Genetic backgrounds and diagnosis of familial hypercholesterolemia.

Lipid disorders play a critical role in the intricate development of atherosclerosis and its clinical consequences, such as coronary heart disease and stroke. These disorders are responsible for a significant number of deaths in many adult populations worldwide. Familial hypercholesterolemia (FH) is a genetic disorder that causes extremely high levels of LDL cholesterol. The most common mutations occur in genes responsible for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). While genetic testing is a dependable method for diagnosing the disease, it may not detect primary mutations in 20%-40% of FH cases.

The Influence of Hybrid Comprehensive Telerehabilitation on Anxiety in Heart Failure Patients: The TELEREH-HF Randomized Clinical Trial.

Telerehabilitation for heart failure (HF) patients is beneficial for physical functioning, prognosis, and psychological status. The study aimed at evaluating the influence of hybrid comprehensive telerehabilitation (HCTR) on the level of anxiety in comparison to usual care (UC). The TELEREH-HF study was a multicenter prospective RCT in 850 clinically stable HF participants. Patients underwent clinical examinations, including the assessment of anxiety, at entry and after the 9-week training program (HCTR) or observation (UC). The State-Trait Anxiety Inventory (STAI) was used. 20.3% HCTR and 20.1% UC patients reported high level of anxiety as a state at baseline, with higher STAI results in younger participants (< 63 y.o.) (p = .048 for HCTR; p = .026 for UC). At both stages of the study, patients with lower level of physical capacity (measured by a peak VO2) had shown significantly higher level of anxiety. There were no significant changes in anxiety levels during the 9-week observation for the entire study population, although there were different patterns of change in anxiety (both trait and state) in younger and older groups,with the decrease in younger patients, and the increase-in the older group.Trial registry number NCT02523560 (Clinical Trials.gov), date of registration: August 14, 2015.

Inflammatory Forms of Cardiomyocyte Cell Death in the Rat Model of Isoprenaline-Induced Takotsubo Syndrome.

Takotsubo syndrome (TTS) is associated with inflammatory response, therefore the aim of the study was to evaluate the presence and dynamics of inflammatory-associated forms of cell death, necroptosis, and pyroptosis in the female rat model of isoprenaline (ISO)-induced TTS. TTS was induced in female Sprague Dawley rats (n = 36) by ISO 150 mg/kg intraperitoneally. Animals were divided into four groups: TTSO (TTS+ovariectomy; n = 10), TTSP (TTS+sham operation; n = 10), CO (0.9% NaCl+ovariectomy; n = 8), CP (0.9% NaCl+sham operation; n = 8). Histopathological analysis, evaluation of plasma concentration, and myocardial expression of pyroptosis- and necroptosis-associated proteins were performed. TTSO and TTSP groups had higher plasma concentrations of interleukin-1ß in comparison with the controls. Low myocardial protein expression of mixed lineage kinase domain-like pseudokinase (MLKL), caspase-1 (Casp-1), and calcium/calmodulin-dependent kinase type II isoform delta (CAMKIIδ) was visible 6 and/or 12 h post-ISO. Twenty-four hours post-ISO, high myocardial and vascular protein expression of CAMKIIδ was visible in TTSO but not TTSP rats, while high myocardial expression of MLKL and Casp-1 was visible both in TTSO and TTSP rats. The course of TTS is associated with activation of inflammatory-associated programmed cell death, necroptosis, and pyroptosis, therefore inflammation may be a primary response occurring simultaneously with cardiomyocyte death in TTS.

Predictors of long-term prognosis based on clinical status and measurements obtained in heart failure patients after 9-week hybrid comprehensive telerehabilitation: A subanalysis of the TELEREH-HF randomized clinical trial.

