Inotropic Challenge Research Articles

Right heart catheterization in advanced systolic heart failure. What are the most useful haemodynamic parameters for risk stratification?

Previous studies have shown that pulmonary hypertension is a predictor of mortality in patients with systolic heart failure (SHF). Persistent pulmonary hypertension after a reactivity test is associated with a worse outcome after transplantation. Recent studies have shown the utility of different haemodynamic parameters. To define best haemodynamic parameters for risk stratification in patients with advanced systolic heart failure. We included 425 consecutive patients who underwent a right heart catheterization with an inotropic challenge if indicated. During a median (interquartile range) follow-up of 1.67 (0.49-4.49) years, there were 151 major cardiac events (126 cardiovascular deaths and 25 postoperative deaths after ventricular assist device implantation or heart transplantation). The most powerful independent predictors of major cardiac events were baseline right atrial pressure (RAP) (hazard ratio [HR]: 1.09, 95% confidence interval [CI]: 1.06-1.12; P<0.0001) and baseline pulmonary vascular resistance (PVR) (HR: 1.10; 95% CI: 1.03-1.17; P=0.002). After inotropic challenge, the only independent predictor was mean pulmonary arterial pressure (mPAP) (HR: 1.06; 95% CI: 1.03-1.09; P<0.0001). The combination of PVR (≤or>3 Wood units), RAP (<or≥9mmHg) and mPAP after the inotropic challenge (≤or>30mmHg) was the best predictor of major events. We suggest using a simple algorithm based on baseline PVR, baseline RAP and mPAP after the inotropic challenge for the risk stratification of stable patients with advanced systolic heart failure.

Myocardial Dysfunction in Cirrhotic Cardiomyopathy is Associated with Alterations of Phospholamban Phosphorylation and IL-6 Levels

Decreased cardiac contractility has been observed in cirrhosis, but the mechanisms that initiate and maintain cardiac dysfunction are not entirely understood. We test the hypothesis that cirrhotic cardiomyopathy is related to deterioration of myocardial contractility due to alterations in calcium-handling proteins expression. In addition, we evaluated whether cardiac pro-inflammatory cytokine levels are associated with this process. Cirrhosis was induced by thioacetamide (TAA, 100mg/kg/i.p., twice weekly for eight weeks). The myocardial performance was evaluated in isolated left ventricle papillary muscles under basal conditions and after inotropic challenge. The cardiac calcium handling protein expression was detected by Western blotting. Cardiac TNF-α and IL-6 levels were measured by ELISA. Thioacetamide induced liver cirrhosis, which was associated with cirrhotic cardiomyopathy characterized by invivo left ventricular diastolic and systolic dysfunction as well as cardiac hypertrophy. Invitro baseline myocardial contractility was lower in cirrhosis. Also, myocardial responsiveness to post-rest contraction stimulus was declined. Protein expression for RYR2, SERCA2, NCX, pPBL Ser16 and L-type calcium channel was quantitatively unchanged; however, pPBL Thr17 was significantly lower while IL-6 was higher. Our study demonstrates that cirrhotic cardiomyopathy is associated with decreased cardiac contractility with alteration of phospholamban phosphorylation in association with higher cardiac pro-inflammatory IL-6 levels. These findings provided molecular and functional insights about the effects of liver cirrhosis on cardiac function.

Cardiac Reserve as Assessed by Augmentation in Cardiac Power Efficiency Predicts Response to Intravascular Ventricular Assist System Support

