Risk Prediction in Male Adolescents With Congenital Long QT Syndrome: Implications for Sex-Specific Risk Stratification in Potassium Channel-Mediated Long QT Syndrome.

BACKGROUND: Sex-specific risk management may improve outcomes in congenital long QT syndrome (LQTS). We recently developed a prediction score for cardiac events (CEs) and life-threatening events (LTEs) in postadolescent women with LQTS. In the present study, we aimed to develop personalized risk estimates for the burden of CEs and LTEs in male adolescents with potassium channel-mediated LQTS. METHODS AND RESULTS: The prognostic model was derived from the LQTS Registry headquartered in Rochester, NY, comprising 611 LQT1 or LQT2 male adolescents from age 10 through 20 years, using the following variables: genotype/mutation location, QTc-specific thresholds, history of syncope, and ß-blocker therapy. Anderson-Gill modeling was performed for the end point of CE burden (total number of syncope, aborted cardiac arrest, and appropriate defibrillator shocks). The applicability of the CE prediction model was tested for the end point of the first LTE (excluding syncope and adding sudden cardiac death) using Cox modeling. A total of 270 CEs occurred during follow-up. The genotype-phenotype risk prediction model identified low-, intermediate-, and high-risk groups, comprising 74%, 14%, and 12% of the study population, respectively. Compared with the low-risk group, high-risk male subjects experienced a pronounced 5.2-fold increased risk of recurrent CEs (P<0.001), whereas intermediate-risk patients had a 2.1-fold (P=0.004) increased risk . At age 20 years, the low-, intermediate-, and high-risk adolescent male patients had on average 0.3, 0.6, and 1.4 CEs per person, respectively. Corresponding 10-year adjusted probabilities for a first LTE were 2%, 6%, and 8%. CONCLUSIONS: Personalized genotype-phenotype risk estimates can be used to guide sex-specific management in male adolescents with potassium channel-mediated LQTS.

Use of oral contraceptives in women with congenital long QT syndrome.

BACKGROUND: Use of oral contraceptives (OCs) may modulate the clinical course of women with congenital long QT syndrome (LQTS). The safety of OC use by sex hormone content has not been assessed in women with LQTS. OBJECTIVE: We aimed to evaluate the association of OCs with the risk of cardiac events (CEs) in women with LQTS. METHODS: Beginning in 2010, information on menarche onset, OC use, pregnancy, and menopause were obtained from women enrolled in the Rochester LQTS Registry. Type of OC was categorized as progestin-only, estrogen-only, or combined (estrogen/progestin). Andersen-Gill multivariate modeling was used to evaluate the association of time-dependent OC use with the burden of CE (total number of syncope, aborted cardiac arrest, and LQTS-related sudden cardiac death) from menarche onset through 40 years. Findings were adjusted for genotype, corrected QT duration, and time-dependent ß-blocker therapy. RESULTS: A total of 1659 women with LQTS followed through March 2021, of whom 370 (22%) were treated with an OC. During a cumulative follow-up of 35,797 years, there were a total of 2027 CE. Multivariate analysis showed that progestin-only OC was associated with a pronounced 2.8-fold (P = .01) increased risk of CEs in women who did not receive ß-blocker therapy, while ß-blockers were highly protective during progestin-only OC treatment (hazard ratio 0.22; P = .01; P = .006 for ß-blocker-by-OC interaction). The risk associated with OC use without concomitant ß-blocker treatment was pronounced in women with LQTS type 2. CONCLUSION: Our findings suggest that progestin-only OC should not be administered in women with LQTS without concomitant ß-blocker therapy. OCs should be used with caution in women with LQTS type 2.

Human RyR2 (Ryanodine Receptor 2) Loss-of-Function Mutations: Clinical Phenotypes and In Vitro Characterization.

[Figure: see text].

Risk Prediction in Women With Congenital Long QT Syndrome.

Background We aimed to provide personalized risk estimates for cardiac events (CEs) and life-threatening events in women with either type 1 or type 2 long QT. Methods and Results The prognostic model was derived from the Rochester Long QT Syndrome Registry, comprising 767 women with type 1 long QT (n=404) and type 2 long QT (n=363) from age 15 through 60 years. The risk prediction model included the following variables: genotype/mutation location, QTc-specific thresholds, history of syncope, and ß-blocker therapy. A model was developed with the end point of CEs (syncope, aborted cardiac arrest, or long QT syndrome-related sudden cardiac death), and was applied with the end point of life-threatening events (aborted cardiac arrest, sudden cardiac death, or appropriate defibrillator shocks). External validation was performed with data from the Mayo Clinic Genetic Heart Rhythm Clinic (N=467; type 1 long QT [n=286] and type 2 long QT [n=181]). The cumulative follow-up duration among the 767 enrolled women was 22 243 patient-years, during which 323 patients (42%) experienced ≥1 CE. Based on genotype-phenotype data, we identified 3 risk groups with 10-year projected rates of CEs ranging from 15%, 29%, to 51%. The corresponding 10-year projected rates of life-threatening events were 2%, 5%, and 14%. C statistics for the prediction model for the 2 respective end points were 0.68 (95% CI 0.65-0.71) and 0.71 (95% CI 0.66-0.76). Corresponding C statistics for the model in the external validation Mayo Clinic cohort were 0.65 (95% CI 0.60-0.70) and 0.77 (95% CI 0.70-0.84). Conclusions This is the first risk prediction model that provides absolute risk estimates for CEs and life-threatening events in women with type 1 or type 2 long QT based on personalized genotype-phenotype data. The projected risk estimates can be used to guide female-specific management in long QT syndrome.

