Contribution of frequency-augmented inward Ca2+ current to myocardial contractility

2009 ◽  
Vol 87 (1) ◽  
pp. 69-75 ◽  
Author(s):  
Leonard D. Parilak ◽  
David G. Taylor ◽  
Yejia Song ◽  
Thomas Burkart ◽  
John C. Shryock ◽  
...  
Keyword(s):  
Heart Rate ◽  
Action Potential ◽  
Myocardial Contractility ◽  
Human Action ◽  
Left Ventricular ◽  
Monophasic Action Potential ◽  
Force Frequency ◽  
Rate Dependent ◽  
Frequency Relationship

The sarcoplasmic reticular Ca2+ pump (SERCA) is thought to be the primary determinant of heart rate-dependent increases in myocardial contractile [Ca2+]i and force (force–frequency relationship (FFR)), an important mechanism to increase cardiac output. This report demonstrates a rate-dependent role for inward Ca2+ current (ICa) in the human and rat FFR. Human action potential plateau height increased linearly with contractility when heart rate increased in vivo, as measured by monophasic action potential catheter and echocardiography. Rat rate-dependent developed force and cytosolic [Ca2+]i transients were quantified in isolated left ventricular papillary muscles, and ICa and action potential duration in cardiomyocytes. ICa and SERCA measurements better reflected [Ca2+]i and force transients than SERCA activity alone. These data support a direct and (or) indirect contribution to myocardial contractility by ICa at heart rates from approximately 1 to 3–4 Hz (60 to 180–240 bpm) in tandem with SERCA to sustain the typical ‘bell shape’ of the FFR across species.

Modulation of force-frequency relation by phospholamban in genetically engineered mice

1999 ◽  
Vol 276 (6) ◽  
pp. H2245-H2250 ◽  
Author(s):  
Vivek J. Kadambi ◽  
Nancy Ball ◽  
Evangelia G. Kranias ◽  
Richard A. Walsh ◽  
Brian D. Hoit
Keyword(s):  
Heart Rate ◽  
Myocardial Contractility ◽  
Left Ventricular ◽  
Atrial Pacing ◽  
Force Frequency ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Peak Rate ◽  
Genetically Engineered Mice ◽  
Frequency Relation

Phospholamban levels regulate cardiac sarcoplasmic reticulum Ca2+ pump activity and myocardial contractility. To determine whether and to what extent phospholamban modulates the force-frequency relation and ventricular relaxation in vivo, we studied transgenic mice overexpressing phospholamban (PLBOE), gene-targeted mice without phospholamban (PLBKO), and isogenic wild-type controls. Contractility was assessed by the peak rate of left ventricular (LV) isovolumic contraction (+dP/d t max), and diastolic function was assessed by both the peak rate (−dP/d t max) and the time constant (τ) of isovolumic LV relaxation, using a high-fidelity LV catheter. Incremental atrial pacing was used to generate heart rate vs. −dP/d t max(force-frequency) relations. Biphasic force-frequency relations were produced in all animals, and the critical heart rate (HRcrit) was taken as the heart rate at which dP/d t max was maximal. The average LV +dP/d t maxincreased in both PLBKO and PLBOE compared with their isogenic controls (both P < 0.05). The HRcrit for LV +dP/d t max was significantly higher in PLBKO (427 ± 20 beats/min) compared with controls (360 ± 18 beats/min), whereas the HRcrit in PLBOE (340 ± 30 beats/min) was significantly lower compared with that in isogenic controls (440 ± 25 beats/min). The intrinsic heart rates were significantly lower, and the HRcrit and the ±dP/d t max at HRcrit were significantly greater in FVB/N than in SvJ control mice. We conclude that 1) the level of phospholamban is a critical negative determinant of the force-frequency relation and myocardial contractility in vivo, and 2) contractile parameters may differ significantly between strains of normal mice.