The intravascular ventricular assist system (iVAS) is a durable, ambulatory counterpulsation device that is currently under investigation for advanced heart failure patients. Baseline cardiac power efficiency (CPE) has previously been reported to predict hemodynamic success after iVAS. We investigated the role of change in CPE after inotropic challenge, a marker of cardiac reserve, as a prognostic tool prior to iVAS support. Hemodynamic data at the time of right heart catheterization was collected on patients just prior to iVAS implantation. A subset of patients underwent milrinone loading followed by repeat hemodynamic assessment 10 min after a 50 mcg/kg milrinone infusion. Cardiac power index (CPI) was calculated as [CPI = cardiac index (CI) x mean arterial pressure (MAP)/451)] and CPE was calculated as [CPE = CPI/Pulmonary capillary wedge pressure (PCWP)]. CPE at baseline and after inotropic challenge was calculated and a percent augmentation of 25% or greater in CPE was used as a cutoff indicative of cardiac reserve. The combined endpoint of independently adjudicated heart failure events, dependency on inotropes 7 days after implant, need for escalation to ECMO or death was evaluated. 40 patients from a single institution underwent iVAS implantation. 39 patients underwent RHC prior to iVAS (11.7 +/- 14.0 days before surgery). 11 patients underwent milrinone loading followed by repeat hemodynamic assessment. Baseline hemodynamics revealed an average CPE of 0.0227 +/- 0.0148 watts*mmHg/m2 for the entire cohort. In the subset of patients who underwent milrinone loading, CPE increased on average 41% from 0.0141 +/- 0.0055 watts*mmHg/m2 to 0.0236 +/- 0.0114 watts*mmHg/m2 (p = 0.003). There was a trend towards freedom from death, ECMO, HF events, or inotrope dependency in those who were able to augment CPE by more than 25% (N = 8), compared to those with less (N = 3) cardiac reserve OR = 0.071 (95% CI 0.003 - 1.73, p = 0.105). Cardiac reserve as defined as a greater than 25% augmentation in CPE after milrinone challenge may predict future success with counterpulsation with iVAS. This hypothesis generating question warrants further investigation.

The influence of Rosenthal effect on the psychological status of pregnant women at risk of miscarriage in early pregnancy

Objective To explore the influence of Rosenthal effect on the psychological status of pregnant women at risk of miscarriage in early pregnancy. Methods From January 2014 to June 2015 151 cases of early pregnancy abortion risk women were set as the control group, and was given conventional psychological intervention. From July 2015 to December 2016 135 cases of early pregnancy abortion risk women were named as the observation group by convenient sampling selection, which was given interventionbased on Rosenthal effect on the basis of routine psychological intervention. The Self-rating Depression Scale (SDS) and the Self-rating Anxiety Scale (SAS) score, the introversion and extroversion scores and the satisfaction degree with intervention were compared between the two groups before and after the intervention. Results There was no significant difference in SDS and SAS scores, inotropic challenge and extroversion challenge between the two groups before treatment (P>0.05). The scores of SDS and SAS, the inotropic challenge and extroversion challenge scores were 41.45 ± 4.26, 40.34 ± 5.82, 4.76 ± 1.03, 5.55 ± 1.26 in the observation group after intervention, and 47.22 ± 3.93,47.18± 7.04,5.39 ± 1.12, 6.43 ± 1.86 respectively in the control group. There were significant difference in scores of SDS and SAS, the inotropic challenge and extroversion challenge (t=2.215-2.573, P<0.05). The satisfaction rates of the observation group and the control group were 93.32% (126/135) and 74.17% (112/151) respectively, the difference was statistically significant (χ2=5.921, P<0.05). Conclusions The intervention based on Rosenthal effect on the basis of conventional psychological intervention for early pregnancy abortion risk women can relieve negative emotions such as anxiety and depression, besides it can also improve satisfaction degree of inpatients with intervention. Key words: Rosenthal effect; Hospitalization; Risk of miscarriage in early pregnancy; Psychological status

Dependence of Cardiac Systolic Function on Elevated Fatty Acid Availability in Obese, Insulin-Resistant Rats

BackgroundClinical data advocating an adverse effect of obesity on left ventricular (LV) systolic function independent of comorbidities is controversial. We hypothesized that in obesity with prediabetic insulin resistance, circulating fatty acids (FAs) become a valuable fuel source in the maintenance of normal systolic function. MethodsMale Wistar rats were fed a high caloric diet for 32 weeks to induce obesity. Myocardial LV systolic function was assessed using echocardiography and isolated heart preparations. ResultsAortic output was reduced in obese rat hearts over a range of filling pressures (for example: 15 cmH2O, obese: 32.6 ± 1.2 ml/min vs control: 46.2 ± 0.9 ml/min, P < .05) when perfused with glucose alone. Similarly, the slope of the LV end-systolic pressure-volume relationship decreased, and there was a right shift in the LV end-systolic stress-strain relationship as determined in Langendorff perfused, isovolumic rat heart preparations in the presence of isoproterenol (10−8M) (LV systolic stress-strain relationship and a reduced load-independent intrinsic systolic myocardial function, obese: 791 ± 62 g/cm2 vs control: 1186 ± 74 g/cm2, P < .01). The addition of insulin to the perfusion buffer improved aortic output, whereas the addition of FAs completely normalized aortic output. LV function was maintained in obese animals in vivo during an inotropic challenge. ConclusionsElevated circulating FA levels may be important to maintain myocardial systolic function in the initial stages of obesity and insulin resistance.