BACKGROUND: Assessing prognosis in heart failure (HF) is of major importance. AIMS: The study aimed to define predictors influencing long-term cardiovascular mortality or HF hospitalization ("composite outcome") based on clinical status and measurements obtained after a 9-week hybrid comprehensive telerehabilitation (HCTR) program. METHODS: This analysis is based on the TELEREH-HF (TELEREHabilitation in Heart Failure) multicenter randomized trial that enrolled 850 HF patients (left ventricular ejection fraction [LVEF] ≤40%). Patients were randomized 1:1 to 9-week HCTR plus usual care (experimental arm) or usual care only (control arm) and followed for median (interquartile range [IQR]) 24 (20-24) months for development of the composite outcome. RESULTS: Over 12-24 months of follow-up, 108 (28.1%) patients experienced the composite outcome. The predictors of our composite outcome were: nonischemic etiology of HF, diabetes, higher serum level of N-terminal prohormone of brain natriuretic peptide, creatinine, and high-sensitivity C-reactive protein; low carbon dioxide output at peak exercise; high minute ventilation and breathing frequency at maximum effort in cardiopulmonary exercise tests; increase in delta of average heart rate in 24-hour Holter ECG monitoring, lower LVEF, and patients' non-adherence to HCTR. The model discrimination C-index was 0.795 and decreased to 0.755 on validation conducted in the control sample which was not used in derivation. The 2-year risk of the composite outcome was 48% in the top tertile versus 5% in the bottom tertile of the developed risk score. CONCLUSION: Risk factors collected at the end of the 9-week telerehabilitation period performed well in stratifying patients based on their 2-year risk of the composite outcome. Patients in the top tertile had an almost ten-fold higher risk compared to patients in the bottom tertile. Treatment adherence, but not peak VO2 or quality of life, was significantly associated with the outcome.

Rate-Responsive Cardiac Pacing: Technological Solutions and Their Applications.

Modern cardiac pacemakers are equipped with a function that allows the heart rate to adapt to the current needs of the patient in situations of increased demand related to exercise and stress ("rate-response" function). This function may be based on a variety of mechanisms, such as a built-in accelerometer responding to increased chest movement or algorithms sensing metabolic demand for oxygen, analysis of intrathoracic impedance, and analysis of the heart rhythm (Q-T interval). The latest technologies in the field of rate-response functionality relate to the use of an accelerometer in leadless endocavitary pacemakers; in these devices, the accelerometer enables mapping of the mechanical wave of the heart's work cycle, enabling the pacemaker to correctly sense native impulses and stimulate the ventricles in synchrony with the cycles of atria and heart valves. Another modern system for synchronizing pacing rate with the patient's real-time needs requires a closed-loop system that continuously monitors changes in the dynamics of heart contractions. This article discusses the technical details of various solutions for detecting and responding to situations related to increased oxygen demand (e.g., exercise or stress) in implantable pacemakers, and reviews the results of clinical trials regarding the use of these algorithms.

Actual status and future directions of cardiac telerehabilitation.

Telerehabilitation (TR) was developed to achieve the same results as would be achieved by the standard rehabilitation process and to overcome potential geographical barriers and staff deficiencies. This is especially relevant in periodic crisis situations, including the recent COVID-19 pandemic. Proper execution of TR strategy requires both well-educated staff and dedicated equipment. Various studies have shown that TR may have similar effects to traditional rehabilitation in terms of clinical outcomes and may also reduce total healthcare costs per participant, including rehospitalization costs. However, as with any method, TR has its advantages and disadvantages, including a lack of direct contact or prerequisite, rudimentary ability of the patients to handle mobile devices, among other competencies. Herein, is a discussion of the current status of TR, focusing primarily on cardiac TR, describing some technical/organizational and legal aspects, highlighting the indications, examining cost-effectiveness, as well as outlining possible future directions.

Predictors of proarrhythmic effect in heart failure patients after 9-week hybrid comprehensive telerehabilitation and their influence on cardiovascular mortality in long-term follow-up: Subanalysis of the TELEREH-HF randomized clinical trial.

