Cognitive Behavioral Therapy for Symptom Preoccupation Among Patients With Premature Ventricular Contractions: Nonrandomized Pretest-Posttest Study.

BACKGROUND: Premature ventricular contractions (PVCs) are a common cardiac condition often associated with disabling symptoms and impaired quality of life (QoL). Current treatment strategies have limited effectiveness in reducing symptoms and restoring QoL for patients with PVCs. Symptom preoccupation, involving cardiac-related fear, hypervigilance, and avoidance behavior, is associated with disability in other cardiac conditions and can be effectively targeted by cognitive behavioral therapy (CBT). OBJECTIVE: The aim of this study was to evaluate the effect of a PVC-specific CBT protocol targeting symptom preoccupation in patients with symptomatic idiopathic PVCs. METHODS: Nineteen patients diagnosed with symptomatic idiopathic PVCs and symptom preoccupation underwent PVC-specific CBT over 10 weeks. The treatment was delivered by a licensed psychologist via videoconference in conjunction with online text-based information and homework assignments. The main components of the treatment were exposure to cardiac-related symptoms and reducing cardiac-related avoidance and control behavior. Self-rated measures were collected at baseline, post treatment, and at 3- and 6-month follow-ups. The primary outcome was PVC-specific QoL at posttreatment assessment measured with a PVC-adapted version of the Atrial Fibrillation Effects on Quality of Life questionnaire. Secondary measures included symptom preoccupation measured with the Cardiac Anxiety Questionnaire. PVC burden was evaluated with 5-day continuous electrocardiogram recordings at baseline, post treatment, and 6-month follow-up. RESULTS: We observed large improvements in PVC-specific QoL (Cohen d=1.62, P<.001) and symptom preoccupation (Cohen d=1.73, P<.001) post treatment. These results were sustained at the 3- and 6-month follow-ups. PVC burden, as measured with 5-day continuous electrocardiogram, remained unchanged throughout follow-up. However, self-reported PVC symptoms were significantly lower at posttreatment assessment and at both the 3- and 6-month follow-ups. Reduction in symptom preoccupation had a statistically significant mediating effect of the intervention on PVC-specific QoL in an explorative mediation analysis. CONCLUSIONS: This uncontrolled pilot study shows preliminary promising results for PVC-specific CBT as a potentially effective treatment approach for patients with symptomatic idiopathic PVCs and symptom preoccupation. The substantial improvements in PVC-specific QoL and symptom preoccupation, along with the decreased self-reported PVC-related symptoms warrant further investigation in a larger randomized controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05087238; https://clinicaltrials.gov/study/NCT05087238.

Cognitive Behavioral Therapy Improves Quality of Life in Patients With Symptomatic Paroxysmal Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is often associated with troubling symptoms leading to impaired quality of life (QoL) and high health care use. Symptom preoccupation, that is, fear of cardiac-related symptoms and avoidance behavior, potentially contributes to disability in AF but is not targeted by current interventions. OBJECTIVES: We sought to evaluate the effect of online cognitive behavior therapy (AF-CBT) on QoL in patients with symptomatic paroxysmal AF. METHODS: Patients with symptomatic paroxysmal AF (n = 127) were randomly assigned to receive AF-CBT (n = 65) or standardized AF education (n = 62). Online AF-CBT lasted 10 weeks and was therapist guided. The main components were exposure to cardiac-related symptoms and reduction of AF-related avoidance behavior. Patients were evaluated at baseline, posttreatment, and at the 3-month follow-up. Primary outcome was AF-specific QoL as assessed by the Atrial Fibrillation Effect on Quality of Life summary score (range: 0-100) at the 3-month follow-up. Secondary outcomes included AF-specific health care consumption and AF burden assessed by 5-day continuous electrocardiogram recording. The AF-CBT group was followed for 12 months. RESULTS: AF-CBT led to large improvements in AF-specific QoL (Atrial Fibrillation Effect on Quality of Life summary score) by 15.0 points (95% CI: 10.1-19.8; P < 0.001). Furthermore, AF-CBT reduced health care consumption by 56% (95% CI: 22-90; P = 0.025). The AF burden remained unchanged. Results on self-assessed outcomes were sustained 12 months after treatment. CONCLUSIONS: In patients with symptomatic paroxysmal AF, online CBT led to large improvements in AF-specific QoL and reduced health care use. If these results are replicated, online CBT may constitute an important addition to AF management. (Internet-Delivered Cognitive Behavior Therapy for Atrial Fibrillation; NCT03378349).