Predictors of Atrial Fibrillation During Long-Term Implantable Cardiac Monitoring Following Cryptogenic Stroke.

Background Following cryptogenic stroke, guidelines recommend cardiac monitoring for occult atrial fibrillation (AF). We aimed to evaluate predictors of AF during long-term implantable cardiac monitoring. Methods and Results We studied 293 consecutive patients who underwent implantable cardiac monitor implant (Medtronic LINQ) following hospitalization for cryptogenic stroke at the University of Rochester Medical Center from January 2013 to September 2018. Multivariable Cox proportional hazards regression modeling was used to identify predictors of AF during long-term monitoring. At 36 months of follow-up, the cumulative rate of implantable cardiac monitor-detected AF events was 32% in the total study population. Multivariable analysis identified age ≥70 years as the most powerful predictor of the development of AF events during follow-up (hazard ratio, 2.28 [95% CI, 1.39-3.76]; P=0.001). Replacing age with the CHA2DS2-VASc (congestive heart failure, hypertension, age, diabetes mellitus, stroke, vascular disease, age, sex category) score resulted in a weaker association, for which each 1-point increment in the CHA2DS2-VASC score was associated with an 18% increased risk of developing AF (95% CI, 1.00-1.38; P=0.047). Consistent results were shown using Kaplan-Meier analysis by age and by the CHA2DS2VASc score. Conclusions Cryptogenic stroke patients continue to develop AF episodes during 36 months of implantable cardiac monitoring following the index event. Age is the most powerful predictor of occult AF in this population.

Fish and omega-3 fatty acid consumption and risk of hypertension.

BACKGROUND: Experimental studies suggest that omega-3 fatty acid have favorable effects on blood pressure (BP). However, data on the association of long-term dietary intake of omega-3 fatty acid or fish with risk of hypertension in healthy subjects are sparse. We examined whether fish or omega-3 fatty acid consumption was associated with incident hypertension in the Physicians' Health Study (PHS). METHODS: In a prospective cohort study, we analyzed data on 12 279 PHS participants (mean age: 53.0 ±â€Š8.7 years) free of hypertension at baseline. Fish and omega-3 fatty acid consumption were assessed from a baseline semiquantitative food-frequency questionnaire. Incident hypertension was ascertained via self-reports on annual follow-up questionnaires. RESULTS: During a mean follow-up of 15.8 years, 6299 men (51.3%) developed hypertension. In a multivariable model controlling for established risk factors for hypertension, fish and omega-3 fatty acid consumption was not significantly associated with incident hypertension. The hazard ratio (95% CI) of hypertension was 1.10 (0.93-1.30) for men who consumed at least five servings per week of fish compared with those who did not consume any fish (P for trend = 0.29). For the highest versus lowest quintile of omega-3 fatty acid intake, the hazard ratio of hypertension was 1.02 (0.94-1.11) (P for trend = 0.34). The associations did not vary by type of fish. There was also no evidence of effect modification by baseline BP, BMI, or history of hypercholesterolemia. CONCLUSION: Overall, long-term dietary intake of fish and omega-3 fatty acid was not associated with incident hypertension in a cohort of middle-aged and older US men.

Ambulatory Intra Aortic Balloon Pump in Advanced Heart Failure.

Cardiac transplantation is the gold standard treatment for patients with advanced congestive heart failure that is refractory to maximal medical therapy. However, donor heart availability remains the major limiting factor, resulting in a large number of patients waiting long periods of time before transplantation. As a result, mechanical circulatory support devices have been increasingly used as a 'bridge' in order to sustain organ function and stabilise haemodynamics while patients remain on the transplant waiting list or undergo left ventricular assist device surgery. Intra aortic balloon pumps (IABP) are commonly used for temporary circulatory support in patients with advanced heart failure. IABP is traditionally placed percutaneously through the transfemoral artery approach. The major limitation with this approach is ambulatory restriction that can promote deconditioning, particularly in situations of prolonged circulatory support. A subclavian/axillary artery approach IABP insertion allows patients to be ambulatory during the pre-transplant period. In this review, we aim to summarise the physiology of IABP, the evidence for its use in advanced CHF and the efficacy and safety of subclavian artery IABP insertion.

Impact of non-cardiovascular disease burden on thirty-day hospital readmission in heart failure patients.