R4496C RyR2 mutation impairs atrial and ventricular contractility

Ryanodine receptor (RyR2) is the major Ca(2+) channel of the cardiac sarcoplasmic reticulum (SR) and plays a crucial role in the generation of myocardial force. Changes in RyR2 gating properties and resulting increases in its open probability (Po) are associated with Ca(2+) leakage from the SR and arrhythmias; however, the effects of RyR2 dysfunction on myocardial contractility are unknown. Here, we investigated the possibility that a RyR2 mutation associated with catecholaminergic polymorphic ventricular tachycardia, R4496C, affects the contractile function of atrial and ventricular myocardium. We measured isometric twitch tension in left ventricular and atrial trabeculae from wild-type mice and heterozygous transgenic mice carrying the R4496C RyR2 mutation and found that twitch force was comparable under baseline conditions (30°C, 2 mM [Ca(2+)]o, 1 Hz). However, the positive inotropic responses to high stimulation frequency, 0.1 µM isoproterenol, and 5 mM [Ca(2+)]o were decreased in R4496C trabeculae, as was post-rest potentiation. We investigated the mechanisms underlying inotropic insufficiency in R4496C muscles in single ventricular myocytes. Under baseline conditions, the amplitude of the Ca(2+) transient was normal, despite the reduced SR Ca(2+) content. Under inotropic challenge, however, R4496C myocytes were unable to boost the amplitude of Ca(2+) transients because they are incapable of properly increasing the amount of Ca(2+) stored in the SR because of a larger SR Ca(2+) leakage. Recovery of force in response to premature stimuli was faster in R4496C myocardium, despite the unchanged rates of recovery of L-type Ca(2+) channel current (ICa-L) and SR Ca(2+) content in single myocytes. A faster recovery from inactivation of the mutant R4496C channels could explain this behavior. In conclusion, changes in RyR2 channel gating associated with the R4496C mutation could be directly responsible for the alterations in both ventricular and atrial contractility. The increased RyR2 Po and fractional Ca(2+) release from the SR induced by the R4496C mutation preserves baseline contractility despite a slight decrease in SR Ca(2+) content, but cannot compensate for the inability to increase SR Ca(2+) content during inotropic challenge.

Oral Abstract session: Stress echo in clinical practice: Friday 5 December 2014, 08:30-10:00 * Location: Agora

Oral Abstract session: Stress echo in clinical practice: Friday 5 December 2014, 08:30-10:00 * Location: Agora

Timeline of cardiac dystrophy in 3–18‐month‐old MDX mice

The dystrophin-deficient (mdx) mouse remains the most commonly used model for Duchenne muscular dystrophy (DMD). Mdx mice show a predominantly covert cardiomyopathy, the hallmark of which is fibrosis. We compared mdx and normal mice at six ages (3, 6, 9, 12, 15, and 18 months) using in vivo assessment of cardiac function, selective collagen staining, and measures of TGF-β mRNA, Evans blue dye infiltration, macrophage infiltration, and aortic wall thickness. Clear temporal progression was demonstrated, including early fragility of cardiomyocyte membranes, which has an unrelated impact on cardiac function but is associated with macrophage infiltration and fibrosis. Aortic wall thickness is less in older mdx mice. Mdx mice display impaired responses to inotropic challenge from a young age; this is indicative of altered adrenoreceptor function. We draw attention to the paradox of ongoing fibrosis in mdx hearts without a strong molecular signature (in the form of TGF-β mRNA expression).