BACKGROUND: Regular exercise training is beneficial in heart failure (HF) patients. However, its potential proarrhythmic effect is possible but has not been sufficiently investigated. OBJECTIVE: To identify patients at risk for proarrhythmic effect after the 9-week of hybrid comprehensive telerehabilitation (HCTR) program vs the 9-week of usual care (UC) and to investigate its predictors and impact on cardiovascular mortality based on data from the TELEREH-HF RCT. METHODS: Proarrhythmic effect, strictly defined on the basis of available standards was evaluated by comparing 24-h Holter ECG before and after 9-week of HCTR or UC of 773 HF patients (The New York Heart Association class I-III, left ventricular ejection fraction ≤40%). RESULTS: The proarrhytmic effect was found in 78 (20.4%) and in 61 (15.6%) patients in the HCTR and UC group respectively, and the difference between groups was not statistically significant (p = 0.081). However, univariate analysis identified several statistically significant predictors of proarrhythmia in HCTR only vs the UC group. After a multivariate analysis ischaemic aetiology of HF (OR = 2.27, p = 0.008), peak oxygen consumption at baseline <14 ml/kg/min (OR = 2.03, p = 0.012) and level of N-terminal-pro B-type natriuretic peptide (NT-proBNP) in the first and the second tercile (OR = 1.85, p = 0.043) were identified to be independent predictors of proarrhytmic effect of exercise training among the HF patients in HCTR group only. CONSLUSIONS: Patients who underwent a 9-week HCTR were not at a higher risk of proarrhythmic effect after its completion compared to UC. However, predictors of proarrhythmia such as ischemic aetiology of HF, poor physical capacity, lower NT-proBNP level were discovered in the HCTR group only, yet it does not cause a significant risk of cardiovascular mortality including sudden cardiac death in long-term follow-up.

Chronotropic incompetence in end-stage liver disease.

BACKGROUND: Cirrhosis causes alterations in the cardiovascular and autonomic nervous systems and leads to cirrhotic cardiomyopathy (CCM). CCM is defined as cardiac dysfunction characterized by an impaired systolic responsiveness to stress or exercise, and/or impaired diastolic function, as well as electrophysiological abnormalities, including chronotropic incompetence (CI), in the absence of other known cardiac disease. CI is a common feature of autonomic neuropathy in cirrhosis. The aim of the study is to assess the role of cardiac exercise stress test in the diagnosis of CCM. METHODS: The analysis included 160 end-stage liver disease (ESLD) patients who underwent a cardiac exercise stress test prior to the orthotopic liver transplantation. CI was defined as the inability to achieve the heart rate reserve (HRR). Pertaining to the therapy with beta-blockers: 80% of HRR was achieved in patients not taking beta-blockers and 62% in patients taking beta-blockers. RESULTS: In the analyzed population, 68.8% of patients met the criteria for CI. CI was more frequent in the more severe ESLD (with a higher MELD score and in a higher Child-Pugh class). In comparison to the viral hepatitis and other etiologies of ESLD, patients with alcoholic cirrhosis had a significantly lower rest heart rate (HR), lower maximal HR, lower median achieved percentage of maximal predicted HR (MPHR), a smaller percentage of patients achieved ≥ 85% of MPHR and a lower heart rate reserve. No significant relationship between the survival of OLT recipients and presence of chronotropic incompetence regarding to class of Child-Pugh scale, MELD score and etiology of ESLD were found. CONCLUSIONS: The prevalence of CI is higher among liver transplant candidates than previously described. The altered chronotropic response may differ in regard to the severity of liver disease correlating with both the Child-Pugh and MELD scores, however CI does not seem to influence the long-term survival post OLT. Exercise stress test is a reliable, safe and useful tool for the diagnosis of CCM in liver transplant candidates and should be included in the standard cardiovascular assessment prior to OLT.

Prognostic Impact of Hybrid Comprehensive Telerehabilitation Regarding Diastolic Dysfunction in Patients with Heart Failure with Reduced Ejection Fraction-Subanalysis of the TELEREH-HF Randomized Clinical Trial.