Invasive hemodynamics and force-frequency relationships in open- versus closed-chest mice

1997 ◽  
Vol 273 (5) ◽  
pp. H2528-H2533 ◽  
Author(s):  
Brian D. Hoit ◽  
Nancy Ball ◽  
Richard A. Walsh
Keyword(s):  
Heart Rate ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Force Frequency ◽  
Closed Chest ◽  
Open Chest ◽  
Systolic And Diastolic Function ◽  
Frequency Relationship ◽  
Maximal Rise ◽  
Open Versus

We compared hemodynamics, ventricular function, and force-frequency relationships in six open-chest and six closed-chest anesthetized mice (FVB/N strain). Left ventricular (LV) pressure was measured with a 1.8- or 1.4-Fr Millar catheter placed via the right carotid artery and the LV apex in the closed- and open-chest state, respectively. Pacing was performed with electrodes placed either directly on atrial appendages (open chest) or with a 1-Fr bipolar catheter via the jugular vein (closed chest). Closed-chest animals had greater spontaneous heart rate (267 ± 106 vs. 147 ± 27 beats/min), LV systolic (81 ± 14 vs. 48 ± 9 mmHg) and diastolic pressures (11.2 ± 4.8 vs. 5.6 ± 2.4 mmHg), and maximal rise (+dP/d t max: 6,208 ± 2,519 vs. 3,682 ± 671 mmHg/s) and fall in pressure development (−dP/d t max: −6,094 ± 2,386 vs. −3,001 ± 399 mmHg/s). LV systolic pressure (98 ± 18 vs. 52 ± 11 mmHg), +dP/d t max (9,240 ± 2,459 vs. 5,777 ± 2,473 mmHg/s), and −dP/d t max(−8,375 ± 2,551 vs. −3,753 ± 1,170 mmHg/s) were significantly higher when animals were matched at a heart rate of 420 beats/min in closed-chest vs. open-chest animals. Biphasic force-frequency relationships were seen in all animals, but the critical heart rate was greater in the closed- than open-chest animals (432 ± 42 vs. 318 ± 42 beats/min). We conclude that 1) there are significant differences between invasive indexes of systolic and diastolic function between the closed- and open-chest preparations, 2) there is a biphasic force-frequency relationship in the anesthetized mouse, and 3) dP/d t max can be used to assess the cardiovascular phenotype.

Quinidine elicits proarrhythmic changes in ventricular repolarization and refractoriness in guinea-pig

2013 ◽  
Vol 91 (4) ◽  
pp. 306-315 ◽  
Author(s):  
Oleg E. Osadchii
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Left Ventricular ◽  
Ventricular Repolarization ◽  
Monophasic Action Potential ◽  
Delayed Rectifier ◽  
Rate Dependent ◽  
Delayed Rectifier Current ◽  
Left Ventricular Chamber ◽  
The Right

Quinidine is a class Ia Na+ channel blocker that prolongs cardiac repolarization owing to the inhibition of IKr, the rapid component of the delayed rectifier current. Although quinidine may induce proarrhythmia, the contributing mechanisms remain incompletely understood. This study examined whether quinidine may set proarrhythmic substrate by inducing spatiotemporal abnormalities in repolarization and refractoriness. The monophasic action potential duration (APD), effective refractory periods (ERPs), and volume-conducted electrocardiograms (ECGs) were assessed in perfused guinea-pig hearts. Quinidine was found to produce the reverse rate-dependent prolongation of ventricular repolarization, which contributed to increased steepness of APD restitution. Throughout the epicardium, quinidine elicited a greater APD increase in the left ventricular chamber compared with the right ventricle, thereby enhancing spatial repolarization heterogeneities. Quinidine prolonged APD to a greater extent than ERP, thus extending the vulnerable window for ventricular re-excitation. This change was attributed to increased triangulation of epicardial action potential because of greater APD lengthening at 90% repolarization than at 30% repolarization. Over the transmural plane, quinidine evoked a greater ERP prolongation at endocardium than epicardium and increased dispersion of refractoriness. Premature ectopic beats and monomorphic ventricular tachycardia were observed in 50% of quinidine-treated heart preparations. In summary, abnormal changes in repolarization and refractoriness contribute greatly to proarrhythmic substrate upon quinidine infusion.