Intracoronary infusion of selected autologous bone marrow stem cells improves longitudinal myocardial strain and strain rate in patients with old anterior myocardial infarction without recent revascularization

We sought to evaluate the efficacy of intracoronary infusion of selected bone marrow stem cells (BMSCs) in patients with remote, anterior non-viable MI by the use of tissue Doppler imaging. We infused selected CD133+ and CD133-CD34+ BMSCs in 10 patients enrolled in the study. Peak systolic strain rate, maximum strain during the cardiac cycle (epsilon(max)), strain during ejection time (epsilon(et)), and post-systolic strain (epsilon(ps)) were measured. Peak systolic strain rate (-0.69 +/- 0.2 vs. -1.15 +/- 0.27, P = 0.001), epsilon(max) (-9.87 +/- 3.30 vs. -15.57 +/- 5, P = 0.006), and epsilon(et) (-7.45+/-2.86 vs. -10.92 +/- 4.45, P = 0.015) improved significantly during the rest study 6 months after cell infusion. Low-dose inotropic challenge also showed significant improvement of longitudinal deformation indices in the follow-up study. Global ejection fraction did not improve significantly after cell therapy. Intracoronary infusion of selected BMSCs in patients with remote, anterior, non-viable myocardial infarction is safe and leads to improvement of longitudinal deformation indices 6 months after the infusion.

Supernormal functional reserve of apical segments in elite soccer players: an ultrasound speckle tracking handgrip stress study

BackgroundUltrasound speckle tracking from grey scale images allows the assessment of regional strain derived from 2D regardless of angle intonation, and it is highly reproducible. The study aimed to evaluate regional left ventricular functional reserve in elite soccer players.Methods50 subjects (25 elite athletes and 25 sedentary controls), aged 26 ± 3.5, were submitted to an echo exam, at rest and after the Hand Grip (HG) test. Both standard echo parameters and strain were evaluated.ResultsEjection fraction was similar in athletes and controls both at rest (athletes 58 ± 2 vs controls 57 ± 4 p ns) and after HG (athletes 60 ± 2 vs controls 58 ± 3 p ns). Basal (septal and anterior) segments showed similar strain values in athletes and controls both at rest (athletes S% -19.9 ± 4.2; controls S% -18.8 ± 4.9 p = ns) and after HG (athletes S% -20.99 ± 2.8; controls S% -19.46 ± 4.4 p = ns). Medium-apical segments showed similar strain values at rest (athletes S% -17.31 ± 2.3; controls S% -20.00 ± 5.3 p = ns), but higher values in athletes after HG (athletes S% -24.47 ± 2.8; controls S% -20.47 ± 5.4 p < 0.05)ConclusionIn athletes with physiological myocardial hypertrophy, a brief isometric effort produces enhancement of the strain in medium-apical left ventricular segments, suggesting the presence of a higher regional function reserve which can be elicited with an inotropic challenge and suitable methods of radial function quantification such as 2D-derived strain.

On substrate selection for ATP synthesis in the failing human myocardium

the heart is an omnivore, able to oxidize a variety of substrates to support ATP synthesis: fatty acids, glucose, lactate, and even some amino acids ([Fig. 1][1]). Substrate selection is a highly dynamic process. For example, the uptake and utilization of substrates change from being primarily

Primary Cardiac Hypertrophy is Associated with Altered Cardiomyocyte Response to Inotropic Challenge

Primary Cardiac Hypertrophy is Associated with Altered Cardiomyocyte Response to Inotropic Challenge

Shifts in the myosin heavy chain isozymes in the mouse heart result in increased energy efficiency

