Decreased level of serum NT-proCNP associates with disease severity in COVID-19.

BACKGROUND: C-type natriuretic peptide (CNP) is an endothelium-derived paracrine molecule with an important role in vascular homeostasis. In septic patients, the serum level of the amino-terminal propeptide of CNP (NT-proCNP) shows a strong positive correlation with inflammatory biomarkers and, if elevated, correlates with disease severity and indicates a poor outcome. It is not yet known whether NT-proCNP also correlates with the clinical outcome of patients suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the current study, we aimed to determine possible changes in the NT-proCNP levels of patients with coronavirus disease 2019 (COVID-19), with special regard to disease severity and outcome. METHODS: In this retrospective analysis, we determined the serum level of NT-proCNP in hospitalized patients with symptoms of upper respiratory tract infection, using their blood samples taken on admission, stored in a biobank. The NT-proCNP levels of 32 SARS-CoV-2 positive and 35 SARS-CoV-2 negative patients were measured to investigate possible correlation with disease outcome. SARS-CoV-2 positive patients were then divided into two groups based on their need for intensive care unit treatment (severe and mild COVID-19). RESULTS: The NT-proCNP was significantly different in the study groups (e.g. severe and mild COVID-19 and non-COVID-19 patients), but showed inverse changes compared to previous observations in septic patients: lowest levels were detected in critically ill COVID-19 patients, while highest levels in the non-COVID-19 group. A low level of NT-proCNP on admission was significantly associated with severe disease outcome. CONCLUSIONS: Low-level NT-proCNP on hospital admission is associated with a severe COVID-19 disease course. The pathomechanism underlying this observation remains to be elucidated, while future studies in larger patient cohorts are necessary to confirm these observations and reveal therapeutic importance. Trial registration DRKS00026655 Registered 26. November 2021.

Predictors of Hospital Mortality in Patients with Acute Coronary Syndrome Complicated by Cardiogenic Shock.

As demonstrated by earlier studies, pre-hospital triage with trans-telephonic electrocardiogram (TTECG) and direct referral for catheter therapy shows great value in the management of out-of-hospital chest pain emergencies. It does not only improve in-hospital mortality in ST-segment elevation myocardial infarction, but it has also been identified as an independent predictor of higher in-hospital survival rate. Since TTECG-facilitated triage shortens both transport time and percutaneous coronary intervention (PCI)-related procedural time intervals, it was hypothesized that even high-risk patients with acute coronary syndrome (ACS) and cardiogenic shock (CS) might also benefit from TTECG-based triage. Here, we decided to examine our database for new triage- and left ventricular (LV) function-related parameters that can influence in-hospital mortality in ACS complicated by CS. ACS patients were divided into two groups, namely, (1) hospital death patients (n = 77), and (2) hospital survivors (control, n = 210). Interestingly, TTECG-based consultation and triage of CS and ACS patients were confirmed as significant independent predictors of lower hospital mortality risk (odds ratio (OR) 0.40, confidence interval (CI) 0.21-0.76, p = 0.0049). Regarding LV function and blood chemistry, a good myocardial reperfusion after PCI (high area at risk (AAR) blush score/AAR LV segment number; OR 0.85, CI 0.78-0.98, p = 0.0178) and high glomerular filtration rate (GFR) value at the time of hospital admission (OR 0.97, CI 0.96-0.99, p = 0.0042) were the most crucial independent predictors of a decreased risk of in-hospital mortality in this model. At the same time, a prolonged time interval between symptom onset and hospital admission, successful resuscitation, and higher peak creatine kinase activity were the most important independent predictors for an increased risk of in-hospital mortality. In ACS patients with CS, (1) an early TTECG-based teleconsultation and triage, as well as (2) good myocardial perfusion after PCI and a high GFR value at the time of hospital admission, appear as major independent predictors of a lower in-hospital mortality rate.

Prophylactic, single-drug cardioprotection in a comparative, experimental study of doxorubicin-induced cardiomyopathy.

