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
- aplikace orální MeSH
- benzylaminy MeSH
- dvojitá slepá metoda MeSH
- hypertrofická kardiomyopatie * farmakoterapie patofyziologie MeSH
- kardiovaskulární látky * farmakologie terapeutické užití MeSH
- kontrakce myokardu účinky léků fyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- obstrukce výtoku ze srdeční komory farmakoterapie patofyziologie etiologie MeSH
- senioři MeSH
- spotřeba kyslíku účinky léků MeSH
- srdeční myosiny antagonisté a inhibitory MeSH
- tolerance zátěže účinky léků MeSH
- uracil analogy a deriváty MeSH
- Valsalvův manévr MeSH
- zátěžový test * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie 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.
- Klíčová slova
- dP/dtmax, Srdeční funkce,
- MeSH
- diagnostické techniky kardiovaskulární klasifikace MeSH
- funkce levé komory srdeční * MeSH
- hemodynamika MeSH
- kontrakce myokardu fyziologie MeSH
- krevní tlak MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy 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.
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
- elektrokardiografie * MeSH
- kardiovaskulární systém * účinky léků MeSH
- kontrakce myokardu * účinky léků fyziologie MeSH
- krevní tlak účinky léků MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- morčata MeSH
- preklinické hodnocení léčiv * MeSH
- srdce účinky léků fyziologie MeSH
- srdeční frekvence MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- morčata MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- rozštěp, klapnutí, Valsavův manévr,
- MeSH
- aortální insuficience diagnóza klasifikace patofyziologie patologie MeSH
- aortální stenóza diagnóza etiologie patofyziologie patologie MeSH
- břicho patologie MeSH
- cyanóza diagnóza etiologie klasifikace patofyziologie patologie MeSH
- defekty komorového septa diagnóza patologie MeSH
- defekty septa síní diagnóza patofyziologie patologie MeSH
- diastola fyziologie MeSH
- diferenciální diagnóza MeSH
- Ebsteinova anomálie diagnóza patofyziologie patologie MeSH
- Eisenmengerův syndrom diagnóza patologie MeSH
- Fallotova tetralogie diagnóza patologie MeSH
- fyzikální vyšetření * klasifikace MeSH
- hlava patologie MeSH
- hrudník patologie MeSH
- insuficience plicnice diagnóza patofyziologie patologie MeSH
- koarktace aorty diagnóza patofyziologie patologie MeSH
- končetiny patologie MeSH
- kontrakce myokardu fyziologie MeSH
- kožní manifestace MeSH
- krk patologie MeSH
- lidé MeSH
- mitrální insuficience diagnóza etiologie klasifikace patofyziologie patologie MeSH
- mitrální stenóza diagnóza etiologie patofyziologie patologie MeSH
- nemoci srdce * diagnóza etiologie klasifikace patofyziologie patologie MeSH
- nemoci srdečních chlopní diagnóza etiologie klasifikace patofyziologie patologie MeSH
- obstrukce výtoku ze srdeční komory diagnóza patologie MeSH
- otevřená tepenná dučej diagnóza patofyziologie patologie MeSH
- palpace MeSH
- perikarditida diagnóza patologie MeSH
- perkuse klasifikace MeSH
- poslech srdce MeSH
- poslech MeSH
- postura těla fyziologie MeSH
- pulz klasifikace MeSH
- šelest na srdci diagnóza etiologie klasifikace patologie MeSH
- srdce - funkce komor MeSH
- srdce - funkce síní MeSH
- srdce patofyziologie MeSH
- srdeční chlopně umělé klasifikace MeSH
- srdeční ozvy fyziologie MeSH
- srdeční selhání diagnóza etiologie klasifikace patofyziologie patologie MeSH
- stenóza pulmonální chlopně diagnóza patologie MeSH
- stetoskopy MeSH
- systola fyziologie MeSH
- trikuspidální insuficience diagnóza etiologie patologie MeSH
- trikuspidální stenóza diagnóza patologie MeSH
- venae jugulares patologie MeSH
