AIMS: The cardiac conduction system (CCS) is progressively specified during development by interactions among a discrete number of transcription factors (TFs) that ensure its proper patterning and the emergence of its functional properties. Meis genes encode homeodomain TFs with multiple roles in mammalian development. In humans, Meis genes associate with congenital cardiac malformations and alterations of cardiac electrical activity; however, the basis for these alterations has not been established. Here, we studied the role of Meis TFs in cardiomyocyte development and function during mouse development and adult life. METHODS AND RESULTS: We studied Meis1 and Meis2 conditional deletion mouse models that allowed cardiomyocyte-specific elimination of Meis function during development and inducible elimination of Meis function in cardiomyocytes of the adult CCS. We studied cardiac anatomy, contractility, and conduction. We report that Meis factors are global regulators of cardiac conduction, with a predominant role in the CCS. While constitutive Meis deletion in cardiomyocytes led to congenital malformations of the arterial pole and atria, as well as defects in ventricular conduction, Meis elimination in cardiomyocytes of the adult CCS produced sinus node dysfunction and delayed atrio-ventricular conduction. Molecular analyses unravelled Meis-controlled molecular pathways associated with these defects. Finally, we studied in transgenic mice the activity of a Meis1 human enhancer related to an single-nucleotide polymorphism (SNP) associated by Genome-wide association studies (GWAS) to PR (P and R waves of the electrocardiogram) elongation and found that the transgene drives expression in components of the atrio-ventricular conduction system. CONCLUSION: Our study identifies Meis TFs as essential regulators of the establishment of cardiac conduction function during development and its maintenance during adult life. In addition, we generated animal models and identified molecular alterations that will ease the study of Meis-associated conduction defects and congenital malformations in humans.

• MeSH
• Action Potentials MeSH
• Phenotype MeSH
• Homeodomain Proteins * genetics   metabolism   MeSH
• Myocytes, Cardiac * metabolism   pathology   MeSH
• Myocardial Contraction MeSH
• Mice, Knockout MeSH
• Sinoatrial Node metabolism   physiopathology   MeSH
• Heart Conduction System * metabolism   physiopathology   growth & development   MeSH
• Arrhythmias, Cardiac physiopathology   metabolism   genetics   MeSH
• Heart Rate * MeSH
• Myeloid Ecotropic Viral Integration Site 1 Protein * genetics   metabolism   deficiency   MeSH
• Age Factors MeSH
• Heart Defects, Congenital metabolism   genetics   physiopathology   MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

Prognostic significance of the timing in the cardiac cycle of the first (TP1) and second (TP2) systolic peak of the central aortic pulse wave is ill-defined. Incidence rates and standardized multivariable-adjusted hazard ratios (HRs) of adverse health outcomes associated with TP1 and TP2, estimated by the SphygmoCor software, were assessed in the International Database of Central Arterial Properties for Risk Stratification (IDCARS) (n = 5529). Model refinement was assessed by the integrated discrimination (ID) and net reclassification (NR) improvement. Over 4.1 years (median), 201 participants died and 248 and 159 patients experienced cardiovascular or cardiac endpoints. Mean TP1 and TP2, standardized for cohort, sex, age, and heart rate, were 103 and 228 ms. Shorter TP1 and TP2 were associated with higher mortality and shorter TP1 with a higher risk of cardiovascular and cardiac endpoints (trend p ≤ 0.004). The HRs relating total mortality and cardiovascular endpoints to TP2 were 0.82 (95% confidence interval [CI]: 0.72-0.94) and 0.87 (0.77-0.98), respectively. The HR relating cardiac endpoints to TP1 was 0.81 (0.68-0.97). For total mortality and cardiovascular endpoints in relation to TP2, NRI was significant (p ≤ 0.010), but not for cardiac endpoints in relation to TP1. Integrated discrimination improvement (IDI) was not significant for any endpoint. The HRs relating total mortality to TP2 were smaller (p ≤ 0.026) in women than men (0.67 vs. 0.95) and in older (≥ 60 years) versus younger (< 60 years) participants (0.80 vs. 0.88). Our study adds to the evidence supporting risk stratification based on aortic pulse analysis by showing that TP2 and TP1 carry prognostic information.