BACKGROUND: Cardiomyopathy is a common side effect of doxorubicin (DOX) chemotherapy. Despite intensive research efforts in the field, there is still no evidence available for routine cardioprotective prophylaxis to prevent cardiotoxicity in the majority of oncological patients at low risk of cardiovascular disease. We have recently demonstrated the advantages of a prophylactic, combined heart failure therapy in an experimental model of DOX-induced cardiomyopathy. In the current work, we focus on individually applied prophylactic medications studied in the same translational environment to clarify their distinct roles in the prevention of DOX cardiotoxicity. METHODS: Twelve-week-old male Wistar rats were divided into 5 subgroups. Prophylactic ß-blocker (BB, bisoprolol), angiotensin-converting enzyme inhibitor (ACEI, perindopril) or aldosterone antagonist (AA, eplerenone) treatments were applied 1 week before DOX administration, then 6 cycles of intravenous DOX chemotherapy were administered. Rats receiving only intravenous DOX or saline served as positive and negative controls. Blood pressure, heart rate, body weight, and echocardiographic parameters were monitored in vivo. Two months after the last DOX administration, the animals were sacrificed, and their heart and serum samples were frozen in liquid nitrogen for histological, mechanical, and biochemical measurements. RESULTS: All prophylactic treatments increased the survival of DOX-receiving animals. The lowest mortality rates were seen in the BB and ACEI groups. The left ventricular ejection fraction was only preserved in the BB group. The DOX-induced increase in the isovolumetric relaxation time could not be prevented by any prophylactic treatment. A decreased number of apoptotic nuclei and a preserved myocardial ultrastructure were found in all groups receiving prophylactic cardioprotection, while the DOX-induced fibrotic remodelling and the increase in caspase-3 levels could only be substantially prevented by the BB and ACEI treatments. CONCLUSION: Primary prophylaxis with cardioprotective agents like BB or ACEI has a key role in the prevention of DOX-induced cardiotoxicity in healthy rats. Future human studies are necessary to implement this finding in the clinical management of oncological patients free of cardiovascular risk factors.

Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy.

BACKGROUND: Chemotherapy-induced left ventricular dysfunction represents a major clinical problem, which is often only recognised at an advanced stage, when supportive therapy is ineffective. Although an early heart failure treatment could positively influence the health status and clinical outcome, there is still no evidence of routine prophylactic cardioprotection for the majority of patients without previous cardiovascular history awaiting potentially cardiotoxic chemotherapy. In this study, we set out to investigate whether a prophylactic cardioprotective therapy relative to a conventionally scheduled heart failure treatment is more effective in preventing cardiotoxicity in a rodent model of doxorubicin (DOX)-induced cardiomyopathy. METHODS: Male Wistar rats (n = 7-11 per group) were divided into 4 subgroups, namely negative controls receiving intravenous saline (CON), positive controls receiving intravenous DOX (6 cycles; D-CON), and DOX-treated animals receiving either prophylactic (PRE, started 1 week before DOX) or conventionally applied (POST, started 1 month after DOX) combined heart failure therapy of oral bisoprolol, perindopril and eplerenone. Blood pressure, heart rate, body weight and echocardiographic parameters were monitored in vivo, whereas myocardial fibrosis, capillarisation, ultrastructure, myofilament function, apoptosis, oxidative stress and mitochondrial biogenesis were studied in vitro. RESULTS: The survival rate in the PRE group was significantly improved compared to D-CON (p = 0.0207). DOX increased the heart rate of the animals (p = 0.0193), while the blood pressure (p ≤ 0.0105) and heart rate (p = 0.0029) were significantly reduced in the PRE group compared to D-CON and POST. The ejection fraction remained preserved in the PRE group compared to D-CON or POST (p ≤ 0.0237), while none of the treatments could prevent the DOX-induced increase in the isovolumetric relaxation time. DOX decreased the rate of the actin-myosin cross-bridge cycle, irrespective of any treatment applied (p ≤ 0.0433). The myocardium of the D-CON and POST animals displayed pronounced ultrastructural damage, which was not apparent in the PRE group (p ≤ 0.033). While the DOX-induced apoptotic activity could be reduced in both the PRE and POST groups (p ≤ 0.0433), no treatment was able to prevent fibrotic remodelling or the disturbed mitochondrial biogenesis. CONCLUSION: For attenuating DOX-induced adverse myocardial effects, prophylactic cardioprotection has many advantages compared to a late-applied treatment.

[Ischaemic heart disease in cancer patients. Questions and problems]. / Ischaemiás szívbetegség és tumoros betegségek együttes elofordulása. Kérdések és problémák.

