Veronica L Dimaano

Role of Tissue Doppler and Strain Echocardiography in Current Clinical Practice

The motion of a muscle, is performed only by the Carnous fibers, and each Carnous fiber has a power of contracting itself…. The force of the whole Muscle is but an aggregate of the contractions of each particular fiber. — —William Croone in De ratione motus musculorum (On the Reason of the Movement of the Muscles), 1664 Visual or semiautomated tracking of the endocardial border provide estimates of cardiac volume, which are used to derive ejection fraction, a quantitative indicator of ventricular function. However, the heart is a complex mechanical organ that undergoes cyclic changes in multiple dimensions that ultimately effect a change in chamber volume that results in ejection of blood. Regardless of imaging technique, ejection fraction is unable to provide information on the underlying myocardial mechanical activity. Also, ejection fraction reflects the sum contribution of several regions and does not provide information on regional function. Regional function assessed visually is subjective and prone to error.1 Quantification of regional myocardial activity (deformation) was feasible only in experimental studies by use of markers attached directly to the myocardium, a technique not practicable in the clinical realm.2 Myocardial tagging with cardiac magnetic resonance (CMR) introduced the opportunity to noninvasively track regional myocardial mechanics.3,4 Modifications to the filter settings on pulsed Doppler to image low-velocity, high-intensity myocardial signal rather than the high-velocity, low-intensity signal from blood flow allows similar assessment by ultrasound. This technique is commonly referred to as tissue Doppler imaging (TDI) or Doppler myocardial imaging.5 The TDI method depicts myocardial motion (measured as tissue velocity) at specific locations in the heart. Tissue velocity indicates the rate at which a particular point in the myocardium moves toward or away from the transducer. Integration of velocity over time yields displacement or the absolute distance moved by that point …

Cardiac Magnetic Resonance Assessment of Dyssynchrony and Myocardial Scar Predicts Function Class Improvement Following Cardiac Resynchronization Therapy

OBJECTIVES We tested a circumferential mechanical dyssynchrony index (circumferential uniformity ratio estimate [CURE]; 0 to 1, 1 = synchrony) derived from magnetic resonance-myocardial tagging (MR-MT) for predicting clinical function class improvement following cardiac resynchronization therapy (CRT). BACKGROUND There remains a significant nonresponse rate to CRT. MR-MT provides high quality mechanical activation data throughout the heart, and delayed enhancement cardiac magnetic resonance (DE-CMR) offers precise characterization of myocardial scar. METHODS MR-MT was performed in 2 cohorts of heart failure patients with: 1) a CRT heart failure cohort (n = 20; left ventricular ejection fraction of 0.23 +/- 0.057) to evaluate the role of MR-MT and DE-CMR prior to CRT; and 2) a multimodality cohort (n = 27; ejection fraction of 0.20 +/- 0.066) to compare MR-MT and tissue Doppler imaging septal-lateral delay for assessment of mechanical dyssynchrony. MR-MT was also performed in 9 healthy control subjects. RESULTS MR-MT showed that control subjects had highly synchronous contraction (CURE 0.96 +/- 0.01), but tissue Doppler imaging indicated dyssynchrony in 44%. Using a cutoff of <0.75 for CURE based on receiver-operator characteristic analysis (area under the curve: 0.889), 56% of patients tested positive for mechanical dyssynchrony, and the MR-MT CURE predicted improved function class with 90% accuracy (positive and predictive values: 87%, 100%); adding DE-CMR (% total scar <15%) data improved accuracy further to 95% (positive and negative predictive values: 93%, 100%). The correlation between CURE and QRS duration was modest in all cardiomyopathy subjects (r = 0.58, p < 0.001). The multimodality cohort showed a 30% discordance rate between CURE and tissue Doppler imaging septal-lateral delay. CONCLUSIONS The MR-MT assessment of circumferential mechanical dyssynchrony predicts improvement in function class after CRT. The addition of scar imaging by DE-CMR further improves this predictive value.