AIMS: The objective of the study was to evaluate the effects of individually prescribed hybrid comprehensive telerehabilitation (HCTR) implemented at patients' homes on left ventricular (LV) diastolic function in heart failure (HF) patients. METHODS AND RESULTS: The Telerehabilitation in Heart Failure Patients trial (TELEREH-HF) is a multicenter, prospective, randomized (1:1), open-label, parallel-group, controlled trial involving HF patients assigned either to HCTR involving a remotely monitored home training program in conjunction with usual care (HCTR group) or usual care only (UC group). The patient in the HCTR group underwent a 9-week HCTR program consisting of two stages: an initial stage (1 week) conducted in hospital and the subsequent stage (eight weeks) of home-based HCTR five times weekly. Due to difficulties of proper assessment and differences in the evaluation of diastolic function in patients with atrial fibrillation, we included in our subanalysis only patients with sinus rhythm. Depending on the grade of diastolic dysfunction, patients were assigned to subgroups with mild diastolic (MDD) or severe diastolic dysfunction (SDD), both in HCTR (HCTR-MDD and HCTR-SDD) and UC groups (UC-MDD and UC-SDD). Changes from baseline to 9 weeks in echocardiographic parameters were seen only in A velocities in HCTR-MDD vs. UC-MDD; no significant shifts between groups of different diastolic dysfunction grades were observed after HCTR. All-cause mortality was higher in UC-SDD vs. UC-MDD with no difference between HCTR-SDD and HCTR-MDD. Higher probability of HF hospitalization was observed in HCTR-SDD than HCTR-MDD and in UC-SDD than UC-MDD. No differences in the probability of cardiovascular mortality and hospitalization were found. CONCLUSIONS: HCTR did not influence diastolic function in HF patients in a significant manner. The grade of diastolic dysfunction had an impact on mortality only in the UC group and HF hospitalization over a 12-24-month follow-up in HCTR and UC groups.

Antiarrhythmic effect of 9-week hybrid comprehensive telerehabilitation and its influence on cardiovascular mortality in long-term follow-up - subanalysis of the TELEREHabilitation in Heart Failure Patients randomized clinical trial.

Introduction: Cardiac rehabilitation is a component of heart failure (HF) management, but its effect on ventricular arrhythmias is not well understood. We analyzed the antiarrhythmic effect of a 9-week hybrid comprehensive telerehabilitation (HCTR) program and its influence on long-term cardiovascular mortality in HF patients taken from the TELEREHabilitation in Heart Failure Patients (TELEREH-HF) trial. Material and methods: We evaluated the presence of non-sustained ventricular tachycardia (nsVT) and frequent premature ventricular complexes ≥ 10 beats/hour (PVCs ≥ 10) in 24-hour ECG monitoring at baseline and after 9-week HCTR or usual care (UC) of 773 HF patients (NYHA I-III, LVEF ≤ 40%). Functional response for HCTR was assessed by changes - delta (Δ) - in peak oxygen consumption (pVO2) as a result of comparing pVO2 from the beginning and the end of the program. Results: Among 143 patients with nsVT, arrhythmia subsided in 30.8% after HCTR. Similarly, among 165 patients randomized to UC who had nsVT 34.5% did not show it after 9 weeks (p = 0.481). There was no significant difference in the decrease in PVC ≥ 10 over 9 weeks between randomization arms (14.9% vs. 17.8%, respectively p = 0.410). Functional response for HCTR in ΔpVO2 > 2.0 ml/kg/min did not affect occurrence of arrhythmias. Multivariable analysis did not identify HCTR as an independent factor determining improvement of nsVT or PVCs ≥ 10. However, only in the HCTR group, the achievement of the antiarrhythmic effect significantly reduced the cardiovascular mortality in 2-year follow-up (p < 0.001). Conclusions: Significant improvement in physical capacity after 9 weeks of HCTR did not correlate with the antiarrhythmic effect in terms of incidence of nsVT or PVCs ≥ 10. An antiarrhythmic effect after the 9-week HCTR affected long-term cardiovascular mortality in HF patients.

The Use of Machine Learning Algorithms in the Evaluation of the Effectiveness of Resynchronization Therapy.