Cardiovascular and oncologic diseases are the causes of more than 50 percent of mortality in Europe. In 2015 oncologic and cardiovascular mortality reached 70 percent in Hungary. Patients who receive anticancer therapies are at a 2- to 7-fold greater long-term risk of acute coronary syndrome; also concomittant oncologic diseases further increase the mortality of myocardial infarction. Unfortunately there is not enough data concerning cardiovascular treatment of oncologic patients because they were excluded from most of the studies and registries. Because there is no clear protocol to treat such patients, only small studies and personal experiences could guide our medical therapies. The role of cardio-oncology is even more important, because due to the new treatments the number of tumor survivors rapidly increases. In the US more than 20 millions survivals are expected by 2025 who were treated by any kind of malignant tumors. It is not surprising that in 2014 the American Society of Cardiology declared cardio-oncology as a special and important field in cardiology, and in 2016 European Society of Cardiology released the first cardio-oncologic guideline. In this review we summarize questions and problems concerning the treatment of oncologic patient with ischaemic heart disease based on resent guidelines, published studies and local protocols. Orv Hetil. 2017; 158(43): 1691-1697.

[New recommendations in oncocardiology]. / Az onkokardiológiai ellátás új irányelvei.

It is well-known that modern oncotherapy significantly reduced the mortality of malignant diseases. However, serious side effects of the applied cancer therapies have evolved, which may adversely affect the cardiovascular system. Early side effects often limit therapeutic success of oncotherapy and may require treatment interruption, while late-onset side effects can adversely influence the long-term survival of patients recovering from cancer. Oncocardiology is a new medical field gaining more and more attention. It aims at the optimisation of the efficacy of cancer therapy and clinical outcome of patients. In the current review we present such important recommendations that may help the management of cardiovascular toxicity of cancer therapy in the everyday clinical practice.

Cardiac Resynchronization Therapy Relieves Intractable Angina Due to Exercise-Induced Left Bundle Branch Block Without Left Ventricular Systolic Dysfunction: A Detailed Case Study.

Exercise-induced left bundle branch block is rare and can be demonstrated with exercise testing. When the heart rate reaches a certain threshold, the QRS widens into left bundle branch block. This paper describes a patient with exercise-induced left bundle branch block related angina and dyspnea, who responded to cardiac resynchronization therapy. We documented the potential benefits of cardiac resynchronization therapy with a left ventricular rapid pacing study prior to its implantation. Although exercise-induced left bundle branch block is not a current indication for cardiac resynchronization therapy in patients such as ours, it could be considered when conventional drug therapy fails.

Transtelephonic electrocardiography in the management of patients with acute coronary syndrome.

BACKGROUND: The efficacy of the transtelephonic ECG system (TTECG) in the management of ST segment elevation myocardial infarction (STEMI) was examined with regard to the ambulance service- and percutaneous coronary intervention (PCI)-related delay times, the prehospital medical therapy and the in-hospital mortality rate. METHODS: The study was conducted as a collaborative effort between the University of Debrecen and the Hungarian National Ambulance Service. Altogether 397 patients were recruited in the TTECG group, while 378 patients transported to the PCI centre without TTECG served as controls. RESULTS: More accurate prehospital medical therapy was achieved in the TTECG group. The PCI-related delay times were significantly shorter, while the in-hospital mortality rate was significantly lower in the TTECG group than among the controls. CONCLUSIONS: The findings illustrate that TTECG is a valuable tool which may potentially improve the regional management of STEMI patients.

The pressure-derived microvascular resistance reserve and its correlation to Doppler MRR measurement-a proof of concept study.