BACKGROUND: Little is known about the impact of non-cardiovascular disease (CVD) burden on 30- -day readmission in heart failure (HF) patients. The aim of the study was to assess the role of non-CVD burden on 30-day readmission in HF patients. \ METHODS: We analyzed the effect of non-CVD burden by frequency of ICD-9 code categories on readmis-sions of patients discharged with a primary diagnosis of HF. We first modeled the probability of readmis-sion within 30 days as a function of demographic and clinical covariates in a randomly selected training dataset of the total cohort. Variable selection was carried out using a bootstrap LASSO procedure with 1000 bootstrap samples, the final model was tested on a validation dataset. Adjusted odds ratios and confidence intervals were reported in the validation dataset. RESULTS: There were a total of 6228 HF hospitalizations, 1523 (24%) with readmission within 30 days of discharge. The strongest predictor for 30-day readmissions was any hospital admission in the prior year (p < 0.001). Cardiovascular risk factors did not enter the final model. However, digestive system diseases increased the risk for readmission by 17% for each diagnosis (p = 0.046), while respiratory diseases and genitourinary diseases showed a trend toward a higher risk of readmission (p = 0.07 and p = 0.09, respectively). Non-CVDs out-competed cardiovascular covariates previously reported to predict readmission. CONCLUSIONS: In patients with HF hospitalization, prior admissions predicted 30-day readmission. Diseases of the digestive system also increase 30-day readmission rates. Assessment of non-CVD burden in HF patients could serve as an important risk marker for 30-day readmissions.

Device-Directed Therapy for Resistant Hypertension.

Hypertension remains a significant risk factor for an array of diseases despite advancements in pharmacotherapy. Patients with resistant hypertension who do not respond to conventional medical treatments and lifestyle modifications are especially at risk for poor health outcomes. With the increasing awareness of resistant hypertension, ever-evolving research efforts continue to focus on innovative interventions, including renal denervation, median nerve stimulation, and baroreceptor activation therapy. This article reviews the current evidence and summarizes previous clinical trials for each of these interventions.

Present and Future of Interventional Treatment of Resistant Hypertension.

The increasing prevalence of hypertension, a significant cause of disability and premature death throughout the world, is a major public health concern. This is especially true for the subset of patients who suffer from resistant hypertension, which is associated with a fourfold greater risk of cardiovascular events as compared to those hypertensive patients able to achieve target blood pressure. Though quite daunting in number and ill effect, hypertension remains the most common and the most important modifiable risk factor for coronary heart disease, congestive heart failure, peripheral vascular disease, stroke, and chronic kidney disease. Therefore, the ongoing development of novel therapies for the management of hypertension is of utmost importance. This review evaluates the present and future of interventional treatment of resistant hypertension, most of which remains investigational and warrants critical assessment.

Baroreceptor Stimulation for Resistant Hypertension.

Hypertension (HTN) is a worldwide epidemic. When untreated, HTN places patients at an elevated risk for several health conditions, including cardiovascular disease and end-organ damage. This effect is particularly pronounced in a subset of patients who experience treatment-resistant HTN despite the utilization of conventional medication and lifestyle interventions. For these challenging patients, ongoing research efforts continue to explore and develop novel nonpharmacologic therapies for resistant HTN. One such avenue is the regulation of the sympathetic nervous system, a large component of circulatory physiology. Innovative therapies have evolved to harness the ability to deliver electrical stimulation to baroreceptors in an effort to modulate the sympathetic system involvement in HTN. This review discusses baroreflex activation therapy and its role in the management of resistant HTN.

Predictors and clinical relevance of ventricular tachyarrhythmias in ambulatory patients with a continuous flow left ventricular assist device.

BACKGROUND: Patients with a left ventricular assist device (LVAD) are at high risk for ventricular tachyarrhythmias (VTAs). OBJECTIVE: We aimed to identify clinical predictors of VTAs and subsequent outcomes after VTA in ambulatory LVAD patients. METHODS: A retrospective study of 149 patients with a continuous flow HeartMate II LVAD who survived to discharge from index hospitalization after LVAD implantation was performed from January 10, 2005, to September 3, 2013. A multivariate Cox model was used to assess clinical predictors of VTAs. RESULTS: During a mean follow-up period of 2.1 ± 1.2 years, 41 patients (28%) experienced VTAs; 30 of these patients (71%) had ventricular tachycardia, and 11 (29%) had ventricular fibrillation. History of VTAs before LVAD (hazard ratio [HR] 3.06; 95% confidence interval [CI] 1.57-5.96; P = .001) and history of atrial fibrillation (AF) (HR 3.13; 95% CI 1.60-6.11; P = .008) were the most powerful predictors of VTAs after LVAD implantation. There were 19 deaths (46%) among patients with VTAs and 15 deaths (14%) among patients without VTAs (P < .001). In multivariate analysis, time-dependent VTAs after LVAD implantation were associated with a significantly higher risk of all-cause mortality when compared with those without VTAs (HR 7.28; 95% CI 3.50-15.15; P < .001). CONCLUSION: In ambulatory LVAD patients, history of VTAs before LVAD implantation and history of AF predict VTAs after LVAD implantation. VTAs are associated with an increased risk of mortality. In such patients, aggressive measures to control VTAs and AF should be considered.