Heart failure-associated alterations in troponin I phosphorylation impair ventricular relaxation-afterload and force-frequency responses and systolic function

2007 ◽  
Vol 292 (1) ◽  
pp. H318-H325 ◽  
Author(s):  
Kenneth C. Bilchick ◽  
Jennifer G. Duncan ◽  
Rajashree Ravi ◽  
Eiki Takimoto ◽  
Hunter C. Champion ◽  
...  
Keyword(s):  
Heart Rate ◽  
Protein Kinase ◽  
Troponin I ◽  
Systolic Function ◽  
Force Frequency ◽  
Rate Dependent ◽  
Isoproterenol Infusion ◽  
Relaxation Delay ◽  
Constitutive Phosphorylation

Recent studies have found that selective stimulation of troponin (Tn)I protein kinase A (PKA) phosphorylation enhances heart rate-dependent inotropy and blunts relaxation delay coupled to increased afterload. However, in failing hearts, TnI phosphorylation by PKA declines while protein kinase C (PKC) activity is enhanced, potentially augmenting TnI PKC phosphorylation. Accordingly, we hypothesized that these site-specific changes deleteriously affect both rate-responsive cardiac function and afterload dependence of relaxation, both prominent phenotypic features of the failing heart. A transgenic (TG) mouse model was generated in which PKA-TnI sites were mutated to mimic partial dephosphorylation (Ser22 to Ala; Ser23 to Asp) and dominant PKC sites were mutated to mimic constitutive phosphorylation (Ser42 and Ser44 to Asp). The two highest-expressing lines were further characterized. TG mice had reduced fractional shortening of 34.7 ± 1.4% vs. 41.3 ± 2.0% ( P = 0.018) and slight chamber dilation on echocardiography. In vivo cardiac pressure-volume studies revealed near doubling of isovolumic relaxation prolongation with increasing afterload in TG animals ( P < 0.001), and this remained elevated despite isoproterenol infusion (PKA stimulation). Increasing heart rate from 400 to 700 beats/min elevated contractility 13% in TG hearts, nearly half the response observed in nontransgenic animals ( P = 0.005). This blunted frequency response was normalized by isoproterenol infusion. Abnormal TnI phosphorylation observed in cardiac failure may explain exacerbated relaxation delay in response to increased afterload and contribute to blunted chronotropic reserve.

Intracellular sodium determines frequency-dependent alterations in contractility in hypertrophied feline ventricular myocytes

2007 ◽  
Vol 292 (2) ◽  
pp. H1129-H1138 ◽  
Author(s):  
Geoffrey D. Mills ◽  
David M. Harris ◽  
Xiongwen Chen ◽  
Steven R. Houser
Keyword(s):  
Ventricular Hypertrophy ◽  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Force Frequency ◽  
Large Mammals ◽  
Frequency Dependent ◽  
Rate Dependent ◽  
Frequency Relationship ◽  
Contractility Reserve

Hypertrophy and failure (H/F) in humans and large mammals are characterized by a change from a positive developed force-frequency relationship (+FFR) in normal myocardium to a flattened or negative developed force-frequency relationship (−FFR) in disease. Altered Ca2+ homeostasis underlies this process, but the role of intracellular Na+ concentration ([Na+]i) in H/F and frequency-dependent contractility reserve is unclear. We hypothesized that altered [Na+]i is central to the −FFR response in H/F feline myocytes. Aortic constriction caused left ventricular hypertrophy (LVH). We found that as pacing rate was increased, contraction magnitude was maintained in isolated control myocytes (CM) but decreased in LVH myocytes (LVH-M). Quiescent LVH-M had higher [Na+]i than CM (LVH-M 13.3 ± 0.3 vs. CM 8.9 ± 0.2 mmol/l; P < 0.001) with 0.5-Hz pacing (LVH-M 14.9 ± 0.5 vs. CM 10.8 ± 0.4 mmol/l; P < 0.001) but were not different at 2.5 Hz (17.0 ± 0.7 vs. control 16.0 ± 0.7 mmol/l; not significant). [Na+]i was altered by patch pipette dialysis to define the effect of [Na+]i on contraction magnitude and action potential (AP) wave shape at slow and fast pacing rates. Using AP clamp, we showed that LVH-M require increased [Na+]i and long diastolic intervals to maintain normal shortening. Finally, we determined the voltage dependence of contraction for Ca2+ current ( ICa)-triggered and Na+/Ca2+ exchanger-mediated contractions and showed that there is a greater [Na+]i dependence of contractility in LVH-M. These data show that increased [Na+]i is essential for maintaining contractility at slow heart rates but contributes to small contractions at fast rates unless rate-dependent AP shortening is prevented, suggesting that altered [Na+]i regulation is a critical contributor to abnormal contractility in disease.