Background: Microvascular resistance reserve (MRR) is a recently introduced specific index of coronary microcirculation. MRR calculation can utilize parameters deriving from coronary flow reserve (CFR) assessment, provided that intracoronary pressure data are also available. The previously proposed pressure-bounded CFR (CFRpb) defines the possible CFR interval on the basis of resting and hyperemic pressure gradients in the epicardial vessel, however, its correlation to the Doppler wire measurement was reported to be rather poor without the correction for hydrostatic pressure. Purpose: We aimed to determine the pressure-bounded coronary MRR interval with hydrostatic pressure correction according to the previously established equations of CFRpb adapted for the MRR concept. Furthermore, we also aimed to design a prediction model using the actual MRR value within the pressure-bounded interval and validate the results against the gold-standard Doppler wire technique. Methods: Hydrostatic pressure between the tip of the catheter and the sensor of the pressure wire was calculated by height difference measurement from a lateral angiographic view. In the derivation cohort the pressure-bounded MRR interval (between MRRpbmin and MRRpbmax) was determined solely from hydrostatic pressure-corrected intracoronary pressure data. The actual MRR was calculated by simple hemodynamic equations incorporating the anatomical data of the three-dimensionally reconstructed coronary artery (MRRp-3D). These results were analyzed by regression analyses to find relations between the MRRpb bounds and the actual MRRp-3D. Results: In the derivation cohort of 23 measurements, linear regression analysis showed a tight relation between MRRpbmax and MRRp-3D (r 2 = 0.74, p < 0.0001). Using this relation (MRRp-3D = 1.04 + 0.51 × MRRpbmax), the linear prediction of the MRR was tested in the validation cohort of 19 measurements against the gold standard Doppler wire technique. A significant correlation was found between the linearly predicted and the measured values (r = 0.54, p = 0.01). If the area stenosis (AS%) was included to a quadratic prediction model, the correlation was improved (r = 0.63, p = 0.004). Conclusions: The MRR can be predicted reliably to assess microvascular function by our simple model. After the correction for hydrostatic pressure error, the pressure data during routine FFR measurement provides a simultaneous physiological assessment of the macro- and microvasculature.

Angiography-based coronary microvascular assessment with and without intracoronary pressure measurements: a systematic review.

BACKGROUND: In recent years, several indices have been proposed for quantifying coronary microvascular resistance. We intended to conduct a comprehensive review that systematically evaluates indices of microvascular resistance derived from angiography. OBJECTIVE: The objective of this study was to identify and analyze angiography-derived indices of microvascular resistance that have been validated against an invasive reference method. We aimed to compare their limits of agreement with their reference methods and explore their advantages and inherent limitations. METHODS AND RESULTS: We searched PubMed from inception until 2022 for studies on different techniques for quantifying microvascular resistance. Seven studies met the inclusion criteria. Five studies included techniques that applied calculations based solely on invasive angiography, and were validated against invasively measured thermodilution-derived index of microvascular resistance. The remaining two studies combined angiography with invasively measured intracoronary pressure data, and were validated against invasive Doppler measurements. We converted the ± 1.96 standard deviation limits of agreement with the reference method from the seven studies into percentages relative to the cut-off value of the reference method. The lower limits of agreement for angiography-based methods ranged from - 122 to - 60%, while the upper limits ranged from 74 to 135%. The range of the limits of agreement was considerably lower for the two combined angiography- and pressure-based methods, standing at - 52 to 60% and - 25 to 27%. CONCLUSION: Our findings suggest that combined angiography- and pressure-based methods provide a more reliable assessment of microvascular resistance compared to methods relying solely on angiography. Central illustration. Comparative assessment of image-based methods quantifying microvascular resistance with and without intracoronary pressure measurements. Angiography-based methods rely on angiography alone to calculate the microvascular resistance by utilizing angiographic frame counting to extrapolate coronary flow (Q) and subsequently deriving distal coronary pressure using fluid dynamic equations. Combined angiography- and pressure-based methods utilize invasive intracoronary pressure gradients measured during rest and maximal vasodilation to determine coronary flow in their calculation of microvascular resistance. The combined methods showed more acceptable levels of agreement with their reference methods compared to angiography-based methods alone.

Cell-to-cell variability in troponin I phosphorylation in a porcine model of pacing-induced heart failure.

We tested the hypothesis that myocardial contractile protein phosphorylation and the Ca(2+) sensitivity of force production are dysregulated in a porcine model of pacing-induced heart failure (HF). The level of protein kinase A (PKA)-dependent cardiac troponin I (TnI) phosphorylation was lower in the myocardium surrounding the pacing electrode (pacing site) of the failing left ventricle (LV) than in the controls. Immunohistochemical assays of the LV pacing site pointed to isolated clusters of cardiomyocytes exhibiting a reduced level of phosphorylated TnI. Flow cytometry on isolated and permeabilized cardiomyocytes revealed a significantly larger cell-to-cell variation in the level of TnI phosphorylation of the LV pacing site than in the opposite region in HF or in either region in the controls: the interquartile range (IQR) on the distribution histogram of relative TnI phosphorylation was wider at the pacing site (IQR = 0.53) than that at the remote site of HF (IQR = 0.42; P = 0.0047) or that of the free wall of the control animals (IQR = 0.36; P = 0.0093). Additionally, the Ca(2+) sensitivities of isometric force production were higher and appeared to be more variable in single permeabilized cardiomyocytes from the HF pacing site than in the healthy myocardium. In conclusion, the level of PKA-dependent TnI phosphorylation and the Ca(2+) sensitivity of force production exhibited a high cell-to-cell variability at the LV pacing site, possibly explaining the abnormalities of the regional myocardial contractile function in a porcine model of pacing-induced HF.