Electrophysiological Consequences of Dyssynchronous Heart Failure and Its Restoration by Resynchronization Therapy

Background— Cardiac resynchronization therapy (CRT) is widely applied in patients with heart failure and dyssynchronous contraction (DHF), but the electrophysiological consequences of CRT in heart failure remain largely unexplored. Methods and Results— Adult dogs underwent left bundle-branch ablation and either right atrial pacing (190 to 200 bpm) for 6 weeks (DHF) or 3 weeks of right atrial pacing followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT). Isolated left ventricular anterior and lateral myocytes from nonfailing (control), DHF, and CRT dogs were studied with the whole-cell patch clamp. Quantitative polymerase chain reaction and Western blots were performed to measure steady state mRNA and protein levels. DHF significantly reduced the inward rectifier K+ current (IK1), delayed rectifier K+ current (IK), and transient outward K+ current (Ito) in both anterior and lateral cells. CRT partially restored the DHF-induced reduction of IK1 and IK but not Ito, consistent with trends in the changes in steady state K+ channel mRNA and protein levels. DHF reduced the peak inward Ca2+ current (ICa) density and slowed ICa decay in lateral compared with anterior cells, whereas CRT restored peak ICa amplitude but did not hasten decay in lateral cells. Calcium transient amplitudes were depressed and the decay was slowed in DHF, especially in lateral myocytes. CRT hastened the decay in both regions and increased the calcium transient amplitude in lateral but not anterior cells. No difference was found in CaV1.2 (α1C) mRNA or protein expression, but reduced CaVβ2 mRNA was found in DHF cells. DHF reduced phospholamban, ryanodine receptor, and sarcoplasmic reticulum Ca2+ ATPase and increased Na+-Ca2+ exchanger mRNA and protein. CRT did not restore the DHF-induced molecular remodeling, except for sarcoplasmic reticulum Ca2+ ATPase. Action potential durations were significantly prolonged in DHF, especially in lateral cells, and CRT abbreviated action potential duration in lateral but not anterior cells. Early afterdepolarizations were more frequent in DHF than in control cells and were reduced with CRT. Conclusions— CRT partially restores DHF-induced ion channel remodeling and abnormal Ca2+ homeostasis and attenuates the regional heterogeneity of action potential duration. The electrophysiological changes induced by CRT may suppress ventricular arrhythmias, contribute to the survival benefit of this therapy, and improve the mechanical performance of the heart.

Reversal of Global Apoptosis and Regional Stress Kinase Activation by Cardiac Resynchronization

Background— Cardiac dyssynchrony in the failing heart worsens global function and efficiency and generates regional loading disparities that may exacerbate stress-response molecular signaling and worsen cell survival. We hypothesized that cardiac resynchronization (CRT) from biventricular stimulation reverses such molecular abnormalities at the regional and global levels. Methods and Results— Adult dogs (n=27) underwent left bundle-branch radiofrequency ablation, prolonging the QRS by 100%. Dogs were first subjected to 3 weeks of atrial tachypacing (200 bpm) to induce dyssynchronous heart failure (DHF) and then randomized to either 3 weeks of additional atrial tachypacing (DHF) or biventricular tachypacing (CRT). At 6 weeks, ejection fraction improved in CRT (2.8±1.8%) compared with DHF (−4.4±2.7; P=0.02 versus CRT) dogs, although both groups remained in failure with similarly elevated diastolic pressures and reduced dP/dtmax. In DHF, mitogen-activated kinase p38 and calcium-calmodulin-dependent kinase were disproportionally expressed/activated (50% to 150%), and tumor necrosis factor-&agr; increased in the late-contracting (higher-stress) lateral versus septal wall. These disparities were absent with CRT. Apoptosis assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, caspase-3 activity, and nuclear poly ADP-ribose polymerase cleavage was less in CRT than DHF hearts and was accompanied by increased Akt phosphorylation/activity. Bcl-2 and BAD protein diminished with DHF but were restored by CRT, accompanied by marked BAD phosphorylation, enhanced BAD-14-3-3 interaction, and reduced phosphatase PP1&agr;, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3&agr; and GSK3&bgr;) were more phosphorylated in DHF than CRT and thus less involved. Conclusions— CRT reverses regional and global molecular remodeling, generating more homogeneous activation of stress kinases and reducing apoptosis. Such changes are important benefits from CRT that likely improve cardiac performance and outcome.