In vivo assessment of acetylcholine-releasing function at cardiac vagal nerve terminals

2001 ◽  
Vol 281 (1) ◽  
pp. H139-H145 ◽  
Author(s):  
Toru Kawada ◽  
Toji Yamazaki ◽  
Tsuyoshi Akiyama ◽  
Toshiaki Shishido ◽  
Masashi Inagaki ◽  
...  
Keyword(s):  
Heart Rate ◽  
Vagal Stimulation ◽  
Left Ventricular ◽  
Vagal Nerve ◽  
Local Administration ◽  
Nerve Terminals ◽  
Ach Release ◽  
Rate Dependent ◽  
Baroreceptor Reflexes

We examined whether the ACh concentration measured by cardiac microdialysis provided information on left ventricular ACh levels under a variety of vagal stimulatory and modulatory conditions in anesthetized cats. Local administration of KCl ( n = 5) and ouabain ( n = 7) significantly increased the ACh concentration in the dialysate to 4.3 ± 0.8 and 7.3 ± 1.3 nmol/l, respectively, from the baseline value of 0.6 ± 0.5 nmol/l. Intravenous administration of phenylbiguanide ( n = 5) and phenylephrine ( n = 6) significantly increased the ACh concentration to 5.4 ± 0.9 and 6.0 ± 1.5 nmol/l, respectively, suggesting that the Bezold-Jarisch and arterial baroreceptor reflexes affected myocardial ACh levels. Modulation of vagal nerve terminal function by local administration of tetrodotoxin ( n = 6), hemicholinium-3 ( n = 6), and vesamicol ( n = 5) significantly suppressed the electrical stimulation-induced ACh release from 20.4 ± 3.9 to 0.6 ± 0.1, 7.2 ± 1.9, and 2.7 ± 0.6 nmol/l, respectively. Increasing the heart rate from 120 to 200 beats/min significantly reduced the myocardial ACh levels during electrical vagal stimulation, suggesting a heart rate-dependent washout of ACh. We conclude that ACh concentration measured by cardiac microdialysis provides information regarding ACh release and disposition under a variety of pathophysiological conditions in vivo.

Abstract 17892: Strain Rate is Affected by Heart Rate in Younger Heart: A Simultaneous Invasive and Noninvasive in vivo Piglet Model

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Etienne Fortin-Pellerin ◽  
Lisa K Hornberger ◽  
James Y Coe ◽  
Lindsay Mills ◽  
Jesus Serrano-Lomelin ◽  
...  
Keyword(s):  
Heart Rate ◽  
Strain Rate ◽  
Atrial Tachycardia ◽  
Young Infant ◽  
Left Ventricular ◽  
Baseline Heart Rate ◽  
Force Frequency ◽  
Filling Time ◽  
Frequency Relationship ◽  
The Impact