[Heart failure with preserved ejection fraction (diastolic heart failure)]. / Szívelégtelenség megorzött ejekciós frakcióval (diasztolés szívelégtelenség).

Diastolic heart failure, which is also called as heart failure with preserved ejection fraction, is a clinical syndrome in which patients have signs and symptoms of heart failure, normal or near normal left ventricular ejection fraction (≥ 50%) and evidence of diastolic dysfunction. Recent epidemiological studies have demonstrated that more than half of all heart failure patients have diastolic heart failure. The syndrome is more common in women than in men and the prevalence increases with age. Patients with diastolic heart failure form a fairly heterogeneous group with complex pathophysiologic mechanisms. The disease is often in association with other comorbidities, such as hypertension, diabetes mellitus or obesity. The diagnosis of diastolic heart failure is best achieved by two-dimensional and Doppler echocardiography, which can detect abnormal myocardial relaxation, decreased compliance and increased filling pressure in the setting of normal left ventricular dimensions and preserved ejection fraction. Unlike heart failure with reduced ejection fraction, there is no such an evidence-based treatment for heart failure with preserved ejection fraction, which would improve clinical outcomes. Thus, pharmacological therapy of diastolic heart failure is based mainly on empiric data, and aims to the normalization of blood pressure, reduction of left ventricular dimensions and increased heart rate, maintenance of normal atrial contraction and treatment of symptoms caused by congestion. Beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers may be utilized in patients with diastolic dysfunction, especially in those with hypertension. Beta-blockers appear to be useful in lowering heart rate and thereby prolonging left ventricular diastolic filling time, while diuretic therapy is the mainstay of treatment for preventing pulmonary congestion. Nonetheless, treatment of the underlying disease is also an important therapeutic approach. This review summarizes the state of current knowledge with regard to diastolic heart failure.

Pressure- and 3D-Derived Coronary Flow Reserve with Hydrostatic Pressure Correction: Comparison with Intracoronary Doppler Measurements.

Purpose: To develop a method of coronary flow reserve (CFR) calculation derived from three-dimensional (3D) coronary angiographic parameters and intracoronary pressure data during fractional flow reserve (FFR) measurement. Methods: Altogether 19 coronary arteries of 16 native and 3 stented vessels were reconstructed in 3D. The measured distal intracoronary pressures were corrected to the hydrostatic pressure based on the height differences between the levels of the vessel orifice and the sensor position. Classical fluid dynamic equations were applied to calculate the flow during the resting state and vasodilatation based on morphological data and intracoronary pressure values. 3D-derived coronary flow reserve (CFRp-3D) was defined as the ratio between the calculated hyperemic and the resting flow and was compared to the CFR values simultaneously measured by the Doppler sensor (CFRDoppler). Results: Haemodynamic calculations using the distal coronary pressures corrected for hydrostatic pressures showed a strong correlation between the individual CFRp-3D values and the CFRDoppler measurements (r = 0.89, p < 0.0001). Hydrostatic pressure correction increased the specificity of the method from 46.1% to 92.3% for predicting an abnormal CFRDoppler < 2. Conclusions: CFRp-3D calculation with hydrostatic pressure correction during FFR measurement facilitates a comprehensive hemodynamic assessment, supporting the complex evaluation of macro-and microvascular coronary artery disease.

Predictors of restenosis following percutaneous coronary stent implantation: The role of trimetazidine therapy.