Cardiac-specific transgenesis in the mouse is widely used to study the basic biology and chemistry of the heart and to model human cardiovascular disease. A fundamental difference between mouse and human hearts is the background motor protein: mouse hearts contain predominantly the αα-myosin heavy chain (MyHC) isozyme while human hearts contain predominantly the ββ-MyHC isozyme. Although the intrinsic differences in mechanical and enzymatic properties of the αα- and ββ-MyHC molecules are well known, the consequences of isozyme shifts on energetics of the intact beating heart remain unknown. Therefore, we compared the free energy of ATP hydrolysis (|ΔG∼ATP|) determined by 31P-NMR spectroscopy in isolated perfused littermate mouse hearts containing the same amount of myosin comprised of either >95% αα-MyHC or ∼83% ββ-MyHC. |ΔG∼ATP| was ∼2 kJ mol−1 higher in the ββ-MyHC hearts at all workloads. Furthermore, upon inotropic challenge, hearts containing predominantly ββ-MyHC hearts increased developed pressure more than αα-MyHC hearts whereas heart rate increased more in αα-MyHC hearts. Thus, hearts containing predominantly the ββ-MyHC isozyme are more energy efficient than αα-MyHC hearts. We suggest that these fundamental differences in the motor protein energy efficiency at the whole heart level should be considered when interpreting results using mouse-based cardiovascular modeling of normal and diseased human hearts.

ECHOCARDIOGRAPHY ASSESSMENT OF MYOCARDIAL FUNCTION AFTER BURN INJURY

Echocardiography provides noninvasive and clinically relevant assessment of left ventricle (LV) function in injury and disease. In this present study, we hypothesized that application of transthoracic echocardiography in awake mice would provide in vivo assessment of myocardial performance that correlates with in vitro assessment of LV function using isolated perfused hearts (Langendorff). Burn over 40% of the total body surface area (or sham burn) was given in C57/BL6 mice 22 to 24 g; lactated Ringer fluid resuscitation was given intraperitoneally. Transthoracic echocardiography was performed at baseline and at designated intervals over 7 days postburn. Subgroups of mice were killed at intervals and hearts perfused to assess LV pressure and +/-dP/dt max responses to inotropic challenge (n = 8/group per time). Burn produced myocardial depression, evidenced by a fall in fractional shortening from 69% +/- 3% at baseline to 50% +/- 2% (12 h postburn), 58% +/- 3% (24 h), 59% +/- 2% (48 h), and 62% +/- 2% (72 h) (P < 0.05). Burn-related changes in in vivo LV performance were paralleled by in vitro evidence of myocardial contractile depression; LV pressure progressively fell from 97 +/- 2 mmHg at baseline to 84 +/- 7 mmHg (12 h), 63 +/- 2 (24 h), 79 +/- 4 mmHg (48 h postburn) (P < 0.05). Analysis of variance and multiple comparison procedure. Myocardial recovery occurred by day 8 postburn. Echocardiography provides measures of cardiac function in a conscious animal, which correlate with contractile depression measured in vitro using Langendorff preparations. Echocardiography is a valuable tool for noninvasive assessment of postburn myocardial function.

Preservation From Left Ventricular Remodeling by Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute Myocardial Infarction by Use of Granulocyte-Colony–Stimulating Factor (FIRSTLINE-AMI)

Considering experimental evidence that stem cells enhance myocardial regeneration and granulocyte colony-stimulating factor (G-CSF) mediates mobilization of CD34+ mononuclear blood stem cells (MNCCD34+), we tested the impact of G-CSF integrated into primary percutaneous coronary intervention (PCI) management of acute myocardial infarction in man. Fifty consecutive patients with ST-segment elevation myocardial infarction were subjected to primary PCI stenting with abciximab and followed up for 6 months; 89+/-35 minutes after successful PCI, 25 patients were randomly assigned in this pilot study (PROBE design) to receive subcutaneous G-CSF at 10 microg/kg body weight for 6 days in addition to standard care, including aspirin, clopidogrel, an ACE inhibitor, beta-blocking agents, and statins. By use of CellQuest software on peripheral blood samples incubated with CD45 and CD34, mobilized MNCCD34+ were quantified on a daily basis. With homogeneous demographics and clinical and infarct-related characteristics, G-CSF stimulation led to mobilization of MNCCD34+ to between 3.17+/-2.93 MNCCD34+/microL at baseline and 64.55+/-37.11 MNCCD34+/microL on day 6 (P<0.001 versus control); there was no indication of leukocytoclastic effects, significant pain, impaired rheology, inflammatory reactions, or accelerated restenosis at 6 months. Within 35 days, G-CSF and MNCCD34+ liberation led to enhanced resting wall thickening in the infarct zone of between 0.29+/-0.22 and 0.99+/-0.32 mm versus 0.49+/-0.29 mm in control subjects (P<0.001); under inotropic challenge with dobutamine (10 microg.kg(-1).min(-1)), wall motion score index showed improvement from 1.66+/-0.23 to 1.41+/-0.21 (P<0.004 versus control) and to 1.35+/-0.24 after 4 months (P<0.001 versus control), respectively, coupled with sustained recovery of wall thickening to 1.24+/-0.31 mm (P<0.001 versus control) at 4 months. Accordingly, resting wall motion score index improved with G-CSF to 1.41+/-0.25 (P<0.001 versus control), left ventricular end-diastolic diameter to 55+/-5 mm (P<0.002 versus control), and ejection fraction to 54+/-8% (P<0.001 versus control) after 4 months. Morphological and functional improvement with G-CSF was corroborated by enhanced metabolic activity and 18F-deoxyglucose uptake in the infarct zone (P<0.001 versus control). G-CSF and mobilization of MNC(CD34+) after reperfusion of infarcted myocardium may offer a pragmatic strategy for preservation of myocardium and prevention of remodeling without evidence of aggravated restenosis.