Introduction: In adult human and pig hearts, left ventricular (LV) systolic strain rate (SR) has been shown to be independent of heart rate (HR) in atrial tachycardia. It has been hypothesized that any increase in contractility related to the force-frequency relationship is balanced by a decrease in contractility due to reduced filling time and preload at higher HRs. In this study, we explore the impact of atrial tachycardia on SR of the young infant heart using a simultaneous invasive and noninvasive piglet model to determine whether SR of the immature heart is similarly not influenced by increasing HR. Methods: Under general anesthesia (propofol, isoflurane), 1 - 15 day old piglets were instrumented intravascularly with Millar high-fidelity and pacing catheters in the left ventricle and right atrium, respectively. After stabilization, invasive hemodynamic and echocardiography parameters were acquired at baseline, and at 200, 230 and 260bpm. Basal circumferential SR was analyzed off-line by speckle tracking (frame rates 247±7 Hz). Each animal was its own control and repeated measure ANOVA was used for comparison, data is expressed as mean ± SE. Results: Fourteen piglets of mean age 8.5±1.8 days, weight 3.6±0.5kg and baseline heart rate of 152±5bpm were assessed. Baseline LV systolic SR was -1.53±0.13 1/s and dP/dt 1656±115mmHg/s. With pacing, LV SR increased significantly (p = 0.002). The increase in SR mirrored the increase in contractility assessed invasively by dP/dt (p<0.001). M-mode LV end diastolic dimension decreased from baseline to 260bpm (73±9.9% of baseline value, p < 0.001) consistent with reduced preload with tachycardia. Conclusion: Our study suggests that in the younger heart, SR is augmented by atrial tachycardia itself even in the presence of decreased preload. This is in keeping with preservation of the force frequency relationship. Given our findings, HR should be taken into account when assessing contractility using SR in young patients.

P2603Impaired right ventricular force-frequency relationship in patients with heart failure is associated with diastolic dysfunction and worse functional capacity

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Giammarresi ◽  
M Losito ◽  
V Labate ◽  
F Bandera ◽  
M Caracciolo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Ejection Fraction ◽  
Right Ventricular ◽  
Left Ventricular ◽  
Peak Exercise ◽  
Force Frequency ◽  
Lv Ejection Fraction ◽  
Frequency Relationship ◽  
The Right

Abstract Background The force-frequency relationship (FFR) is an important intrinsic regulatory mechanism of cardiac contractility, related to changes in Ca2+ availability within the myocardial cell. In normal hearts this relationship is positive, so that an increase in contractile force is induced by elevation of the stimulation frequency. In heart failure (HF), the force-frequency relationship can be markedly depressed, but most studies focused their attention on left ventricular function and little is known about the right ventricle (RV). Purpose We aimed at performing a comprehensive analysis of HF phenotypes based on the right ventricular force-frequency relationship. To this purpose we stratified a large cohort of HF patients using the relationship between RV function (assessed by tricuspid annular plane systolic excursion, TAPSE) and heart rate (HR) during a symptom-limited cardiopulmonary exercise test (CPET). Material and methods We prospectively enrolled 184 HF patients, irrespective of their LV ejection fraction. We performed a stress echocardiographic evaluation using a tiltable cycle ergometer, recording standard images to assess LV systolic, diastolic, and valvular function. We divided patients in 2 groups using the slope of the linear relationship between TAPSE and HR at rest and at peak exercise, as follows: slope ≥0,01 for “positive” FFR, slope <0,01 for “flat or negative” FFR. Differences between groups were tested using unpaired t-tests for continuous variables (or Mann-Whitney U tests, when appropriate) and chi-square tests for categorical variables. Results 55 patients had a “flat or negative” FFR: they were slighty older (age 70±10 vs. 66±12; p=0,036), but the 2 groups had similar clinical characteristics such as hypertension, diabetes or COPD rate. Patients with a “flat or negative” FFR had a worse diastolic function, with higher left ventricular filling pressures (E/e' ratio 24±10 vs. 19±11 p=0,022) and left atrial volume (LAVi 55±29 ml/m2 vs. 44±20 ml/m2; p=0,009). No differences in LV ejection fraction, mitral regurgitation and pulmonary artery systolic pressure were observed between the groups. TAPSE at rest was similar between the groups (18±5 mm vs. 18±4 mm; p=0,553) but significantly different at peak exercise (16±4 mm vs. 22±5 mm; p<0,001). Average peak heart rate was similar in the 2 groups. Patients with a “flat or negative” FFR exhibited a significantly lower peak VO2 (11,6±3,0 ml/min/kg vs. 13,5±4,4 ml/min/kg; p=0,003), whereas they had a higher VE/VCO2 slope (35,1±9,6 vs. 32,3±8,2 p=0,05). RV Force-Frequency relationship Conclusion The “flat or negative” right ventricular force-frequency relationship identifies a peculiar phenotype, with a higher grade of diastolic dysfunction and an impaired exercise capacity. The inability to adapt right ventricular contractility with increasing heart rate seems not related to RV afterload (similar PASP increase) but rather to an intrinsic failure of the right heart.