Aims: In-stent restenosis (ISR) is an unresolved problem following percutaneous coronary intervention (PCI), having a negative impact on clinical outcome. The main goal of this study was to find new independent predictors that may influence the development of ISR. Methods and results: In this retrospective analysis, 653 PCI patients were involved. All patients had coronary stent implantation and a follow-up coronary angiography. Based on the presence of ISR at follow-up, patients were divided into two groups: 221 in the ISR and 432 in the control group. When evaluating the medical therapy of patients, significantly more patients were on trimetazidine (TMZ) in the control compared to the ISR group (p = 0.039). TMZ was found to be an independent predictor of a lower degree of ISR development (p = 0.007). TMZ treatment was especially effective in bare metal stent (BMS)-implanted chronic coronary syndrome (CCS) patients with narrow coronary arteries. The inflammation marker neutrophil to lymphocyte ratio (NLR) was significantly elevated at baseline in the ISR group compared to controls. The reduction of post-PCI NLR was associated with improved efficacy of TMZ to prevent ISR development. Drug eluting stent implantation (p < 0.001) and increased stent diameter (p < 0.001) were the most important independent predictors of a lower degree of ISR development, while the use of longer stents (p = 0.005) was a major independent predictor of an increased ISR risk. Conclusion: TMZ reduces the occurrence of ISR following PCI, with special effectiveness in BMS-implanted patients having CCS and narrow coronary arteries. TMZ treatment may help to lower ISR formation in countries with high BMS utilization rates.

Novel Method to Detect Pitfalls of Intracoronary Pressure Measurements by Pressure Waveform Analysis.

Potential pitfalls of fractional flow reserve (FFR) measurements are well-known drawbacks of invasive physiology measurement, e.g., significant drift of the distal pressure trace may lead to the misclassification of stenoses. Thus, a simultaneous waveform analysis of the pressure traces may be of help in the quality control of these measurements by online detection of such artefacts as the drift or the wedging of the catheter. In the current study, we analysed the intracoronary pressure waveform with a dedicated program. In 130 patients, 232 FFR measurements were performed and derivative pressure curves were calculated. Local amplitude around the dicrotic notch was calculated from the distal intracoronary pressure traces (δdPn/dt). A unidimensional arterial network model of blood flow was employed to simulate the intracoronary pressure traces at different flow rates. There was a strong correlation between δdPn/dt values measured during hyperaemia and FFR (r = 0.88). Diagnostic performance of distal δdPn/dt ≤ 3.52 for the prediction of FFR ≤ 0.80 was 91%. The correlation between the pressure gradient and the corresponding δdPn/dt values obtained from all measurements independently of the physiological phase was also significant (r = 0.80). During simulation, the effect of flow rate on δdPn/dt further supported the close correlation between the pressure ratios and δdPn/dt. Discordance between the FFR and the δdPn/dt can be used as an indicator of possible technical problems of FFR measurements. Hence, an online calculation of the δdPn/dt may be helpful in avoiding some pitfalls of FFR evaluation.

The Genetic Architecture of Hypertrophic Cardiomyopathy in Hungary: Analysis of 242 Patients with a Panel of 98 Genes.

Hypertrophic cardiomyopathy (HCM) is a primary disease of the myocardium most commonly caused by mutations in sarcomeric genes. We aimed to perform a nationwide large-scale genetic analysis of a previously unreported, representative HCM cohort in Hungary. A total of 242 consecutive HCM index patients (127 men, 44 ± 11 years) were studied with next generation sequencing using a custom-designed gene-panel comprising 98 cardiomyopathy-related genes. A total of 90 patients (37%) carried pathogenic/likely pathogenic (P/LP) variants. The percentage of patients with P/LP variants in genes with definitive evidence for HCM association was 93%. Most of the patients with P/LP variants had mutations in MYBPC3 (55 pts, 61%) and in MYH7 (21 pts, 23%). Double P/LP variants were present in four patients (1.7%). P/LP variants in other genes could be detected in ≤3% of patients. Of the patients without P/LP variants, 46 patients (19%) carried a variant of unknown significance. Non-HCM P/LP variants were identified in six patients (2.5%), with two in RAF1 (p.Leu633Val, p.Ser257Leu) and one in DES (p.Arg406Trp), FHL1 (p.Glu96Ter), TTN (p.Lys23480fs), and in the mitochondrial genome (m.3243A>G). Frameshift, nonsense, and splice-variants made up 82% of all P/LP MYBPC3 variants. In all the other genes, missense mutations were the dominant form of variants. The MYBPC3 p.Gln1233Ter, the MYBPC3 p.Pro955ArgfsTer95, and the MYBPC3 p.Ser593ProfsTer11 variants were identified in 12, 7, and 13 patients, respectively. These three variants made up 36% of all patients with identified P/LP variants, raising the possibility of a possible founder effect for these mutations. Similar to other HCM populations, the MYBPC3 and the MYH7 genes seemed to be the most frequently affected genes in Hungarian HCM patients. The high prevalence of three MYBPC3 mutations raises the possibility of a founder effect in our HCM cohort.