• MeSH
• Pulse Wave Analysis * methods   MeSH
• Aorta physiopathology   MeSH
• Risk Assessment methods   statistics & numerical data   MeSH
• Hypertension epidemiology   mortality   physiopathology   MeSH
• Cardiovascular Diseases * mortality   epidemiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Prognosis MeSH
• Risk Factors MeSH
• Aged MeSH
• Heart Rate physiology   MeSH
• Systole physiology   MeSH
• Vascular Stiffness physiology   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Pediatric blood pressure (BP) assessment and management is increasingly important. Uncontrolled systolic and combined hypertension leads to hypertension-mediated organ damage. The impact of isolated diastolic hypertension is less clearly understood. METHODS: We analyzed the prevalence of ambulatory isolated diastolic hypertension (IDH) in primary (PH) and secondary (SH) hypertension, and associations with BMI Z-score (BMIz) and left ventricular mass index adjusted to the 95th percentile (aLVMI) in a large, multicenter cohort of hypertensive children. Hypertensive children were divided and analyzed in three ambulatory hypertension subgroups: 24-h, daytime, and nighttime. Specifically, we sought to determine the prevalence of ambulatory 24-h, daytime, or nighttime IDH. RESULTS: Prevalence of IDH varied based on ambulatory phenotypes, ranging from 6 to 12%, and was highest in children with SH. Children with IDH tended to be more likely female and, in some cases, were leaner than those with isolated systolic hypertension (ISH). Despite previous pediatric studies suggesting no strong association between diastolic blood pressure and left ventricular hypertrophy (LVH), we observed that children with IDH were equally likely to have LVH and had comparable aLVMI to those with ISH and combined systolic-diastolic hypertension. CONCLUSIONS: In summary, ambulatory IDH appears to be a unique phenotype with a female sex, and younger age predilection, but equal risk for LVH in children with either PH or SH.

• MeSH
• Blood Pressure Monitoring, Ambulatory * MeSH
• Diastole MeSH
• Child MeSH
• Hypertension * epidemiology   diagnosis   etiology   MeSH
• Hypertrophy, Left Ventricular * epidemiology   etiology   diagnosis   MeSH
• Blood Pressure * MeSH
• Humans MeSH
• Adolescent MeSH
• Child, Preschool MeSH
• Prevalence MeSH
• Risk Factors MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

• MeSH
• Administration, Oral MeSH
• Benzylamines MeSH
• Double-Blind Method MeSH
• Cardiomyopathy, Hypertrophic * drug therapy   physiopathology   MeSH
• Cardiovascular Agents * pharmacology   therapeutic use   MeSH
• Myocardial Contraction drug effects   physiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Ventricular Outflow Obstruction drug therapy   physiopathology   etiology   MeSH
• Aged MeSH
• Oxygen Consumption drug effects   MeSH
• Cardiac Myosins antagonists & inhibitors   MeSH
• Exercise Tolerance drug effects   MeSH
• Uracil analogs & derivatives   MeSH
• Valsalva Maneuver MeSH
• Exercise Test * MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

Efektivita práce levé komory vyžaduje udržení srdečního výdeje, který je nárokován systémovým oběhem, a to bez vysokých metabolických nároků nebo nároků na kyslík ze strany myokardu levé komory. V tomto článku je levá komora uvažována jako pumpa a výkonnost je založena na hodnocení měření jejích tlaků, objemů a průtoku. Analýza funkce komory z hlediska vztahů mezi tlakem a objemem umožňuje plně analyzovat globální a regionální dynamiku komory, kterou lze poměrně snadno a přesně získat pomocí vodivostního katétru. Maximální změna tlaku za jednotku času v levé komoře je považována za ukazatel kontraktility levé komory, za jistých situací může být alternativou arteriální dP/dt max jakožto méně invazivní metoda. Při hodnocení nových kardiostimulačních technik a srdeční resynchronizační terapie se jako nejpraktičtější metoda jeví invazivní systolický krevní tlak s průměrováním více tepů a doplněním o několikrát opakované střídání stimulací

Effective performance of the left ventricle requires the maintenance of a cardiac output as demanded by the systemic circulation without a high hemodynamic cost or pressure and without a high metabolic cost or oxygen demand by the left ventricular myocardium. In this article the left ventricle is considered as a pump and performance is based on evaluation of measurements of its pressure, volumes, and flow. Analysis of ventricular function in terms of pressure-volume relationships allows global and regional ventricular dynamics to be fully analyzed and relatively easily and precisely obtained with conductance catheter. The maximum rate of left ventricular pressure is classically considered as a marker of left ventricular contractility and in specific situation arterial dP/dtmax, as minimally invasive method, can be an alternative. When assessing new pacing techniques and cardiac resynchronization therapy, invasive systolic blood pressure appears to be the most practical measure with multi-beat averaging and the addition of multiple spaced repeated alternations.