Mechanisms of Enhanced β-Adrenergic Reserve From Cardiac Resynchronization Therapy

Background— Cardiac resynchronization therapy (CRT) is the first clinical heart failure treatment that improves chamber systolic function in both the short-term and long-term yet also reduces mortality. The mechanical impact of CRT is immediate and well documented, yet its long-term influences on myocyte function and adrenergic modulation that may contribute to its sustained benefits are largely unknown. Methods and Results— We used a canine model of dyssynchronous heart failure (DHF; left bundle ablation, atrial tachypacing for 6 weeks) and CRT (DHF for 3 weeks, biventricular tachypacing for subsequent 3 weeks), contrasting both to nonfailing controls. CRT restored contractile synchrony and improved systolic function compared with DHF. Myocyte sarcomere shortening and calcium transients were markedly depressed at rest and after isoproterenol stimulation in DHF (both anterior and lateral walls), and CRT substantially improved both. In addition, &bgr;1 and &bgr;2 stimulation was enhanced, coupled to increased &bgr;1 receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (G&agr;i) suppression of &bgr;-adrenergic stimulation was greater in DHF and reversed by CRT. G&agr;i expression itself was unaltered; however, expression of negative regulators of G&agr;i signaling (particularly RGS3) rose uniquely with CRT over DHF and controls. CRT blunted elevated myocardial catecholamines in DHF, restoring levels toward control. Conclusions— CRT improves rest and &bgr;-adrenergic-stimulated myocyte function and calcium handling, upregulating &bgr;1 receptors and adenylate cyclase activity and suppressing Gi-coupled signaling associated with novel RGS upregulation. The result is greater rest and sympathetic reserve despite reduced myocardial neurostimulation as components underlying its net benefit.

Inhibiting Mitochondrial Na+/Ca2+ Exchange Prevents Sudden Death in a Guinea Pig Model of Heart Failure

Rationale: In cardiomyocytes from failing hearts, insufficient mitochondrial Ca2+ accumulation secondary to cytoplasmic Na+ overload decreases NAD(P)H/NAD(P)+ redox potential and increases oxidative stress when workload increases. These effects are abolished by enhancing mitochondrial Ca2+ with acute treatment with CGP-37157 (CGP), an inhibitor of the mitochondrial Na+/Ca2+ exchanger. Objective: Our aim was to determine whether chronic CGP treatment mitigates contractile dysfunction and arrhythmias in an animal model of heart failure (HF) and sudden cardiac death (SCD). Methods and Results: Here, we describe a novel guinea pig HF/SCD model using aortic constriction combined with daily &bgr;-adrenergic receptor stimulation (ACi) and show that chronic CGP treatment (ACi plus CGP) attenuates cardiac hypertrophic remodeling, pulmonary edema, and interstitial fibrosis and prevents cardiac dysfunction and SCD. In the ACi group 4 weeks after pressure overload, fractional shortening and the rate of left ventricular pressure development decreased by 36% and 32%, respectively, compared with sham-operated controls; in contrast, cardiac function was completely preserved in the ACi plus CGP group. CGP treatment also significantly reduced the incidence of premature ventricular beats and prevented fatal episodes of ventricular fibrillation, but did not prevent QT prolongation. Without CGP treatment, mortality was 61% in the ACi group <4 weeks of aortic constriction, whereas the death rate in the ACi plus CGP group was not different from sham-operated animals. Conclusions: The findings demonstrate the critical role played by altered mitochondrial Ca2+ dynamics in the development of HF and HF-associated SCD; moreover, they reveal a novel strategy for treating SCD and cardiac decompensation in HF.

Gαs-Biased β2-Adrenergic Receptor Signaling from Restoring Synchronous Contraction in the Failing Heart