The impact of hydrostatic pressure on the result of physiological measurements in various coronary segments.

The effect of hydrostatic pressure on physiological intracoronary measurements is usually ignored in the daily clinical practice. Our aim was to investigate this effect on Pd/Pa (distal/aortic pressure) and FFR (fractional flow reserve). 41 FFR measurements between 0.7 and 0.9 were selected. The difference in the height of the orifice and that of the sensor was defined in mm on the basis of 3D coronary reconstruction. Resting Pd/Pa and FFR were adjusted by subtracting the hydrostatic pressure gradient from the distal pressure. Height measurements were also performed from 2D lateral projections for each coronary segment (n = 305). In case of the LAD, each segment was located higher (proximal: - 13.69 ± 5.4; mid: - 46.13 ± 6.1; distal: - 56.80 ± 7.7 mm), whereas for the CX, each segment was lower (proximal: 14.98 ± 8.3; distal: 28.04 ± 6.3 mm) compared to the orifice. In case of the RCA, the distances from the orifice were much less (proximal: - 6.39 ± 2.9; mid: - 6.86 ± 7.0; distal: 17.95 ± 6.6 mm). The effect of these distances on pressure ratios at 100 Hgmm aortic pressure was between - 0.044 and 0.023. The correction for height differences changed the interpretation of the measurement (negative/positive result) in 5 (12%) and 11 (27%) cases for the FFR (cut-off value at 0.80) and the resting Pd/Pa (cut-off value at 0.92), respectively. The clinical implementation of hydrostatic pressure calculation should be considered during intracoronary pressure measurements. A correction for this parameter may become crucial in case of a borderline significant coronary artery stenosis, especially in distal coronary artery segments.

The Holistic Coronary Physiology Display: Calculation of the Flow Separation Index in Vessel-Specific Individual Flow Range during Fractional Flow Reserve Measurement Using 3D Coronary Reconstruction.

In order to make optimal decisions on the treatment of atherosclerotic coronary heart disease (CHD), appropriate evaluation is necessary, including both the anatomical and physiological assessment of the coronary arteries. According to current guidelines, a fractional flow reserve (FFR)-based clinical decision is recommended, but coronary flow reserve (CFR) measurements and microvascular evaluation should also be considered in special cases for a detailed exploration of the coronary disease state. We aimed to generate an extended physiological evaluation during routine FFR measurement and define a new pathological flow-related prognostic factor. Fluid dynamic equations were applied to calculate CFR on the basis of the three-dimensional (3D) reconstruction of the invasively acquired coronary angiogram and the measured intracoronary pressure data. A new, potentially robust prognostic parameter of a coronary lesion called the "flow separation index" (FSi), which is thought to detect the pathological flow amount through a stenosis was introduced in a vessel-specific flow range. Correlations between FSi and the clinically established physiological indices (CFR and FFR) were determined. The FSi was calculated in 19 vessels of 16 patients, including data from the pre- and post-stent revascularization treatment of 3 patients. There was no significant correlation between the FSi and the CFR (r = -0.23, p = 0.34); however, there was significant negative correlation between the FSi and the FFR (r = -0.66, p = 0.002). An even stronger correlation was found between the FSi and the ratio of the resting pressure ratio and the FFR (r = 0.92, p < 0.0001). The diagnostic power of the FSi for predicting the FFR value of <0.80, as a gold standard prognostic factor, was tested by receiver operating characteristic analysis. FSi > 0.022 proved to be the cutoff value of the prediction of a pathologically low FFR with a 0.856 area under the curve (95% confidence interval: 0.620 to 0.972). The present flow-pressure-velocity display provides a comprehensive summary of patient-specific pathophysiology in CHD. The consequences of epicardial stenoses can be evaluated together with their complex relations to microvascular conditions. Based on these values, clinical decision-making concerning both pharmacological therapy and percutaneous or surgical revascularization may be more precisely guided.

Anatomical Assessment vs. Pullback REsting full-cycle rAtio (RFR) Measurement for Evaluation of Focal and Diffuse CoronarY Disease: Rationale and Design of the "READY Register".