scholarly journals Computational Investigation of Transmural Differences in Left Ventricular Contractility

2016 ◽  
Vol 138 (11) ◽  
Author(s):  
Hua Wang ◽  
Xiaoyan Zhang ◽  
Shauna M. Dorsey ◽  
Jeremy R. McGarvey ◽  
Kenneth S. Campbell ◽  
...  
Keyword(s):  
Myocardial Contractility ◽  
Ex Vivo ◽  
Experimental Studies ◽  
Contractile Force ◽  
Left Ventricular ◽  
Lv Function ◽  
Fe Model ◽  
Myocardial Layers ◽  
Best Fit

Myocardial contractility of the left ventricle (LV) plays an essential role in maintaining normal pump function. A recent ex vivo experimental study showed that cardiomyocyte force generation varies across the three myocardial layers of the LV wall. However, the in vivo distribution of myocardial contractile force is still unclear. The current study was designed to investigate the in vivo transmural distribution of myocardial contractility using a noninvasive computational approach. For this purpose, four cases with different transmural distributions of maximum isometric tension (Tmax) and/or reference sarcomere length (lR) were tested with animal-specific finite element (FE) models, in combination with magnetic resonance imaging (MRI), pressure catheterization, and numerical optimization. Results of the current study showed that the best fit with in vivo MRI-derived deformation was obtained when Tmax assumed different values in the subendocardium, midmyocardium, and subepicardium with transmurally varying lR. These results are consistent with recent ex vivo experimental studies, which showed that the midmyocardium produces more contractile force than the other transmural layers. The systolic strain calculated from the best-fit FE model was in good agreement with MRI data. Therefore, the proposed noninvasive approach has the capability to predict the transmural distribution of myocardial contractility. Moreover, FE models with a nonuniform distribution of myocardial contractility could provide a better representation of LV function and be used to investigate the effects of transmural changes due to heart disease.

Rate-dependent shortening of action potential duration increases ventricular vulnerability in failing rabbit heart

2011 ◽  
Vol 300 (2) ◽  
pp. H565-H573 ◽  
Author(s):  
Masahide Harada ◽  
Yukiomi Tsuji ◽  
Yuko S. Ishiguro ◽  
Hiroki Takanari ◽  
Yusuke Okuno ◽  
...  
Keyword(s):  
Action Potential ◽  
High Frequency ◽  
Rabbit Heart ◽  
Left Ventricular ◽  
High Frequency Stimulation ◽  
Electrophysiological Properties ◽  
Rate Dependent ◽  
Frequency Stimulation ◽  
And Control

Congestive heart failure (CHF) predisposes to ventricular fibrillation (VF) in association with electrical remodeling of the ventricle. However, much remains unknown about the rate-dependent electrophysiological properties in a failing heart. Action potential properties in the left ventricular subepicardial muscles during dynamic pacing were examined with optical mapping in pacing-induced CHF ( n = 18) and control ( n = 17) rabbit hearts perfused in vitro. Action potential durations (APDs) in CHF were significantly longer than those observed for controls at basic cycle lengths (BCLs) >1,000 ms but significantly shorter at BCLs <400 ms. Spatial APD dispersions were significantly increased in CHF versus control (by 17–81%), and conduction velocity was significantly decreased in CHF (by 6–20%). In both groups, high-frequency stimulation (BCLs <150 ms) always caused spatial APD alternans; spatially concordant alternans and spatially discordant alternans (SDA) were induced at 60% and 40% in control, respectively, whereas 18% and 82% in CHF. SDA in CHF caused wavebreaks followed by reentrant excitations, giving rise to VF. Incidence of ventricular tachycardia/VFs elicited by high-frequency dynamic pacing (BCLs <150 ms) was significantly higher in CHF versus control (93% vs. 20%). In CHF, left ventricular subepicardial muscles show significant APD shortenings at short BCLs favoring reentry formations following wavebreaks in association with SDA. High-frequency excitation itself may increase the vulnerability to VF in CHF.

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