Synchronizing abnormal contraction in the failing hearts permanently alters β2-adrenergic signaling, pointing to a new therapeutic approach. Salubrious Synchrony for the Heart Like rowers in a shell stroking in unison, the human heart works most efficiently when all sides contract simultaneously, sending blood to the body more effectively. In some patients with heart failure, a defective conduction system causes the ventricles to beat out of phase, further reducing the efficiency of an already damaged heart. An implanted pacemaker can resynchronize the ventricles, improving heart function, correcting some of the anatomical abnormalities of the weakened heart, and decreasing mortality. Hearts treated with resynchronization therapy are stronger and healthier. To find out why, Chakir et al. resynchronized the heartbeats of dogs with heart failure and discovered that their previously feeble response to β-adrenergic agonists (normal regulators of heartbeat) was restored to normal, a result of enhancement of two key regulators of G protein–coupled signaling—RGS2 and RGS3. The authors propose that drugs targeting this pathway may help people with all sorts of heart failure. Heart cells taken from dogs with failing hearts, whether they were beating dyssychronously or synchronously, showed depressed contractile responses to β2-adrenergic stimulation, but resynchronization therapy only improved function when applied to previously desynchronized tissue. Further dissection of β2-adrenergic control of the heart showed that resynchronization recoupled the β2-adrenergic receptor to the stimulatory Gαs G protein rather than the inhibitory Gαi G protein. This Gαs coupling resulted in more cyclic AMP generation and protein kinase A activity at the sarcoplasmic reticulum. Up-regulation of the pathway modulators RGS2 and RGS3 accounted for the effects of resynchronization. Finding the pathway responsible for the therapeutic effects of cardiac resynchronization therapy should, in theory, allow the development of drugs that mimic its resynchronizaton-induced up-regulation, for use more generally in heart failure. But the authors found another potential therapy that is easier to develop than new drugs: Forcing a period of dyssynchrony in dogs with synchronous heart failure restored normal β2-adrenergic signaling. Perhaps a bit of independence makes for better cooperation later. Cardiac resynchronization therapy (CRT), in which both ventricles are paced to recoordinate contraction in hearts that are dyssynchronous from conduction delay, is the only heart failure (HF) therapy to date to clinically improve acute and chronic function while also lowering mortality. CRT acutely enhances chamber mechanical efficiency but chronically alters myocyte signaling, including improving β-adrenergic receptor reserve. We speculated that the latter would identify unique CRT effects that might themselves be effective for HF more generally. HF was induced in dogs by 6 weeks of atrial rapid pacing with (HFdys, left bundle ablated) or without (HFsyn) dyssynchrony. We used dyssynchronous followed by resynchronized tachypacing (each 3 weeks) for CRT. Both HFdys and HFsyn myocytes had similarly depressed rest and β-adrenergic receptor sarcomere and calcium responses, particularly the β2-adrenergic response, whereas cells subjected to CRT behaved similarly to those from healthy controls. CRT myocytes exhibited suppressed Gαi signaling linked to increased regulator of G protein (heterotrimeric guanine nucleotide–binding protein) signaling (RGS2, RGS3), yielding Gαs-biased β2-adrenergic responses. This included increased adenosine cyclic AMP responsiveness and activation of sarcoplasmic reticulum–localized protein kinase A. Human CRT responders also showed up-regulated myocardial RGS2 and RGS3. Inhibition of Gαi (with pertussis toxin, RGS3, or RGS2 transfection), stimulation with a Gαs-biased β2 agonist (fenoterol), or transient (2-week) exposure to dyssynchrony restored β-adrenergic receptor responses in HFsyn to the values obtained after CRT. These results identify a key pathway that is triggered by restoring contractile synchrony and that may represent a new therapeutic approach for a broad population of HF patients.

Assessment of distribution and evolution of Mechanical dyssynchrony in a porcine model of myocardial infarction by cardiovascular magnetic resonance

BackgroundWe sought to investigate the relationship between infarct and dyssynchrony post- myocardial infarct (MI), in a porcine model. Mechanical dyssynchrony post-MI is associated with left ventricular (LV) remodeling and increased mortality.MethodsCine, gadolinium-contrast, and tagged cardiovascular magnetic resonance (CMR) were performed pre-MI, 9 ± 2 days (early post-MI), and 33 ± 10 days (late post-MI) post-MI in 6 pigs to characterize cardiac morphology, location and extent of MI, and regional mechanics. LV mechanics were assessed by circumferential strain (eC). Electro-anatomic mapping (EAM) was performed within 24 hrs of CMR and prior to sacrifice.ResultsMean infarct size was 21 ± 4% of LV volume with evidence of post-MI remodeling. Global eC significantly decreased post MI (-27 ± 1.6% vs. -18 ± 2.5% (early) and -17 ± 2.7% (late), p < 0.0001) with no significant change in peri-MI and MI segments between early and late time-points. Time to peak strain (TTP) was significantly longer in MI, compared to normal and peri-MI segments, both early (440 ± 40 ms vs. 329 ± 40 ms and 332 ± 36 ms, respectively; p = 0.0002) and late post-MI (442 ± 63 ms vs. 321 ± 40 ms and 355 ± 61 ms, respectively; p = 0.012). The standard deviation of TTP in 16 segments (SD16) significantly increased post-MI: 28 ± 7 ms to 50 ± 10 ms (early, p = 0.012) to 54 ± 19 ms (late, p = 0.004), with no change between early and late post-MI time-points (p = 0.56). TTP was not related to reduction of segmental contractility. EAM revealed late electrical activation and greatly diminished conduction velocity in the infarct (5.7 ± 2.4 cm/s), when compared to peri-infarct (18.7 ± 10.3 cm/s) and remote myocardium (39 ± 20.5 cm/s).ConclusionsMechanical dyssynchrony occurs early after MI and is the result of delayed electrical and mechanical activation in the infarct.

Prevalence and Pathophysiologic Attributes of Ventricular Dyssynchrony in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

OBJECTIVES This study sought to investigate the prevalence and mechanisms underlying right ventricular (RV) dyssynchrony in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) using tissue Doppler echocardiography (TDE). BACKGROUND An ARVD/C is characterized by fibrofatty replacement of RV myocardium and RV dilation. These pathologic changes may result in electromechanical dyssynchrony. METHODS Echocardiography, both conventional and TDE, was performed in 52 ARVD/C patients fulfilling Task Force criteria and 25 control subjects. The RV end-diastolic and -systolic areas, right ventricular fractional area change (RVFAC), and left ventricular (LV) volumes and function were assessed. Mechanical synchrony was assessed by measuring differences in time-to-peak systolic velocity (T(SV)) between the RV free wall, ventricular septum, and LV lateral wall. An RV dyssynchrony was defined as the difference in T(SV) between the RV free wall and the ventricular septum, >2 SD above the mean value for control subjects. RESULTS The mean difference in RV T(SV) was higher in ARVD/C compared with control subjects (55 +/- 34 ms vs. 26 +/- 15 ms, p < 0.001). Significant RV dyssynchrony was not noted in any of the control subjects. Based on a cutoff value of 56 ms, significant RV dyssynchrony was present in 26 ARVD/C patients (50%). Patients with RV dyssynchrony had a larger RV end-diastolic area (22 +/- 5 cm(2) vs. 19 +/- 4 cm(2), p = 0.02), and lower RVFAC (29 +/- 8% vs. 34 +/- 8%, p = 0.03) compared with ARVD/C patients without RV dyssynchrony. No differences in QRS duration, LV volumes, or function were present between the 2 groups. CONCLUSIONS An RV dyssynchrony may occur in up to 50% of ARVD/C patients, and is associated with RV remodeling. This finding may have therapeutic and prognostic implications in ARVD/C.

Comparison of Outcomes in Patients With Nonobstructive, Labile-Obstructive, and Chronically Obstructive Hypertrophic Cardiomyopathy

Patients with nonobstructive hypertrophic cardiomyopathy (HC) are considered low risk, generally not requiring aggressive intervention. However, nonobstructive and labile-obstructive HC have been traditionally classified together, and it is unknown if these 2 subgroups have distinct risk profiles. We compared cardiovascular outcomes in 293 patients HC (96 nonobstructive, 114 labile-obstructive, and 83 obstructive) referred for exercise echocardiography and magnetic resonance imaging and followed for 3.3 ± 3.6 years. A subgroup (34 nonobstructive, 28 labile-obstructive, 21 obstructive) underwent positron emission tomography. The mean number of sudden cardiac death risk factors was similar among groups (nonobstructive: 1.4 vs labile-obstructive: 1.2 vs obstructive: 1.4 risk factors, p = 0.2). Prevalence of late gadolinium enhancement (LGE) was similar across groups but more non-obstructive patients had late gadolinium enhancement ≥20% of myocardial mass (23 [30%] vs 19 [18%] labile-obstructive and 8 [11%] obstructive, p = 0.01]. Fewer labile-obstructive patients had regional positron emission tomography perfusion abnormalities (12 [46%] vs nonobstructive 30 [81%] and obstructive 17 [85%], p = 0.003]. During follow-up, 60 events were recorded (36 ventricular tachycardia/ventricular fibrillation, including 30 defibrillator discharges, 12 heart failure worsening, and 2 deaths). Nonobstructive patients were at greater risk of VT/VF at follow-up, compared to labile obstructive (hazed ratio 0.18, 95% confidence interval 0.04 to 0.84, p = 0.03) and the risk persisted after adjusting for age, gender, syncope, family history of sudden cardiac death, abnormal blood pressure response, and septum ≥3 cm (p = 0.04). Appropriate defibrillator discharges were more frequent in nonobstructive (8 [18%]) compared to labile-obstructive (0 [0%], p = 0.02) patients. In conclusion, nonobstructive hemodynamics is associated with more pronounced fibrosis and ischemia than labile-obstructive and is an independent predictor of VT/VF in HC.