- vrozené srdeční vady diagnóza klasifikace patofyziologie patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Continuous, reliable evaluation of left ventricular (LV) contractile function in patients with advanced heart failure requiring intensive care remains challenging. Continual monitoring of dP/dtmax from the arterial line has recently become available in hemodynamic monitoring. However, the relationship between arterial dP/dtmax and LV dP/dtmax remains unclear. This study aimed to determine the relationship between arterial dP/dtmax and LV dP/dtmax assessed using echocardiography in patients with acute heart failure. METHODS: Forty-eight patients (mean age 70.4 years [65% male]) with acute heart failure requiring intensive care and hemodynamic monitoring were recruited. Hemodynamic variables, including arterial dP/dtmax, were continually monitored using arterial line pressure waveform analysis. LV dP/dtmax was assessed using continuous-wave Doppler analysis of mitral regurgitation flow. RESULTS: Values from continual arterial dP/dtmax monitoring were significantly correlated with LV dP/dtmax assessed using echocardiography (r = 0.70 [95% confidence interval (CI) 0.51-0.82]; P < 0.0001). Linear regression analysis revealed that LV dP/dtmax = 1.25 × (arterial dP/dtmax) (P < 0.0001). Arterial dP/dtmax was also significantly correlated with stroke volume (SV) (r = 0.63; P < 0.0001) and cardiac output (CO) (r = 0.42; P = 0.0289). In contrast, arterial dP/dtmax was not correlated with SV variation, dynamic arterial elastance, heart rate, systemic vascular resistance (SVR), or mean arterial pressure. Markedly stronger agreement between arterial and LV dP/dtmax was observed in subgroups with higher SVR (N = 28; r = 0.91; P < 0.0001), lower CO (N = 26; r = 0.81; P < 0.0001), and lower SV (N = 25; r = 0.60; P = 0.0014). A weak correlation was observed in the subjects with lower SVR (N = 20; r = 0.61; P = 0.0004); in the subgroups with higher CO (N = 22) and higher SV (N = 23), no significant correlation was found. CONCLUSION: Our results suggest that in patients with acute heart failure requiring intensive care with an arterial line, continuous calculation of arterial dP/dtmax may be used for monitoring LV contractility, especially in those with higher SVR, lower CO, and lower SV, such as in patients experiencing cardiogenic shock. On the other hand, there was only a weak or no significant correlation in the subgroups with higher CO, higher SV, and lower SVR.
- MeSH
- dopplerovská echokardiografie metody MeSH
- funkce levé komory srdeční fyziologie MeSH
- kontrakce myokardu fyziologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- minutový srdeční výdej fyziologie MeSH
- pilotní projekty MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- srdeční frekvence fyziologie MeSH
- srdeční selhání diagnostické zobrazování patofyziologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Cardiomyocytes (CM) placed on microelectrode array (MEA) were simultaneously probed with cantilever from atomic force microscope (AFM) system. This electric / nanomechanical combination in real time recorded beating force of the CMs cluster and the triggering electric events. Such "organ-on-a-chip" represents a tool for drug development and disease modeling. The human pluripotent stem cells included the WT embryonic line CCTL14 and the induced dystrophin deficient line reprogrammed from fibroblasts of a patient affected by Duchenne Muscular Dystrophy (DMD, complete loss of dystrophin expression). Both were differentiated to CMs and employed with the AFM/MEA platform for diseased CMs' drug response testing and DMD characterization. The dependence of cardiac parameters on extracellular Ca2+ was studied. The differential evaluation explained the observed effects despite variability of biological samples. The β-adrenergic stimulation (isoproterenol) and antagonist trials (verapamil) addressed ionotropic and chronotropic cell line-dependent features. For the first time, a distinctive beating-force relation for DMD CMs was measured on the 3D cardiac in vitro model.
