Gender Disparities in Clinical Outcome After Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy in the Chinese Han Population: A Cohort Study.

BACKGROUND: Sex differences in the long-term prognosis of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) patients undergoing alcohol septal ablation (ASA) remain unclear, especially in the Chinese Han population. METHOD: This cohort study included 320 HOCM Chinese Han patients who underwent ASA because of symptomatic left ventricular outflow tract (LVOT) obstruction. Patients were grouped according to sex: females (mean±standard deviation age [SD] 50.7±6.8 years) and males (mean±SD age 52.6±7.3 years). Individuals were followed over the long term. RESULTS: Pre-procedure, women had more symptoms (New York Heart Association [NYHA] class III-IV 67.3% vs 56.3%, p=0.03), more atrial fibrillation (23.5% vs 14.6%, p=0.047) than men. Transient complete atrioventricular block after ASA was more common in woman than in men (34.0 vs 23.4%; p=0.048). Residual LVOT gradient, post-procedural residual left ventricular wall thickness, NYHA functional class, and adverse arrhythmic events were comparable between the two groups. The 10-year survival rate (77% vs 89%, p=0.037) and the annual adverse arrhythmic event rate (1.3% vs 0.4%, p<0.01) following ASA were significantly worse in women compared with men. Kaplan-Meier analysis showed a significantly lower survival in women compared with men (p=0.023). In multivariable modelling, female sex remained independently associated with higher all-cause mortality (hazard ratio, 1.12; 95% confidence interval, 1.08-1.27; p=0.03) when adjusted for age, NYHA class III-IV symptoms, and other cardiovascular comorbidities. CONCLUSIONS: Female patients with HOCM undergoing ASA tended to have more severe symptoms and adverse arrhythmic events. The 10-year survival rate after ASA was significantly worse in women compared with men with HOCM. Sex may need to be considered as an important factor in the clinical management of patients with symptomatic HOCM.

Transcatheter septal ablation in hypertrophic obstructive cardiomyopathy: a technical guide and review of published results.

Transcatheter alcohol septal ablation (ASA) treatment of symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM) is based on the existence and degree of intraventricular obstruction. Patients with significant gradient and symptoms who do not respond to optimal medical therapy are eligible to gradient reduction through a surgical (septal myectomy) or a transcatheter (alcohol septal ablation) septal reduction. The latter encompasses occlusion of a septal branch perfusing the hypertrophied septum, which is involved in the generation of obstruction, by injecting ethanol into the supplying septal branch(es). ASA has been established as a highly effective and safe method and has outnumbered the surgical gold standard. Although the technique is straightforward, patient selection and some technical details may influence the efficacy and safety of the procedure. The technique is based on echocardiographic contrast guidance, which allows accurate target septal branch selection and optimisation of the result. Published long-term results from high-volume centres have confirmed the effectiveness of ASA and have shown excellent survival, which is comparable to that in the general population. Choice and performance of the surgical or interventional treatment should be implemented in highly specialised centres in terms of a heart-team approach, taking notice of anatomic characteristics as well as comorbidities. Involvement of all cases in international registries may reveal the individual merits and indications for the surgical and interventional treatment in HOCM.

Cystamine slows but not inverses the progression of monocrotaline-induced pulmonary arterial hypertension in rats.

Tissue transglutaminase (TG2) plays an important role in pulmonary arterial hypertension (PAH). Previous research indicate that TG2 and protein serotonylation catalyzed by TG2 are upregulated in PAH. Serotonin transporter inhibitor fluoxetine ameliorates PAH via inhibition of protein serotonylation. It is still unknown whether PAH is inhibited through direct inhibition of TG2. Therefore, the present study aimed to investigate the effects of TG2 inhibitor cystamine on monocrotaline-induced PAH in rats. Rats were treated with monocrotaline (60 mg·kg-1, i.p.) in combination with or without cystamine (20, 40 mg·kg-1·day-1, p.o.). The results showed that compared with monocrotaline alone, combination of monocrotaline with cystamine (40 mg·kg-1·day-1, p.o.) relieved right ventricle hypertrophy, inhibited pulmonary arteriolar remodeling, and downregulated protein expression of TG2, phosphorylated protein kinase B (Akt), and extracellular regulated protein kinase (ERK) at day 21. However, except for TG2 expression, these changes were not significantly inhibited by cystamine at day 35. In addition, cystamine dose-dependently enhanced the survival rate of rats injected with monocrotaline at day 35. The findings suggest that cystamine slows but not reverses monocrotaline-induced PAH in rats, which was largely associated with the inhibition of TG2 protein expression and Akt and ERK activation.

Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy: A 16-Year Australian Single Centre Experience.

BACKGROUND: Alcohol septal ablation (ASA), is a well-established treatment for symptomatic hypertrophic obstructive cardiomyopathy (HOCM). We report the acute, short and long-term clinical and echocardiographic outcomes of our experience in a single Australian centre over 16 years. METHODS: We retrospectively analysed consecutive patients presenting to our centre for ASA between March 2000 and July 2016. Local databases were interrogated along with direct patient or physician contact occurred where required. RESULTS: Alcohol septal ablation was performed in 80 patients with symptomatic, medication refractory HOCM (mean age 61±15 years; range 22-84 years; 50% male). All patients had transthoracic echocardiography prior to the procedure, within 48hours of the procedure, 6 weeks, 6 months, 1 year and yearly thereafter to a median follow-up of 80±40months. At baseline, mean resting and provoked LVOT gradients were 80±49mmHg and 97±40mmHg respectively. Compared with baseline, ASA led to a reduction in resting LVOT gradients at all time points, particularly at 2 days-52±41mmHg, p<0.001; 12 months-29±34mmHg, p<0.001; and last follow-up 12±21mmHg, p<0.001. Provoked LVOT gradients were also reduced at 2 days-64±44mmHg and last follow-up of 19±29mmHg, p<0.001. Compared to baseline (19.8±4.2mm), ASA was associated with a reduction in interventricular septal (IVS) thickness at all time intervals with last echocardiographic follow-up at 80 months being 16.0±4.9mm, (

Crystal Structure of G Protein-coupled Receptor Kinase 5 in Complex with a Rationally Designed Inhibitor.

G protein-coupled receptor kinases (GRKs) regulate cell signaling by initiating the desensitization of active G protein-coupled receptors. The two most widely expressed GRKs (GRK2 and GRK5) play a role in cardiovascular disease and thus represent important targets for the development of novel therapeutic drugs. In the course of a GRK2 structure-based drug design campaign, one inhibitor (CCG215022) exhibited nanomolar IC50 values against both GRK2 and GRK5 and good selectivity against other closely related kinases such as GRK1 and PKA. Treatment of murine cardiomyocytes with CCG215022 resulted in significantly increased contractility at 20-fold lower concentrations than paroxetine, an inhibitor with more modest selectivity for GRK2. A 2.4 Å crystal structure of the GRK5·CCG215022 complex was determined and revealed that the inhibitor binds in the active site similarly to its parent compound GSK180736A. As designed, its 2-pyridylmethyl amide side chain occupies the hydrophobic subsite of the active site where it forms three additional hydrogen bonds, including one with the catalytic lysine. The overall conformation of the GRK5 kinase domain is similar to that of a previously determined structure of GRK6 in what is proposed to be its active state, but the C-terminal region of the enzyme adopts a distinct conformation. The kinetic properties of site-directed mutants in this region are consistent with the hypothesis that this novel C-terminal structure is representative of the membrane-bound conformation of the enzyme.

Conservative versus invasive treatment in hypertrophic obstructive cardiomyopathy: an echocardiography study.

AIM AND METHODS: The aim of our study was to compare the development of echocardiographic parameters and functional status of patients with hypertrophic obstructive cardiomyopathy (HOCM) treated conservatively (n = 41) or by alcohol septal ablation (ASA; n = 39). RESULTS: Left ventricular outflow tract gradient (LVOTG) decreased in the first year by 53.7±36.4 mmHg in ASA group versus 5.5±47.1 mmHg in conservatively treated group (p<0.001), in the third year by 53.1±41.4 mmHg versus 23.9±42.7 mmHg (p = NS) and in the fifth year, the reduction of LVOTG was 52.1±44.5 mmHg in ASA group and 3.0±63.2 mmHg in conservatively treated group (p<0.05).Change in NYHA class in the first year was -1.1±0.4 versus 0.1±0.5, in the third year -1.0±0.6 versus 0.1±0.4 and in the fifth year -0.8±0.5 versus 0.1±0.4 (all p<0.001). CONCLUSION: Our results showed for the first time that decline of LVOTG after ASA creates a favorable left ventricle remodeling and leads to significant improvement of functional status of HOCM patients in comparison with conservative treatment (Tab. 3, Fig. 2, Ref. 42).

Unjailing of the septal perforator using a rotational atherectomy device prior to alcohol septal ablation in a patient with symptomatic hypertrophic obstructive cardiomyopathy.

We report a novel approach in which successful unjailing of the septal perforator was performed through the side branch of a coronary stent using a rotational atherectomy device for the purpose of alcohol septal ablation in a patient with symptomatic hypertrophic obstructive cardiomyopathy.

Quantification of changes in septal strain after alcohol septal ablation in hypertrophic obstructive cardiomyopathy-cases from the three-dimensional speckle tracking echocardiographic MAGYAR-path study.

Patients with hypertrophic obstructive cardiomyopathy undergoing alcohol septal ablation are presented. Three-dimensional speckle tracking echocardiography (3DSTE) is a new, noninvasive tool for quantification of myocardial deformation. In both cases, 3DSTE was performed 1 day before and 3 days after alcohol septal ablation to quantify changes in septal strain of ablated area. Results could suggest the possible role of 3DSTE in the quantitative evaluation of the success of alcohol septal ablation.

Rescue alcohol septal ablation in sepsis with multiorgan failure.

A 55 year old male patient with a diagnosis of hypertrophic cardiomyopathy was admitted with features of sepsis related to cholangitis. Initial management with intravenous (i.v.) fluids and antibiotics did not cause any change in his general condition mandating an emergency endoscopic retrograde cholangio-pancreatography (ERCP). After successful retrieval of CBD stone on ERCP, patient had massive upper gastrointestinal bleed leading to hypotension and shock. Addition of inotropes had led to further deterioration in his clinical status with a mean arterial BP falling to 44 mm of Hg. His echocardiography showed a resting left ventricular outflow tract (LVOT) gradient of 90 mm of Hg and thus was taken up for emergency alcohol septal ablation (ASA). Immediately after ASA, patient had significant decrease in LVOT obstruction and rise of systemic arterial pressures. After 10 days of antibiotic therapy patient was discharged with a residual LVOT obstruction of 28 mm of Hg.

Effects of ACE2 inhibition in the post-myocardial infarction heart.

BACKGROUND: There is evidence that angiotensin-converting enzyme 2 (ACE2) is cardioprotective. To assess this in the post-myocardial infarction (MI) heart, we treated adult male Sprague-Dawley rats with either placebo (PL) or C16, a selective ACE2 inhibitor, after permanent coronary artery ligation or sham operation. METHODS AND RESULTS: Coronary artery ligation resulting in MI between 25% to 50% of the left ventricular (LV) circumference caused substantial cardiac remodeling. Daily C16 administration from postoperative days 2 to 28 at a dose that inhibited myocardial ACE2 activity was associated with a significant increase in MI size and reduction in LV % fractional shortening. Treatment with C16 did not significantly affect post-MI increases in LV end-diastolic dimension but did inhibit increases in wall thickness and fibrosis in non-infarcted LV. On postoperative day 7, C16 had no significant effect on the increased level of apoptosis in the infarct and border zones nor did it significantly affect capillary density surrounding the MI. It did, however, significantly reduce the number of c-kit(+) cells in the border region. CONCLUSIONS: These findings support the notion that ACE2 exerts cardioprotective effects by preserving jeopardized cardiomyocytes in the border zone. The reduction in hypertrophy and fibrosis with C16, however, suggests that ACE2 activity has diverse effects on post-MI remodeling.

Coronary morphology and conduction system disturbance induced by therapeutic embolization of the coronary septal artery.

BACKGROUND: Percutaneous transluminal septal myocardial alcohol ablation (PTSMAA) is not a procedure without complications. It may produce heart arrhythmias, especially those due to disturbances of atrioventricular (AV) and interventricular (IV) electrical conduction. OBJECTIVE: The goal of this study was to evaluate the relationship between the anatomical patterns of the right coronary artery and the left anterior descending artery (LAD) and to relate them to the AV and IV bundle branch blocks provoked by PTSMAA. METHOD: Twenty patients with obstructive hypertrophic cardiomyopathy resistant to treatment with drugs successfully underwent PTSMAA. Electrocardiographic analyses were done before and after PTSMAA, and the results were compared with the abnormal septal anatomy. RESULTS: The effectiveness of PTSMAA was obtained in 18 (90%) of the 20 patients by ethanolization of the first great septal branch. In the other 2 patients (10%), 2 septal branches underwent alcoholization. First-grade temporary AV block (AVB) was observed in 6 patients (30%). Ten patients experienced severe bradycardia due to total AVB that required a temporary pacemaker, but 3 of the patients (15%) required a permanent pacemaker. Fourteen patients (70%) experienced permanent complete right branch block, and 2 developed incomplete left anterior block and incomplete left posterior block. Six patients presented with no electrical conduction disturbance at all. CONCLUSION: According to the results of the present investigation with the AV node artery derived from the right coronary artery in all cases, complete and permanent AV conduction system blockade occurred after PTSMAA in all types of anatomy regarding the observed LAD.

Choice of Septal Reduction Therapies and Alcohol Septal Ablation.

In patients with resting or provoked gradients and symptoms refractory to optimal medical therapy, alcohol septal ablation or surgical septal myectomy may be considered. Given the overall comparable outcomes after ablation and myectomy, there is, for many patients, equipoise between the two procedures. Septal ablation is performed with standard angioplasty guiding catheters, guidewires, and balloon catheters. In the Euro-ASA registry, NYHA functional class fell from 2.9 ± 0.5 to 1.6 ± 0.7 and gradient from 67 ± 36 to 16 ± 21 mm Hg at mean 3.9-year follow-up after septal ablation.

Effect of alcohol septal ablation in patients with hypertrophic cardiomyopathy on the electrocardiographic pattern.

Alcohol septal ablation (ASA) of patients with hypertrophic cardiomyopathy (HC) allows study of the electrocardiographic effects of myocardial necrosis confined to the base of the interventricular septum, a rare event in atherothrombotic coronary artery disease. Eighty-four consecutive patients were studied after ASA for HC. After excluding 20 with pacing before ASA and 6 with no available preprocedure electrocardiograms, the electrocardiograms of the remaining 58 patients were compared with those of 58 consecutive patients with anterior ST elevation myocardial infarctions who underwent primary intervention for left anterior descending coronary artery (LAD) occlusions. In 25 patients, the occlusions were proximal to the first septal perforator, and in 33 patients, the occlusions were more distal. All electrocardiograms were analyzed with respect to conduction abnormalities and ST-segment changes. Patients with HC developed right bundle branch block significantly more often than those with LAD occlusions (50% vs 14%, p = 0.001) Moreover, patients with HC required postprocedure pacing more frequently (14% vs 2%, p <0.05). A distinctive pattern of ST displacement was found. There was more frequent ST depression in leads I and aVF and greater ST elevation in lead V(1) in patients who underwent ASA, indicating a greater tendency toward a rightward direction than was true in patients with LAD occlusions. In conclusion, in addition to more frequent right bundle branch block after ASA, a distinctive a characteristic pattern of ST-segment deviation similar to but distinct from that produced by proximal LAD occlusion appeared.

Left ventricular outflow tract obstruction in the presence of asymmetric septal hypertrophy and accessory mitral valve tissue treated with alcohol septal ablation.

Redundant or accessory mitral valve tissue (AMVT) is a rare clinical condition. It is an even rarer cause of left ventricular outflow tract obstruction. We report a case of an adult male with medically unresponsive hypertrophic obstructive cardiomyopathy in whom real-time three-dimensional transesophageal echocardiography was used to both diagnose the presence of coexistent asymmetric septal hypertrophy and AMVT as well as confirm the safety and efficacy of treatment with alcohol septal ablation.

Effect of alcohol-induced septal ablation on left atrial volume and ejection fraction assessed by real time three-dimensional transthoracic echocardiography in patients with hypertrophic cardiomyopathy.

Alcohol-induced septal ablation (AISA) is an accepted treatment for hypertrophic cardiomyopathy (HCM) patients with left ventricular (LV) outflow obstruction who are unresponsive to medical therapy. As left atrial (LA) enlargement has been correlated with increased morbidity and mortality in HCM, we assessed LA volumes and ejection fraction (EF) prior to and after AISA using real time three-dimensional (3D) transthoracic echocardiography (TTE) in 12 patients (9 women; mean age 52 +/- 15 years; 11 Caucasian). All patients underwent successful AISA with no complications and their resting left ventricular outflow gradients decreased from 40.5 +/- 22.2 to 9.1 +/- 17.6 mmHg (P < 0.001) while their gradients with provocation decreased from 126.2 +/- 31.7 to 21.8 +/- 28.0 mmHg (P < 0.001). All patients showed improvements in their New York Heart Association (NYHA) functional class. Both the LA end-systolic (45.2 +/- 12.9 to 37.2 +/- 13.7 ml, P < 0.0001) and end-diastolic (79.6 +/- 18.9 to 77.1 +/- 18.6 ml, P = 0.001) volumes decreased after AISA. The LA EF increased from 43.1 +/- 9.0 to 52.5 +/- 8.8% (P = 0.001). The increase in LA EF correlated with the decrease in the resting left ventricular outflow gradient (R =-0.647, P = 0.03). In conclusion, 3D echocardiography can be utilized to follow LA function after AISA for HCM. AISA results in clinical improvement in patients with HCM and in improvement of LA EF that is correlated with the decrease in the left ventricular outflow gradient.

Analysis of action potentials in the canine ventricular septum: no phenotypic expression of M cells.

OBJECTIVE: Transmural heterogeneity in the ventricular free wall, enhanced by the midmyocardial long action potential duration (APD) of M cells, plays an important role in the arrhythmogenesis of long QT syndrome. Although we observed dynamic expression of M cell phenotypes in the canine ventricular free wall, it is still unclear whether similar phenomena are present in the interventricular septum. This study evaluated transmural heterogeneity of APD in the septum. METHODS: We isolated and perfused 22 canine septal preparations through the septal branch of the anterior descending coronary artery, and optically mapped 256 channels of action potentials on their cut-exposed transseptal surfaces before and after treatment with sotalol (I(Kr) blocker), anemone toxin II (ATX-II, which slows the inactivation of I(Na)), or drug-free state in 6, 9, and 22 preparations, respectively. The preparations were paced from the left ventricular endocardium at cycle lengths of 500, 1000, 2000, and 4000 ms. RESULTS: We observed progressively lengthening of APD across the septum from the right ventricular to the left ventricular endocardium without a midmyocardial maximum under all conditions. All action potentials had minor phase-1 notches, resembling the endocardial action potential in the ventricular free wall. Increasing cycle lengths and concentrations of sotalol and ATX-II prolonged APD without midmyocardial preference and increased the transseptal dispersion of APDs. CONCLUSIONS: Canine interventricular septal action potentials are similar in shape to the endocardial action potentials in the ventricular free wall, with smooth transseptal transition in APD. We found no phenotypical expression of M cells in the canine interventricular septum.

Determination of endogenous norepinephrine levels in different chambers of the rat heart by capillary electrophoresis coupled with amperometric detection.

Capillary electrophoresis with end-column amperometric detection (CE-EC) was used to determine the regional distribution of norepinephrine (NE) in the hearts of sympathetically innervated (control) and chemically sympathectomized rats. Key features of the method are (i) the sample preparation and clean-up step that involved the application of off-line solid phase extraction (SPE) with a 95% NE recovery and (ii) the use of a diamond microelectrode for detection. NE was quantified in the left and right ventricle, the ventricular septum, and the left and right atrium. The NE concentration in the atria was three to five times higher than in the ventricles and ventricular septum of control rats. Basal NE levels in the left and right ventricle and the ventricular septum were reduced to below the detection limit (0.034 microg/g tissue) in tissues treated with the neurotoxin, 6-hydroxydopamine (6-OHDA), while only a moderate reduction was observed in the left and right atrium. Importantly, the diamond microelectrode provided low and stable background current and low peak-to-peak noise

Delayed electrocardiographic changes after percutaneous transluminal septal myocardial ablation in hypertrophic obstructive cardiomyopathy.

OBJECTIVES: This work aimed to study the delayed electrocardiographic changes, including Q-T interval, corrected Q-T dispersion, and heart rate variability (HRV) 3 years after percutaneous transluminal septal myocardial ablation (PTSMA), in symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM). METHODS: In 26 patients (11 women, 15 men; average age, 37.4 +/- 11.2 years) with symptomatic and medically refractory HOCM, 1.4 +/- 0.5 septal branches were occluded with an injection of 3.8 +/- 1.3 mL of alcohol (95%) to ablate the hypertrophied interventricular septum. Baseline and 3 days and 3 years postprocedure 24-hour Holter electrocardiographic findings were determined. RESULTS: One patient developed complete atrioventricular block requiring permanent pacing. The PR interval was significantly prolonged 3 days after ablation, but recovered 3 years postprocedure. Three days after the procedure, all patients developed right bundle branch block, which was present in 24 patients after 3 years. The QRS duration was significantly prolonged 3 days after ablation and during 3 years of follow-up. There was significant and persistent prolongation of QT interval and transient prolongation of corrected QT dispersion 3 days after ablation and returned to preablation values 3 years postprocedure, but JT interval and corrected JT dispersion were not significantly changed after PTSMA. Heart rate variability data (time domain and frequency domain) 3 days and 3 years after PTSMA, including low frequency, high frequency, root mean squared successive difference interval, and the percent of sinus cycles differing from the preceding cycle by more than 50 milliseconds, significantly increased compared to that before the procedure. Low frequency/high frequency, SD of all normal-to-normal intervals, and SD of 5-minute average normal-to-normal intervals were not significantly changed after PTSMA. CONCLUSIONS: Percutaneous transluminal septal myocardial ablation for HOCM induces significant delayed electrocardiographic changes in most patients. The changes include QRS prolongation, new right bundle branch block, persistent QT prolongation, transient QT dispersion and PR prolongation, and changes in HRV data. Electrocardiographic long-term follow-up of a larger series of patients is required to determine the conclusive therapeutic significance.