BACKGROUND: Cardiovascular disease remains the leading cause of death in the European Union and worldwide. Constant improvement in cardiac care is leading to an increased number of patients with heart failure, which is a challenging condition in terms of clinical management. Cardiac resynchronization therapy is becoming more popular because of its grounded position in guidelines and clinical practice. However, some patients do not respond to treatment as expected. One way of assessing cardiac resynchronization therapy is with ECG analysis. Artificial intelligence is increasing in terms of everyday usability due to the possibility of everyday workflow improvement and, as a result, shortens the time required for diagnosis. A special area of artificial intelligence is machine learning. AI algorithms learn on their own based on implemented data. The aim of this study was to evaluate using artificial intelligence algorithms for detecting inadequate resynchronization therapy. METHODS: A total of 1241 ECG tracings were collected from 547 cardiac department patients. All ECG signals were analyzed by three independent cardiologists. Every signal event (QRS-complex) and rhythm was manually classified by the medical team and fully reviewed by additional cardiologists. The results were divided into two parts: 80% of the results were used to train the algorithm, and 20% were used for the test (Cardiomatics, Cracow, Poland). RESULTS: The required level of detection sensitivity of effective cardiac resynchronization therapy stimulation was achieved: 99.2% with a precision of 92.4%. CONCLUSIONS: Artificial intelligence algorithms can be a useful tool in assessing the effectiveness of resynchronization therapy.

Relationship between physical capacity and depression in heart failure patients undergoing hybrid comprehensive telerehabilitation vs. usual care: subanalysis from the TELEREH-HF Randomized Clinical Trial.

AIMS: The hybrid comprehensive telerehabilitation (HCTR) consisting of telecare (with psychological telesupport), telerehabilitation, and remote monitoring of cardiovascular implantable electronic devices might be an option to improve both physical capacity and depressive symptoms. The aim of the study was to investigate the influence of HCTR on depressive symptoms and physical capacity in heart failure (HF) patients in comparison with usual care (UC). METHODS AND RESULTS: The present analysis formed part of a multicentre, randomized trial that enrolled 850 HF patients (New York Heart Association I-III, left ventricular ejection fraction ≤ 40%). Patients were randomized 1:1 to HCTR or UC. Patients underwent an HCTR programme (1 week in hospital and 8 weeks at home; exercise training 5 times weekly) or UC with observation. The Beck Depression Inventory II (BDI-II) score (cut point for depression ≥ 14) was used to assess depression and the physical capacity was measured by peak oxygen consumption (peak VO2; mL/kg/min). Measurements were made before and after 9-week intervention/observation (HCTR/UC group). Both groups were comparable in terms of demographic and clinical characteristics. In HCTR group, at entry, 23% of the sample obtained BDI-II scores ≥14 vs. 27.5% in UC group. There were no significant differences between groups regarding ΔBDI-II score (P = 0.992) after 9-week HCTR/UC. There was a significant improvement in physical capacity only in the HCTR group in both patients with (P = 0.033) and without (P < 0.001) depression. CONCLUSIONS: In HF patients, HCTR provided similar reduction of depressive symptoms as UC. HCTR resulted in a significant improvement in physical capacity in patients with and without depression.

Isoprenaline induced Takotsubo syndrome: Histopathological analyses of female rat hearts.

BACKGROUND: Takotsubo syndrome (TTS) is a stress-induced disorder affecting mostly postmenopausal women. The aim of the study was to evaluate isoprenaline (ISO) dependent female rat model and histopathological characteristics in TTS. METHODS: Forty-nine Sprague Dawley female rats, 12 weeks old, were injected intraperitoneally with a single dose of ISO at doses 50 (n = 8), 75 (n = 6), 100 (n = 3), 150 (n = 27) and 200 (n = 5) mg/kg body weight (bw). The control group (n = 6) was injected with physiological saline. The echocardiographic examination to assess wall motion abnormalities took place 24, 48, 72 h, and 7 days post-ISO. Histopathological analysis was performed on the basis of hematoxylin-eosin staining. RESULTS: The total mortality rate was 3/49 (6.12%). The optimum dose of ISO to induce TTS was 150 mg/kg bw and 21/27 (77.77%) rats showed apical ballooning. Histopathological analysis revealed focal necrosis/apoptosis of cardiomyocytes with inflammatory and fibroblast-like cell infiltration. Foci were the most numerous in the central muscle layer with apical-basal gradient 24, 48, 72 h post-ISO (p < 0.05). Significant differences were noted 48 h post-ISO in the central layer in apical vs basal segments (p = 0.0032), in the endocardial layer in apical vs basal segments (0.00024) and in mid-cavital vs. basal segments (p = 0.0483). The number of foci in endocardium of apical region differ 48 h post-ISO in rats with a dose of 150 vs. 200 mg/kg bw (p = 0.0084). CONCLUSIONS: The ISO female rat model of TTS is associated with higher optimum dose and lower mortality in comparison with the male TTS model. TTS presents as a singles cardiomyocyte disorder, foci concerned mainly central muscle layer with apical-basal gradient.