- MeSH
- biosenzitivní techniky * MeSH
- buněčná diferenciace genetika MeSH
- Duchennova muskulární dystrofie patofyziologie MeSH
- dystrofin genetika MeSH
- fibroblasty účinky léků ultrastruktura MeSH
- indukované pluripotentní kmenové buňky metabolismus ultrastruktura MeSH
- isoprenalin farmakologie MeSH
- kardiomyocyty cytologie MeSH
- kontrakce myokardu genetika fyziologie MeSH
- lidé MeSH
- mikroelektrody MeSH
- mikroskopie atomárních sil MeSH
- verapamil farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Pioglitazone (PIO) is a thiazolidindione antidiabetic agent which improves insulin sensitivity and reduces blood glucose in experimental animals and treated patients. At the cellular level the actions of PIO in diabetic heart are poorly understood. A previous study has demonstrated shortened action potential duration and inhibition of a variety of transmembrane currents including L-type Ca(2+) current in normal canine ventricular myocytes. The effects of PIO on shortening and calcium transport in ventricular myocytes from the Goto-Kakizaki (GK) type 2 diabetic rat have been investigated. 10 min exposure to PIO (0.1-10 microM) reduced the amplitude of shortening to similar extents in ventricular myocytes from GK and control rats. 1 microM PIO reduced the amplitude of the Ca(2+) transients to similar extents in ventricular myocytes from GK and control rats. Caffeine-induced Ca(2+) release from the sarcoplasmic reticulum and recovery of Ca(2+) transients following application of caffeine and myofilament sensitivity to Ca(2+) were not significantly altered in ventricular myocytes from GK and control rats. Amplitude of L-type Ca(2+) current was not significantly decreased in myocytes from GK compared to control rats and by PIO treatment. The negative inotropic effects of PIO may be attributed to a reduction in the amplitude of the Ca(2+) transient however, the mechanisms remain to be resolved.
- MeSH
- biologický transport účinky léků MeSH
- diabetes mellitus 2. typu farmakoterapie patofyziologie MeSH
- experimentální diabetes mellitus farmakoterapie patofyziologie MeSH
- hypoglykemika farmakologie terapeutické užití MeSH
- kardiomyocyty účinky léků fyziologie MeSH
- kontrakce myokardu účinky léků fyziologie MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- srdeční komory účinky léků MeSH
- thiazolidindiony farmakologie terapeutické užití MeSH
- vápníková signalizace účinky léků fyziologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Recent studies have shown that left ventricle (LV) exhibits considerable transmural differences in active mechanical properties induced by transmural differences in electrical activity, excitation-contraction coupling, and contractile properties of individual myocytes. It was shown that the time between electrical and mechanical activation of myocytes (electromechanical delay: EMD) decreases from subendocardium to subepicardium and, on the contrary, the myocyte shortening velocity (MSV) increases in the same direction. To investigate the physiological importance of this inhomogeneity, we developed a new finite element model of LV incorporating the observed transmural gradients in EMD and MSV. Comparative simulations with the model showed that when EMD or MSV or both were set constant across the LV wall, the LV contractility during isovolumic contraction (IVC) decreased significantly ((dp/dt)max was reduced by 2 to 38% and IVC was prolonged by 18 to 73%). This was accompanied by an increase of transmural differences in wall stress. These results suggest that the transmural differences in EMD and MSV play an important role in physiological contractility of LV by synchronising the contraction of individual layers of ventricular wall during the systole. Reduction or enhancement of these differences may therefore impair the function of LV and contribute to heart failure.
- MeSH
- kontrakce myokardu fyziologie MeSH
- lidé MeSH
- modely kardiovaskulární * MeSH
- počítačová simulace * MeSH
- srdce - funkce komor fyziologie MeSH
- srdeční komory * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Hodnocení srdeční funkce je klíčový prvek pro odhad prognózy srdečních onemocnění. Posouzení srdeční funkce in vivo je však ovlivněno mnoha faktory, univerzální parametr, který by definoval status „mechanicky zdravého srdce“, proto neexistuje. V přehledu jsou nové i stávající ukazatele srdeční funkce rozděleny podle toho, zda vyjadřují kontraktilitu nebo mechanickou energii srdeční činnosti. Je diskutována jejich role v hodnocení srdeční fyziologie, způsoby stanovení, možné klinické využití i nevýhody.
Heart function evaluation is a key element in predicting heart disease prognosis. However, in vivo cardiac function assessment is influenced by many factors, and therefore there is no universal parameter defining the status of a "mechanically healthy heart". In this review, new and existing parameters of heart function are divided according to whether they express contractility or mechanical energy of cardiac function. Their role in the evaluation of cardiac physiology, methods of assessment, possible clinical use and disadvantages are discussed.
- Klíčová slova
- systolická elastance, srdeční kontraktilita, endsystolická elastance, preload recruitable stroke work, srdeční výkon, ejekční frakce,
- MeSH
- funkční vyšetření srdce metody MeSH
- infarkt myokardu diagnóza MeSH
- kontrakce myokardu * fyziologie MeSH
- lidé MeSH
- minutový srdeční výdej fyziologie MeSH
- srdce - funkce komor * fyziologie MeSH
- srdeční frekvence fyziologie MeSH
- systola fyziologie MeSH
- tepový objem * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