• Keywords
• dP/dtmax, Srdeční funkce,
• MeSH
• Diagnostic Techniques, Cardiovascular classification   MeSH
• Ventricular Function, Left * MeSH
• Hemodynamics MeSH
• Myocardial Contraction physiology   MeSH
• Blood Pressure MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

The pressure-volume (PV) analysis is used for an accurate assessment of load-independent cardiac function and is important for the study of cardiovascular diseases and various therapeutic modalities. PV analysis is often performed on one of the ventricles, or on both ventricles but sequentially. Since both ventricles interact with each other and their functions are mutually interdependent, especially in various disease conditions such as pulmonary hypertension or heart failure, it is important to quantify the function of both ventricles at the same time. Therefore, our aim was to describe a standardized protocol for simultaneous right (RV) and left (LV) ventricle of PV analysis, including an especially controllable preload reduction manoeuver. Our second aim was to test whether simultaneous catheterization of both LV and RV is necessary for the determination of biventricular PV relationship compared to sequential measurement of both ventricles separately. In this article, we showed the feasibility and the value of simultaneous biventricular PV analysis in the measurement of contractility parameters (end-systolic pressure-volume relationship (ESPVR), ventricular pressure over time (dP/dt)max, divided by end-diastolic volume (dP/dt max-EDV)) with a comparison to the sequential measurement of the RV and LV ventricles separately. We described in detail the protocol for simultaneous biventricular PV analysis in rats using a pair of conductance-micromanometer catheters with a preload-reducing manoeuver using balloon catheter inflation in the inferior vena cava. We also described technical tips and show examples of PV loop data obtained in normotensive and hypertensive rats, with and without heart failure due to volume overload. This protocol could be useful for scientists studying hemodynamics and cardiac contractility in various models of cardiovascular diseases with a focus on biventricular differences and ventricular interdependence.

• MeSH
• Hemodynamics MeSH
• Cardiovascular Diseases * MeSH
• Myocardial Contraction physiology   MeSH
• Rats MeSH
• Heart Ventricles MeSH
• Heart Failure * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: The role of pulse pressure (PP) 'widening' at older and younger age as a cardiovascular risk factor is still controversial. Mean PP, as determined from repeated blood pressure (BP) readings, can be expressed as a sum of two components: 'elastic PP' (elPP) and 'stiffening PP' (stPP) associated, respectively, with stiffness at the diastole and its relative change during the systole. We investigated the association of 24-h ambulatory PP, elPP, and stPP ('PP variables') with mortality and composite cardiovascular events in different age classes. METHOD: Longitudinal population-based cohort study of adults with baseline observations that included 24-h ambulatory BP. Age classes were age 40 or less, 40-50, 50-60, 60-70, and over 70 years. Co-primary endpoints were total mortality and composite cardiovascular events. The relative risk expressed by hazard ratio per 1SD increase for each of the PP variables was calculated from multivariable-adjusted Cox regression models. RESULTS: The 11 848 participants from 13 cohorts (age 53 ± 16 years, 50% men) were followed for up for 13.7 ± 6.7 years. A total of 2946 participants died (18.1 per 1000 person-years) and 2093 experienced a fatal or nonfatal cardiovascular event (12.9 per 1000 person-years). Mean PP, elPP, and stPP were, respectively, 49.7, 43.5, and 6.2 mmHg, and elPP and stPP were uncorrelated ( r = -0.07). At age 50-60 years, all PP variables displayed association with risk for almost all outcomes. From age over 60 years to age over 70 years, hazard ratios of of PP and elPP were similar and decreased gradually but differently for pulse rate lower than or higher than 70 bpm, whereas stPP lacked predictive power in most cases. For age 40 years or less, elPP showed protective power for coronary events, whereas stPP and PP predicted stroke events. Adjusted and unadjusted hazard ratio variations were similar over the entire age range. CONCLUSION: This study provides a new basis for associating PP components with outcome and arterial properties in different age groups and at different pulse rates for both old and young age. The similarity between adjusted and unadjusted hazard ratios supports the clinical usefulness of PP components but further studies are needed to assess the prognostic significance of the PP components, especially at the young age.