Repetitive use of LEvosimendan in Ambulatory Heart Failure patients (LEIA-HF) - The rationale and study design.

PURPOSE: Clinical practice forces the necessity to conduct a clinical trial concerning the group of outpatients with chronically advanced heart failure in III or IV NYHA functional class, frequently requiring hospitalizations due to HF exacerbation, and often left without any additional therapeutic option. The current trial aims to determine the efficacy and safety of repeated levosimendan infusions in the group of severe outpatients with reduced ejection fraction (HFrEF). MATERIAL AND METHODS: LEIA-HF (LEvosimendan In Ambulatory Heart Failure Patients) is a multicentre, randomized, double-blind, placebo-controlled, phase 4 clinical trial to determine whether the repetitive use of levosimendan reduces the incidence of adverse cardiovascular events in ambulatory patients with chronic, advanced HFrEF. A total of 350 patients will be randomized in a 1:1 ratio to receive either levosimendan or placebo, which will be administered as continuous 24 â€‹h infusions, every 4 weeks for 48 weeks (12 infusions in total - phase I), and followed by double-blind 6 visits, every 4 weeks (phase II of the trial including the option of restarting levosimendan or placebo, based on the fulfillment of additional criteria). The primary endpoint for efficacy assessment will be death from any cause or unplanned hospitalization for HF assessed together, whichever occurs first, in a 12-month follow-up period. CONCLUSIONS: A well-designed study with a consistent protocol, including the drug side effects, comprehensive clinical assessment, appropriate definition of endpoints, and monitoring therapy, may provide a complete overview of the effectiveness and safety profile of the repetitive levosimendan administration in ambulatory severe HFrEF patients.

Quality of life in heart failure patients undergoing hybrid comprehensive telerehabilitation versus usual care - results of the Telerehabilitation in Heart Failure Patients (TELEREH-HF) Randomized Clinical Trial.

INTRODUCTION: Hybrid comprehensive telerehabilitation (HCTR) consisting of telecare (with psychological telesupport), telerehabilitation and remote monitoring of implantable devices might be an innovative option improving heart failure (HF) patients' quality of life (QoL) and emotional health. The aim of the study was to investigate the influence of HCTR on various facets of QoL in HF patients in comparison with usual care (UC) alone. MATERIAL AND METHODS: The present analysis formed part of a multicenter, randomized trial that enrolled 850 HF patients (NYHA I-III, LVEF ≤ 40%). Patients were randomized 1 : 1 to HCTR plus UC or UC only. Patients underwent either an HCTR program or UC with observation. The psychological intervention in the HCTR group included supportive psychological counseling via mobile phone. The Medical Outcome Survey Short Form 36 Questionnaire was used to assess QoL. Measurements were made before and after a 9-week intervention (HCTR group)/observation (UC group). RESULTS: After the intervention, the HCTR group showed significant improvement in overall QoL, physical domain (PD) of QoL, and 4 areas of QoL (physical functioning (PhF), role functioning related to physical state (RF), general health (GH), vitality (VI)). A significant positive change in QoL in the UC group was observed only in VI and social functioning. There were also significant differences in QoL after 9-week intervention/observation between the two groups. The results showed greater improvement in HCTR for overall QoL (p = 0.009), PD of QoL (p = 0.0003) and three specific areas of QoL: PhF (p = 0.001), RF (p = 0.003), bodily pain (BP) (p = 0.015). CONCLUSIONS: In comparison to UC, HCTR resulted in improvement in overall QoL, PD of QoL and 3 specific areas of QoL: PhF, RF and BP.