39.2% vs. 33.1%, P<0.05). Combinations of three components were significantly more common in men than in women, while combinations of four-five components were more common in women (55.6% vs. 41.4%, P<0.001; and 58.6% vs. 44.4%, P<0.01). The most common combination of three components in men was AH+AO+HTG and in women--AH+AO+low HDL-C; the most common combination of four components in both men and women was AH+AO+HTG+low HDL-C. CONCLUSION. In the metabolic syndrome, the differences between the components of atherogenic dyslipidemia in patients with acute ischemic syndromes were related to the patients' gender: men significantly more frequently had increased TG concentration and women--decreased HDL-C concentration; this is the problem to be addressed in further studies of dyslipidemia.