Use of intracardiac transvalvular impedance for hemodynamic assessment. animal experience with implanted sophòs¿ pacemaker

Intracardiac impedance (Z) has been shown to be a marker of right ventricular preload (end-diastolic volume, EDV) and contractility. Thus, Z-derived contractility could be used for pacemaker (PM) rate control, since increased metabolic demands cause neuro-hormonal changes affecting simultaneously chronotropism and contractility. The purpose of this study was to determine the efficacy of implanted Sophos PMs (Medico SpA, Padova) to detect the intracardiac transvalvular Z (TVI) waveform. Efficacy criteria were: 1. PM TVI should compare favorably to external, high-resolution Z-device; 2. End-diastolic Z (EDZ) should be always smaller than end-systolic Z (ESZ). 3. TVI-derived rate prediction basedon contractility should match the animal's intrinsic sinus rate during inotropic challenge. Methods Three adult, castrated male sheep with implanted DDDR Sophos PMs were studied according to the Guide for the Care and Use of Laboratory Animals (US National Research Council,1996). Prior to PM implant, a high-resolution Z device was used to record TVI. At 4 weeks post-implant Isoproterenol (Iso) was infused until sinus rate approached 170 bpm. Before, during and after Iso, PM TVI waveforms were retrieved by telemetry at 15 sec-intervals. Z was converted to volume assuming an EDV of 140 ml and end-systolic volume of 70 ml. Contractility was calculated as preload-corrected stroke volume (SVc) and beat-by-beat rate was calculated as: TVI-Rate = SVcPrev / SVcR * RateR , where SVcPrev= prevailing SVc, SVcR= Resting SVc, and RateR= resting heart rate. Results 1. TVI telemetry waveforms compared favorably to waveforms from external Z device; 2. EDZ was consistently smaller than ESZ. 3. TVI behavior during Iso was physiological, and TVI rate matched closely the animal's sinus rate, with R2 values of 0.92, 0.84 and 0.92 (all P-values < 0.001). Conclusion Implanted Sophos PMs accurately detected changes in RV volumes and allowed calculation of contractility-derived rate during inotropic challenge.

Protein kinase Cepsilon overexpression alters myofilament properties and composition during the progression of heart failure.

We report characterization of a transgenic mouse that overexpresses constitutively active protein kinase Cepsilon in the heart and slowly develops a dilated cardiomyopathy with failure. The hemodynamic, mechanical, and biochemical properties of these hearts demonstrate a series of temporal events that mark the progression of the disease. In the 3-month transgenic (TG) animals, contractile properties and gene expression measurements are normal, but an increase in myofibrillar Ca2+ sensitivity and thin filament protein phosphorylation is noted. At 6 months, there is a decrease in the myofibrillar Ca2+ sensitivity, a significant increase in beta-myosin heavy chain mRNA and protein, normal cardiac function, but a blunted response to an inotropic challenge. The transition at 9 months is especially interesting because age-related changes appear to contribute to the decline in function seen in the TG heart. At this point, there is a decline in baseline function and maximum tension produced by the myofibrils, which is coincident with the onset of atrial myosin light chain isoform re-expression in the ventricles. In the 12-month TG mice, there is clear hemodynamic and geometric evidence of failure. Alterations in the composition of the myofibrils persist but the phosphorylation of myosin light chain 2v is dramatically different at this age compared with all others. We interpret these data to implicate the disruption of the myofibrillar proteins and their interactions in the propagation of dilated cardiac disease.

Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T

The thin filament protein cardiac troponin T (cTnT) is an important regulator of myofilament activation. Here we report a significant change in cardiac energetics in transgenic mice bearing the missense mutation R92Q within the tropomyosin-binding domain of cTnT, a mutation associated with a clinically severe form of familial hypertrophic cardiomyopathy. This functional domain of cTnT has recently been shown to be a crucial modulator of contractile function despite the fact that it does not directly interact with the ATP hydrolysis site in the myosin head. Simultaneous measurements of cardiac energetics using 31P NMR spectroscopy and contractile performance of the intact beating heart revealed both a decrease in the free energy of ATP hydrolysis available to support contractile work and a marked inability to increase contractile performance upon acute inotropic challenge in hearts from R92Q mice. These results show that alterations in thin filament protein structure and function can lead to significant defects in myocardial energetics and contractile reserve.

Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T.

The thin filament protein cardiac troponin T (cTnT) is an important regulator of myofilament activation. Here we report a significant change in cardiac energetics in transgenic mice bearing the missense mutation R92Q within the tropomyosin-binding domain of cTnT, a mutation associated with a clinically severe form of familial hypertrophic cardiomyopathy. This functional domain of cTnT has recently been shown to be a crucial modulator of contractile function despite the fact that it does not directly interact with the ATP hydrolysis site in the myosin head. Simultaneous measurements of cardiac energetics using 31P NMR spectroscopy and contractile performance of the intact beating heart revealed both a decrease in the free energy of ATP hydrolysis available to support contractile work and a marked inability to increase contractile performance upon acute inotropic challenge in hearts from R92Q mice. These results show that alterations in thin filament protein structure and function can lead to significant defects in myocardial energetics and contractile reserve.

Importance of diastolic fractional flow reserve and dobutamine challenge in physiologic assessment of myocardial bridging

ObjectivesThis study reports a comparative assessment of the hemodynamic relevance of myocardial bridges (MB) using two modalities of fractional flow reserve (FFR), with and without concomitant inotropic challenge. BackgroundExtravascular coronary compression by means of MB is modulated by myocardial inotropism and causes intracoronary systolic pressure overshooting and negative systolic gradients across the MB. The former characteristic suggests that adequate hemodynamic assessment of MB should include inotropic stimulation. The latter characteristic might interfere with FFR by decreasing the mean pressure gradient. MethodsWe compared the hemodynamic relevance of 12 lone MB in symptomatic patients using conventional (mean) and diastolic FFR. Diastolic FFR was obtained from post-processed, digitally acquired electrocardiogram and pressure signals. Previously validated cut off values of 0.75 (mean FFR) and 0.76 (diastolic FFR) for hemodynamic relevance were used. Measurements were performed at baseline and after incremental intravenous dobutamine doses. ResultsFractional flow reserve decreased during dobutamine challenge: mean FFR was 0.90 ± 0.04 at baseline and 0.84 ± 0.06 after dobutamine (p = 0.0008); similarly, diastolic FFR was 0.88 ± 0.05 and 0.77 ± 0.10 before and after dobutamine, respectively (p = 0.0006). Diastolic FFR identified hemodynamic relevance in five patients, whereas mean FFR did so in only one patient. The discrepancy between mean FFR and diastolic FFR increased with dobutamine challenge: the ratio of mean FFR/diastolic FFR was 1.03 at baseline and 1.09 after dobutamine (p = 0.02). During the administration of dobutamine, the discrepancy was inversely related to the systolic pressure gradient (r = 0.58, p = 0.04). ConclusionsPhysiologic assessment of MB should include dobutamine challenge. Because the overshooting of systolic pressure interferes with and is a cause of error in FFR measurements based on mean pressures, diastolic FFR appears to be the technique of choice for MB assessment, whereas mean FFR should be used with caution.