• MeSH
• Blood Pressure Monitoring, Ambulatory MeSH
• Adult MeSH
• Hypertension * MeSH
• Cardiovascular Diseases * diagnosis   MeSH
• Cohort Studies MeSH
• Blood Pressure physiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Systole physiology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Based on the World Health Organization statistics, cardiovascular diseases represent the major cause of death worldwide. Although a wide range of treatment approaches and pharmaceuticals is available, the therapy is often not effective enough and therefore health risks for the patient persist. Thus, it is still essential to test new drug candidates for the treatment of various pathophysiological conditions related to cardiovascular system. In vivo models represent indispensable part of preclinical testing of such substances. Anesthetized guinea pig as a whole-body model allows to evaluate complex reactions of cardiovascular system to tested substance. Moreover, action potential of guinea pig cardiomyocyte is quite comparable to that of human. Hence, the results from this model are then quite well translatable to clinical medicine. Aim of this paper was to summarize the methodology of this model, including its advantages and/or limitations and risks, based on the effects of two substances with adrenergic activity on the ECG parameters. The model of anesthetized guinea pig proved to be valuable and suitable for testing of drugs with cardiovascular effects.

• MeSH
• Electrocardiography * MeSH
• Cardiovascular System * drug effects   MeSH
• Myocardial Contraction * drug effects   physiology   MeSH
• Blood Pressure drug effects   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Guinea Pigs MeSH
• Drug Evaluation, Preclinical * MeSH
• Heart drug effects   physiology   MeSH
• Heart Rate MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Guinea Pigs MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Arterial compliance (C) is a complex parameter influencing ventricular-arterial coupling depending on structural (arterial wall remodeling) and functional (blood pressure, smooth muscles tone) changes. Based on Windkessel model, C can be calculated as the ratio of a time constant Tau characterizing diastolic blood pressure decay and total peripheral resistance (TPR). The aim of this study was to assess changes of C in the context of systolic arterial pressure (SAP) perturbations during four physiological states (supine rest, head-up tilt, supine recovery, mental arithmetic). In order to compare pressure independent changes of C a new index of C120 was proposed predicting C value at 120 mm Hg of SAP. Eighty-one healthy young subjects (48 f, average age 18.6 years) were examined. Hemodynamic parameters were measured beat-to-beat using volume-clamp photoplethysmographic method and impedance cardiography. We observed that C was strongly related to SAP values on the beat-to-beat time scale. Interestingly, C120 decreased significantly during stress phases. In conclusion, potential changes of SAP should be considered when measuring C. Arterial compliance changes in the opposite direction to TPR pointing towards influence of vascular tone changes on its value.

• MeSH
• Arterial Pressure * MeSH
• Time Factors MeSH
• Vascular Resistance MeSH
• Adaptation, Physiological MeSH
• Humans MeSH
• Mathematical Concepts MeSH
• Adolescent MeSH
• Young Adult MeSH
• Models, Cardiovascular MeSH
• Patient Positioning MeSH
• Supine Position MeSH
• Systole MeSH
• Tilt-Table Test MeSH
• Vascular Stiffness * MeSH
• Healthy Volunteers MeSH
• Check Tag
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

Beta-adrenergic receptors (beta-ARs) play a pivotal role in the cardiovascular regulation. In the human heart beta1- and beta2-ARs dominate in atria as well as in ventricle influencing heart rate and myocardial contractility. Some single nucleotide polymorphisms (SNPs) of beta-ARs might influence cardiovascular function. However, the influence of beta-AR genes SNPs on hemodynamic parameters at rest and their reactivity under stress is still not well known. We aimed to explore the associations between four selected beta-ARs gene polymorphisms and selected cardiovascular measures in eighty-seven young healthy subjects. While in beta1-AR polymorphism rs1801252 no significant association was observed, second beta1-AR polymorphism rs1801253 was associated with decreased cardiac output and cardiac index during all phases and with decreased flow time corrected and ejection time index at rest and during mental arithmetics. Polymorphism rs1042713 in beta2-AR was associated with alterations in blood pressure variability at rest and during head-up-tilt, while rs1042714 was associated predominantly with decreased parameters of cardiac contractility at rest and during mental arithmetics. We conclude that complex analysis of various cardiovascular characteristics related to the strength of cardiac contraction and blood pressure variability can reveal subtle differences in cardiovascular sympathetic nervous control associated with beta-ARs polymorphisms.

• MeSH
• Receptors, Adrenergic, beta-1 genetics   MeSH
• Receptors, Adrenergic, beta-2 genetics   MeSH
• Phenotype MeSH
• Ventricular Function, Left genetics   MeSH
• Genotype MeSH
• Polymorphism, Single Nucleotide * MeSH
• Myocardial Contraction genetics   MeSH
• Blood Pressure genetics   MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Healthy Volunteers MeSH
• Check Tag
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH