Percutaneous left atrial appendage occlusion: impact on left atrial deformation indices.

BACKGROUND: Percutaneous left atrial appendage occlusion (LAAO) is an accepted alternative to thromboprophylaxis in patients with atrial fibrillation (AF) who are: (i) intolerant to oral anticoagulation (OAC) (e.g. life-threatening haemorrhage), (ii) non-adherent to OAC, or (iii) at a high bleeding risk with OAC. Improvement in LA mechanics was shown post-LAAO in the LAFIT-LARIAT study, using the Lariat device. No significant change was seen in LA mechanics after LAAO with the Watchman device in the LAFIT-Watchman study. The impact of LAAO with the Amplatzer or Amulet device on LA deformation mechanics has not been investigated. PURPOSE: To evaluate the impact of LAAO with the Amplatzer or Amulet device on echocardiographic LA deformation indices. METHODS: All patients undergoing percutaneous LAAO from 2013 to 2021 at a single centre were included from an ongoing clinical registry. LA reservoir (εreservoir), conduit (εconduit) and contractile strain (εcontractile) and strain rate (SRreservoir, SRconduit, SRcontractile) were assessed with two-dimensional speckle tracking echocardiography from an apical four-chamber view. Conduit and contractile strain and strain rates were only recorded for patients without AF at the time of echocardiography. Changes in LA deformation indices over time were compared with a linear mixed model. RESULTS: 28 LAAO recipients (mean age 73 ± 12 years, 68% male) were analysed. 5 (18%) patients had AF pre- or post-procedure. After a mean follow-up of 1.6 ± 1.4 months, the mean LA εreservoir increased from 10.15 ± 6.44% to 10.18 ± 8.72% (p = 0.985), the mean LA εconduit increased from 5.12 ± 5.48% to 5.31 ± 6.11% (p = 0.891) and the mean LA εcontractile decreased from 5.14 ± 4.32% to 4.95 ± 5.30% (p = 0.898). During the same time interval, the mean LA SRreservoir decreased from + 0.54 ± 0.23.s- 1 to + 0.48 ± 0.43.s- 1 (p = 0.566), the mean LA SRconduit remained stable: -0.47 ± 0.41.s- 1 to -0.47 ± 0.32.s- 1 (p = 0.997) and the mean LA SRcontractile decreased from - 0.66 ± 0.50.s- 1 to -0.55 ± 0.46.s- 1 (p = 0.660). CONCLUSION: No significant improvement in LA mechanical function was seen after LAAO with the Amplatzer or Amulet device. Different LAAO devices therefore appear to have divergent effects on LA deformation, the clinical implications of which may warrant further study.

Renal denervation prevents subclinical atrial fibrillation in patients with hypertensive heart disease: Randomized, sham-controlled trial.

BACKGROUND: Catheter-based renal denervation (RD), in addition to pulmonary vein isolation (PVI), reduces atrial fibrillation (AF) recurrence in hypertensive patients. Whether RD, without additional PVI, can prevent subclinical atrial fibrillation (SAF) in patients with hypertensive heart disease (HHD) is unknown. OBJECTIVE: The purpose of this study was to assess the efficacy of RD in preventing SAF in patients with HHD. METHODS: A single-center, randomized, sham-controlled pilot trial, including patients >55 years in sinus rhythm, but with a high risk of developing SAF was conducted. Patients had uncontrolled hypertension despite taking 3 antihypertensive drugs, including a diuretic. The primary endpoint was the first SAF episode lasting ≥6 minutes recorded via an implantable cardiac monitor scanned every 6 months for 24 months. A blinded independent monitoring committee assessed electrocardiographic rhythm recordings. Change in SAF burden (SAFB), and office and 24-hour ambulatory blood pressure (BP) at 6-month follow-up were secondary endpoints. RESULTS: Eighty patients were randomly assigned to RD (n = 42) or sham groups (n = 38). After 24 months of follow-up, SAF occurred in 8 RD patients (19%) and 15 sham patients (39.5%) (hazard ratio 0.40; 95% confidence interval 0.17-0.96; P = .031). Median [interquartile range] SAFB was low in both groups but was significantly lower in the RD vs sham group (0% [0-0] vs 0% [0-0.3]; P = .043). Fast AF (>100 bpm) occurred less frequently in the RD than sham group (2% vs 26%; P = .002). After adjusting for baseline values, there were no significant differences in office or 24-hour BP changes between treatment groups. CONCLUSION: RD reduced incident SAF events, SAFB, and fast AF in patients with HHD. The observed effects may occur independent of BP lowering.

Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region.

AIMS: Mutation type, location, dominant-negative IKs reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent IKs stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk. METHODS AND RESULTS: Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P < 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of IKs regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation. CONCLUSION: KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent IKs enhancement correlates with its phenotypic severity. Cellular studies providing further insights into IKs-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.

Generation of two human induced pluripotent stem cell (hiPSC) lines from a long QT syndrome South African founder population.

We generated PSMi001-A and PSMi008-A hiPSC lines from two individuals belonging to a South African (SA) founder population in which the malignant KCNQ1-A341V mutation cosegregates with the Long QT Syndrome (LQTS) phenotype. PSMi001-A was derived from an asymptomatic KCNQ1-A341V mutation carrier, whereas PSMi008-A was derived from a healthy non-mutation carrier, heterozygous for the minor variant rs16847548 on the NOS1AP gene, associated with QT prolongation in the general population, and with a greater risk for cardiac arrest in the affected members of the SA founder population. The hiPSCs, generated using the Yamanaka's retroviruses, display pluripotent stem cell features and trilineage differentiation potential.

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi007-A from a Long QT Syndrome type 1 patient carrier of two common variants in the NOS1AP gene.

We generated human induced pluripotent stem cells (hiPSCs) from a symptomatic Long QT Syndrome (LQTS) type 1 patient, belonging to a South African (SA) founder population segregating the heterozygous mutation c.1022C > T p.A341V on the KCNQ1 gene. The patient is also homozygous for the two minor variants rs4657139 and rs16847548 on the NOS1AP gene, associated with greater risk for cardiac arrest and sudden death in LQTS mutation carriers of the founder population. hiPSCs, obtained using four retroviruses encoding the reprogramming factors OCT4, SOX2, cMYC and KLF4, display pluripotent stem cell characteristics, and can be differentiated into spontaneously beating cardiomyocytes (hiPSC-CMs).

Renal Denervation in High-risk Patients with Hypertension.

Hypertension is a common health problem, which leads to a substantial mortality and morbidity burden, globally. The management of patients with high-risk and treatment-resistant hypertension remains a major clinical challenge to the treating physician. Renal denervation (RD) is an emerging technique, comprising modification of the renal sympathetic nerve supply which courses around the renal arteries. Endovascular access is obtained to the renal arteries, followed by delivery of heat energy to the peri-renal sympathetic nerves. This leads to the reduction of blood pressure with or without the addition of anti-hypertensive pharmacotherapy. Earlier trials led to clinical equipoise, but more recent trials (e.g. SPYRAL HTN-OFF MED, SPYRAL HTN-ON MED and RADIANCE-HTN SOLO), which were designed to overcome the limitations of the initial studies, have provided support for the efficacy of RD in hypertension management. Evidence (from randomised, non-randomised, sham-controlled and non-sham-controlled trials) for the use of RD in the treatment of hypertension is reviewed in this article. Finally, the current clinical role, gaps in evidence, and the expected future evolution of RD are discussed.

Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3' Untranslated Region of KCNQ1?

BACKGROUND: Long-QT syndrome is an inherited cardiac channelopathy characterized by delayed repolarization, risk of life-threatening arrhythmia, and significant clinical variability even within families. Three single-nucleotide polymorphisms (SNPs) in the 3' untranslated region of KCNQ1 were recently suggested to be associated with suppressed gene expression and hence decreased disease severity when located on the same haplotype with a disease-causing KCNQ1 mutation. We sought to replicate this finding in a larger and a genetically more homogeneous population of KCNQ1 mutation carriers. METHODS AND RESULTS: The 3 SNPs (rs2519184, rs8234, and rs10798) were genotyped in a total of 747 KCNQ1 mutation carriers with A341V, G589D, or IVS7-2A>G mutation. The SNP haplotypes were assigned based on family trees. The SNP allele frequencies and clinical severity differed between the 3 mutation groups. The different SNP haplotypes were neither associated with heart rate-corrected QT interval duration (QTc) nor cardiac events in any of the 3 mutation groups. When the mutation groups were combined, the derived SNP haplotype of rs8234 and rs10798 located on the same haplotype with the mutation was associated with a shorter QTc interval (P<0.05) and a reduced occurrence of cardiac events (P<0.01), consistent with the previous finding. However, when the population-specific mutation was controlled for, both associations were no longer evident. CONCLUSIONS: 3' Untranslated region SNPs are not acting as genetic modifiers in a large group of LQT1 patients. The confounding effect of merging a genetically and clinically heterogeneous group of patients needs to be taken into account when studying disease modifiers.

Diagnostic disparity and identification of two TNNI3 gene mutations, one novel and one arising de novo, in South African patients with restrictive cardiomyopathy and focal ventricular hypertrophy.

INTRODUCTION: The minimum criterion for the diagnosis of hypertrophic cardiomyopathy (HCM) is thickening of the left ventricular wall, typically in an asymmetrical or focal fashion, and it requires no functional deficit. Using this criterion, we identified a family with four affected individuals and a single unrelated individual essentially with restrictive cardiomyopathy (RCM). Mutations in genes coding for the thin filaments of cardiac muscle have been described in RCM and HCM with 'restrictive features'. One such gene encodes for cardiac troponin I (TNNI3), a sub-unit of the troponin complex involved in the regulation of striated muscle contraction. We hypothesised that mutations in TNNI3 could underlie this particular phenotype, and we therefore screened TNNI3 for mutations in 115 HCM probands. METHODS: Clinical investigation involved examination, echocardiography, chest X-ray and an electrocardiogram of both the index cases and close relatives. The study cohort consisted of 113 South African HCM probands, with and without known founder HCM mutations, and 100 ethnically matched control individuals. Mutation screening of TNNI3 for diseasecausing mutations were performed using high-resolution melt (HRM) analysis. RESULTS: HRM analyses identified three previously described HCM-causing mutations (p.Pro82Ser, p.Arg162Gln, p.Arg170Gln) and a novel exonic variant (p.Leu144His). A previous study involving the same amino acid identified a p.Leu144Gln mutation in a patient presenting with RCM, with clinical features of HCM. We observed the novel p.Leu144His mutation in three siblings with clinical RCM and varying degrees of ventricular hypertrophy. The isolated index case with the de novo p.Arg170Gln mutation presented with a similar phenotype. Both mutations were absent in a healthy control group. CONCLUSION: We have identified a novel disease-causing p.Leu144His mutation and a de novo p.Arg170Gln mutation associated with RCM and focal ventricular hypertrophy, often below the typical diagnostic threshold for HCM. Our study provides information regarding TNNI3 mutations underlying RCM in contrast to other causes of a similar presentation, such as constrictive pericarditis or infiltration of cardiac muscle, all with marked right-sided cardiac manifestations. This study therefore highlights the need for extensive mutation screening of genes encoding for sarcomeric proteins, such as TNNI3 to identify the underlying cause of this particular phenotype.

Autonomic control of heart rate and QT interval variability influences arrhythmic risk in long QT syndrome type 1.

BACKGROUND: A puzzling feature of the long QT syndrome (LQTS) is that family members carrying the same mutation often have divergent symptoms and clinical outcomes. OBJECTIVES: This study tested the hypothesis that vagal and sympathetic control, as assessed by spectral analysis of spontaneous beat-to-beat variability of RR and QT intervals from standard 24-h electrocardiogram Holter recordings, could modulate the severity of LQTS type 1 (LQT1) in 46 members of a South-African LQT1 founder population carrying the clinically severe KCNQ1 A341V mutation. METHODS: Nonmutation carriers (NMCs) (n = 14) were compared with mutation carriers (MCs) (n = 32), 22 with and 10 without major symptoms. We assessed the effect of circadian rhythm and beta-blocker therapy over traditional time and frequency domain RR and QT variability indexes. RESULTS: The asymptomatic MCs differed significantly from the symptomatic MCs and from NMCs in less vagal control of heart rate and more reactive sympathetic modulation of the QT interval, particularly during daytime when arrhythmia risk for patients with LQT1 is greatest. CONCLUSIONS: The present data identified an additional factor contributing to the differential arrhythmic risk among patients with LQT1 carrying the same mutation. A healthy autonomic control confers a high risk, whereas patients with higher sympathetic control of the QT interval and reduced vagal control of heart rate are at lower risk. This differential "autonomic make-up," likely under genetic control, will allow refinement of risk stratification within families with LQTS, leading to more targeted management.

Time, frequency and information domain analysis of heart period and QT variability in asymptomatic long QT syndrome type 2 patients.

This study was designed to characterize in time, frequency and information domains heart period (HP) and QT interval variabilities in asymptomatic (ASYMP) long QT syndrome type 2 (LQT2) subjects. HP, approximated as the temporal distance between two consecutive R-wave peaks, and QT, approximated as the temporal distance between the R-wave peak and the T-wave offset, were automatically derived from 24h Holter recordings in 10 ASYMP LQT2 patients and 13 healthy non mutation carriers (NMC) subjects. All analyses were carried out during DAY (from 2 to 6 PM) and NIGHT (from 12 to 4 AM). Mean, variance, spectral power and complexity indices at short, medium and long time scales were assessed over HP and QT beat-to-beat series. Circadian rhythmicity was evident in both NMC and ASYMP LQT2 but ASYMP LQT2 subjects were characterized by higher HP, QT interval and HP variability during both DAY and NIGHT. In addition, multiscale complexity analysis was able to differentiate the groups by showing a higher HP complexity and a lower QT complexity at long time scales in ASYMP LQT2 during DAY. ASYMP LQT2 exhibited a different autonomic control compared to NMC and such a differentiation could be protective and assure them a lower risk profile.

AKAP9 is a genetic modifier of congenital long-QT syndrome type 1.

BACKGROUND: Long-QT syndrome (LQTS), a cardiac arrhythmia disorder with variable phenotype, often results in devastating outcomes, including sudden cardiac death. Variable expression, independently from the primary disease-causing mutation, can partly be explained by genetic modifiers. This study investigates variants in a known LQTS-causative gene, AKAP9, for potential LQTS-type 1-modifying effects. METHODS AND RESULTS: Members of a South African LQTS-type 1 founder population (181 noncarriers and 168 mutation carriers) carrying the identical-by-descent KCNQ1 p.Ala341Val (A341V) mutation were evaluated for modifying effects of AKAP9 variants on heart rate-corrected QT interval (QTc), cardiac events, and disease severity. Tag single nucleotide polymorphisms in AKAP9 rs11772585, rs7808587, rs2282972, and rs2961024 (order, 5'-3'positive strand) were genotyped. Associations between phenotypic traits and alleles, genotypes, and haplotypes were statistically assessed, adjusting for the degree of relatedness and confounding variables. The rs2961024 GG genotype, always represented by CGCG haplotype homozygotes, revealed an age-dependent heart rate-corrected QT interval increase (1% per additional 10 years) irrespective of A341V mutation status (P=0.006). The rs11772585 T allele, found uniquely in the TACT haplotype, more than doubled (218%) the risk of cardiac events (P=0.002) in the presence of A341V; additionally, it increased disease severity (P=0.025). The rs7808587 GG genotype was associated with a 74% increase in cardiac event risk (P=0.046), whereas the rs2282972 T allele, predominantly represented by the CATT haplotype, decreased risk by 53% (P=0.001). CONCLUSIONS: AKAP9 has been identified as an LQTS-type 1-modifying gene. Variants investigated altered heart rate-corrected QT interval irrespective of mutation status, as well as cardiac event risk, and disease severity, in mutation carriers.

Multiscale complexity analysis of the cardiac control identifies asymptomatic and symptomatic patients in long QT syndrome type 1.

The study assesses complexity of the cardiac control directed to the sinus node and to ventricles in long QT syndrome type 1 (LQT1) patients with KCNQ1-A341V mutation. Complexity was assessed via refined multiscale entropy (RMSE) computed over the beat-to-beat variability series of heart period (HP) and QT interval. HP and QT interval were approximated respectively as the temporal distance between two consecutive R-wave peaks and between the R-wave apex and T-wave end. Both measures were automatically taken from 24-hour electrocardiographic Holter traces recorded during daily activities in non mutation carriers (NMCs, n = 14) and mutation carriers (MCs, n = 34) belonging to a South African LQT1 founder population. The MC group was divided into asymptomatic (ASYMP, n = 11) and symptomatic (SYMP, n = 23) patients according to the symptom severity. Analyses were carried out during daytime (DAY, from 2PM to 6PM) and nighttime (NIGHT, from 12PM to 4AM) off and on beta-adrenergic blockade (BBoff and BBon). We found that the complexity of the HP variability at short time scale was under vagal control, being significantly increased during NIGHT and BBon both in ASYMP and SYMP groups, while the complexity of both HP and QT variability at long time scales was under sympathetic control, being smaller during NIGHT and BBon in SYMP subjects. Complexity indexes at long time scales in ASYMP individuals were smaller than those in SYMP ones regardless of therapy (i.e. BBoff or BBon), thus suggesting that a reduced complexity of the sympathetic regulation is protective in ASYMP individuals. RMSE analysis of HP and QT interval variability derived from routine 24-hour electrocardiographic Holter recordings might provide additional insights into the physiology of the cardiac control and might be fruitfully exploited to improve risk stratification in LQT1 population.

Filtering approach based on empirical mode decomposition improves the assessment of short scale complexity in long QT syndrome type 1 population.

This study assesses the complexity of heart period (HP) and QT variability series through sample entropy (SampEn) in long QT syndrome type 1 individuals. In order to improve signal-to-noise ratio SampEn was evaluated over the original series (SampEn0) and over the residual computed by subtracting the first oscillatory mode identified by empirical mode decomposition (SampEn(EMD1R)). HP and QT interval were continuously extracted during daytime (2:00-6:00 PM) from 24 hour Holter recordings in 14 non mutation carriers (NMCs) and 34 mutation carriers (MCs) subdivided in 11 asymptomatic (ASYMP) and 23 symptomatic (SYMP). Both NMCs and MCs belonged to the same family line. While SampEn0 did not show differences among the three groups, Samp(EnEMD1R) assessed over the QT series significantly decreased in ASYMP subjects. SampEn(EMD1R) identified a possible factor (i.e. the lower short scale QT complexity) that might contribute to the different risk profile of the ASYMP group.

Long QT syndrome in South Africa: the results of comprehensive genetic screening.

Congenital long QT syndrome (cLQTS) is a genetic disorder predisposing to ventricular arrhythmia, syncope and sudden death. Over 700 different cLQTS-causing mutations in 13 genes are known. The genetic spectrum of LQTS in 44 South African cLQTS patients (23 known to carry the South African founder mutation p.A341V in KCNQ1) was established by screening for mutations in the coding regions of KCNQ1, KCNH2, KCNE1, KCNE2 and SCN5A, the most frequently implicated cLQTS-causing genes (five-gene screening). Fourteen disease-causing mutations were identified, eight (including the founder mutation) in KCNQ1, five in KCNH2 and one in KCNE1. Two mutations were novel. Two double heterozygotes were found among the 23 families (8.5%) carrying the founder mutation. In conclusion, cLQTS in South Africa reflects both a strong founder effect and a genetic spectrum similar to that seen in other populations. Consequently, five-gene screening should be offered as a standard screening option, as is the case internationally. This will disclose compound and double heterozygotes. Fivegene screening will most likely be even more informative in other South African sub-populations with a greater genetic diversity.

Refined multiscale entropy analysis of heart period and QT interval variabilities in long QT syndrome type-1 patients.

This study assesses complexity of cardiovascular control in patients affected by type-1 variant of long QT (LQT1) syndrome. Complexity was assessed by refined multiscale entropy of heart period (HP) and QT interval variabilities. HP was taken as the time distance between two consecutive R peaks (RR) and QT interval was approximated as the time distance between the R-peak and T-wave apex (RTa) and between R-peak and T-wave end (RTe). RR, RTa and RTe intervals were automatically extracted from 24h Holter recordings and the daytime period was analyzed (from 02:00 to 06:00 PM). Non mutation carrier (NMC) individuals (n=11), utilized as a control group, were taken from the same family line of the mutation carrier (MC) subjects (n=26). We found that, while NMC and MC groups were indistinguishable based on time domain and complexity analyses of RR dynamics, complexity analysis of RTa and RTe variabilities clearly separates the two populations and suggests an impairment in the cardiac control mechanisms acting on the ventricles.

Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome.

BACKGROUND: Long-QT syndrome (LQTS) is characterized by such striking clinical heterogeneity that, even among family members carrying the same mutation, clinical outcome can range between sudden death and no symptoms. We investigated the role of genetic variants as modifiers of risk for cardiac events in patients with LQTS. METHODS AND RESULTS: In a matched case-control study including 112 patient duos with LQTS from France, Italy, and Japan, 25 polymorphisms were genotyped based on either their association with QTc duration in healthy populations or on their role in adrenergic responses. The duos were composed of 2 relatives harboring the same heterozygous KCNQ1 or KCNH2 mutation: 1 with cardiac events and 1 asymptomatic and untreated. The findings were then validated in 2 independent founder populations totaling 174 symptomatic and 162 asymptomatic patients with LQTS, and a meta-analysis was performed. The KCNQ1 rs2074238 T-allele was significantly associated with a decreased risk of symptoms 0.34 (0.19-0.61; P<0.0002) and with shorter QTc (P<0.0001) in the combined discovery and replication cohorts. CONCLUSIONS: We provide evidence that the KCNQ1 rs2074238 polymorphism is an independent risk modifier with the minor T-allele conferring protection against cardiac events in patients with LQTS. This finding is a step toward a novel approach for risk stratification in patients with LQTS.