Internet-Delivered Exposure-Based Therapy for Symptom Preoccupation in Atrial Fibrillation: Uncontrolled Pilot Trial.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia in the adult population. AF is associated with a poor quality of life (QoL) and, in many patients, current medical treatments are inadequate in alleviating AF symptoms (eg, palpitations). Patients often present with symptom preoccupation in terms of symptom fear, avoidance, and control behaviors. Internet-delivered cognitive behavior therapy is effective for treating other somatic disorders but has never been evaluated in patients with AF. OBJECTIVE: The aim of this study is to evaluate the efficacy and feasibility of AF-specific internet-delivered cognitive behavior therapy. METHODS: We conducted an uncontrolled pilot study in which 19 patients with symptomatic paroxysmal AF underwent internet-delivered cognitive behavior therapy. Participants completed self-assessments at pretreatment, posttreatment, and at a 6-month follow-up along with handheld electrocardiogram measurements with symptom registration. The treatment lasted 10 weeks and included exposure to physical sensations, reduction in avoidance behavior, and behavioral activation. RESULTS: We observed large within-group improvements in the primary outcome, AF-specific QoL (Cohen d=0.80; P<.001), and in symptom preoccupation (Cohen d=1.24; P<.001) at posttreatment; the results were maintained at the 6-month follow-up. Treatment satisfaction and adherence rates were also high. We observed an increased AF burden, measured by electrocardiogram, at the 6-month follow-up, but a significant decrease was observed in the overestimation of AF symptoms at posttreatment and 6-month follow-up. Exploratory mediation analysis showed that a reduction in symptom preoccupation mediated the effects of internet-delivered cognitive behavior therapy on AF-specific QoL. CONCLUSIONS: This study presents preliminary evidence for the potential efficacy and feasibility of a novel approach in treating patients with symptomatic AF with internet-delivered cognitive behavior therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02694276; https://clinicaltrials.gov/ct2/show/NCT02694276.

Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR.

BACKGROUND: Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene (LDLR) cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in LDLR with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in LDLR that have a large effect on LDL cholesterol levels. METHODS: We analyzed whole-genome sequencing data from 43 202 Icelanders. Single-nucleotide polymorphisms and structural variants including deletions, insertions, and duplications were genotyped using whole-genome sequencing-based data. LDL cholesterol associations were carried out in a sample of >100 000 Icelanders with genetic information (imputed or whole-genome sequencing). Molecular analyses were performed using RNA sequencing and protein expression assays in Epstein-Barr virus-transformed lymphocytes. RESULTS: We discovered a 2.5-kb deletion (del2.5) overlapping the 3' untranslated region of LDLR in 7 heterozygous carriers from a single family. Mean level of LDL cholesterol was 74% lower in del2.5 carriers than in 101 851 noncarriers, a difference of 2.48 mmol/L (96 mg/dL; P=8.4×10-8). Del2.5 results in production of an alternative mRNA isoform with a truncated 3' untranslated region. The truncation leads to a loss of target sites for microRNAs known to repress translation of LDLR. In Epstein-Barr virus-transformed lymphocytes derived from del2.5 carriers, expression of alternative mRNA isoform was 1.84-fold higher than the wild-type isoform (P=0.0013), and there was 1.79-fold higher surface expression of the LDL receptor than in noncarriers (P=0.0086). We did not find a highly penetrant detrimental impact of lifelong very low levels of LDL cholesterol due to del2.5 on health of the carriers. CONCLUSIONS: Del2.5 is the first reported gain-of-function mutation in LDLR causing a large reduction in LDL cholesterol. These data point to a role for alternative polyadenylation of LDLR mRNA as a potent regulator of LDL receptor expression in humans.

Variants in NKX2-5 and FLNC Cause Dilated Cardiomyopathy and Sudden Cardiac Death.

BACKGROUND: Dilated cardiomyopathy (DCM) is an important cause of heart failure. Variants in >50 genes have been reported to cause DCM, but causative variants have been found in less than half of familial cases. Variants causing DCM in Iceland have not been reported before. METHODS: We performed a genome-wide association study on DCM based on whole genome sequencing. We tested the association of 32.5 million sequence variants in 424 cases and 337 689 population controls in Iceland. RESULTS: We identified 2 DCM variants in established cardiomyopathy genes, a missense variant p.Phe145Leu in NKX2-5 carried by 1 in 7100 Icelanders ( P=7.0×10-12) and a frameshift variant p.Phe1626Serfs*40 in FLNC carried by 1 in 3600 Icelanders ( P=2.1×10-10). Both variants associate with heart failure and sudden cardiac death. Additionally, p.Phe145Leu in NKX2-5 associates with high degree atrioventricular block and atrial septal defect ( P<1.4×10-4). The penetrance of serious heart disease among carriers of the NKX2-5 variant is high and higher than that of the FLNC variant. CONCLUSIONS: Two rare variants in NKX2-5 and FLNC, carried by 1 in 2400 Icelanders, cause familial DCM in Iceland. These genes have recently been associated with DCM. Given the serious consequences of these variants, we suggest screening for them in individuals with DCM and their family members, with subsequent monitoring of carriers, offering early intervention.