Background: The morphology and functional severity of coronary stenosis show poor correlation. However, in clinical practice, the visual assessment of the invasive coronary angiography is still the most common means for evaluating coronary disease. The fractional flow reserve (FFR), the coronary flow reserve (CFR), and the resting full-cycle ratio (RFR) are established indices to determine the hemodynamic significance of a coronary stenosis. Design/Methods: The READY register (NCT04857762) is a prospective, multicentre register of patients who underwent invasive intracoronary FFR and RFR measurement. The main aim of the registry is to compare the visual estimate of coronary lesions and the functional severity of the stenosis assessed by FFR, as well as the RFR pullback. Characterizations of the coronary vessel for predominantly focal, diffuse, or mixed type disease according to visual vs. RFR pullback determination will be compared. The secondary endpoint of the study is a composite of major adverse cardiac events, including death, myocardial infarction, and repeat coronary revascularization at 1 year. These endpoints will be compared in patients with non-ischemic FFR in the subgroup of cases where the local pressure drop indicates a focal lesion according to the definition of ΔRFR > 0.05 (for <25 mm segment length) and in the subgroup without significant ΔRFR. In case of an FFR value above 0.80, an extended physiological analysis is planned to diagnose or exclude microvascular disease using the CFR/FFR index. This includes novel flow dynamic modeling for CFR calculation (CFRp-3D). Conclusion: The READY register will define the effect of RFR measurement on visual estimation-based clinical decision-making. It can identify a prognostic value of ΔRFR during RFR pullback, and it would also explore the frequency of microvascular disease in the patient population with FFR > 0.80. Clinical Trial Registration: ClinicalTrials.gov (NCT04857762).

Interventricular Differences of Signaling Pathways-Mediated Regulation of Cardiomyocyte Function in Response to High Oxidative Stress in the Post-Ischemic Failing Rat Heart.

Standard heart failure (HF) therapies have failed to improve cardiac function or survival in HF patients with right ventricular (RV) dysfunction suggesting a divergence in the molecular mechanisms of RV vs. left ventricular (LV) failure. Here we aimed to investigate interventricular differences in sarcomeric regulation and function in experimental myocardial infarction (MI)-induced HF with reduced LV ejection fraction (HFrEF). MI was induced by LAD ligation in Sprague-Dawley male rats. Sham-operated animals served as controls. Eight weeks after intervention, post-ischemic HFrEF and Sham animals were euthanized. Heart tissue samples were deep-frozen stored (n = 3-5 heart/group) for ELISA, kinase activity assays, passive stiffness and Ca2+-sensitivity measurements on isolated cardiomyocytes, phospho-specific Western blot, and PAGE of contractile proteins, as well as for collagen gene expressions. Markers of oxidative stress and inflammation showed interventricular differences in post-ischemic rats: TGF-ß1, lipid peroxidation, and 3-nitrotyrosine levels were higher in the LV than RV, while hydrogen peroxide, VCAM-1, TNFα, and TGF-ß1 were increased in both ventricles. In addition, nitric oxide (NO) level was significantly decreased, while FN-1 level was significantly increased only in the LV, but both were unchanged in RV. CaMKII activity showed an 81.6% increase in the LV, in contrast to a 38.6% decrease in the RV of HFrEF rats. Cardiomyocyte passive stiffness was higher in the HFrEF compared to the Sham group as evident from significantly steeper Fpassive vs. sarcomere length relationships. In vitro treatment with CaMKIIδ, however, restored cardiomyocyte passive stiffness only in the HFrEF RV, but had no effect in the HFrEF LV. PKG activity was lower in both ventricles in the HFrEF compared to the Sham group. In vitro PKG administration decreased HFrEF cardiomyocyte passive stiffness; however, the effect was more pronounced in the HFrEF LV than HFrEF RV. In line with this, we observed distinct changes of titin site-specific phosphorylation in the RV vs. LV of post-ischemic rats, which may explain divergent cardiomyocyte stiffness modulation observed. Finally, Ca2+-sensitivity of RV cardiomyocytes was unchanged, while LV cardiomyocytes showed increased Ca2+-sensitivity in the HFrEF group. This could be explained by decreased Ser-282 phosphorylation of cMyBP-C by 44.5% in the RV, but without any alteration in the LV, while Ser-23/24 phosphorylation of cTnI was decreased in both ventricles in the HFrEF vs. the Sham group. Our data pointed to distinct signaling pathways-mediated phosphorylations of sarcomeric proteins for the RV and LV of the post-ischemic failing rat heart. These results implicate divergent responses for oxidative stress and open a new avenue in targeting the RV independently of the LV.