Reconstitution of ß-adrenergic regulation of CaV1.2: Rad-dependent and Rad-independent protein kinase A mechanisms.

L-type voltage-gated CaV1.2 channels crucially regulate cardiac muscle contraction. Activation of ß-adrenergic receptors (ß-AR) augments contraction via protein kinase A (PKA)-induced increase of calcium influx through CaV1.2 channels. To date, the full ß-AR cascade has never been heterologously reconstituted. A recent study identified Rad, a CaV1.2 inhibitory protein, as essential for PKA regulation of CaV1.2. We corroborated this finding and reconstituted the complete pathway with agonist activation of ß1-AR or ß2-AR in Xenopus oocytes. We found, and distinguished between, two distinct pathways of PKA modulation of CaV1.2: Rad dependent (∼80% of total) and Rad independent. The reconstituted system reproduces the known features of ß-AR regulation in cardiomyocytes and reveals several aspects: the differential regulation of posttranslationally modified CaV1.2 variants and the distinct features of ß1-AR versus ß2-AR activity. This system allows for the addressing of central unresolved issues in the ß-AR-CaV1.2 cascade and will facilitate the development of therapies for catecholamine-induced cardiac pathologies.

HeartMate 3: new challenges in ventricular tachycardia ablation.

AIM: To describe clinical characteristics, procedural details, specific challenges, and outcomes in patients with HeartMate3™ (HM3), a left ventricular assist device system with a magnetically levitated pump, undergoing ventricular tachycardia ablation (VTA). METHODS AND RESULTS: Data were collected from patients with an HM3 system who underwent VTA in seven tertiary centres. Data included baseline patient characteristics, procedural data, mortality, and arrhythmia-free survival. The study cohort included 19 patients with cardiomyopathy presenting with ventricular tachycardia (VT) (53% with VT storm). Ventricular tachycardias were induced in 89% of patients and a total of 41 VTs were observed. Severe electromagnetic interference was present on the surface electrocardiogram. Hence, VT localization required analysis of intra-cardiac signals or the use of filter in the 40-20 Hz range. The large house pump HM3 design obscured the cannula inflow and therefore multi imaging modalities were necessary to avoid catheter entrapment in the cannula. A total of 32 VTs were mapped and were successfully ablated (31% to the anterior wall, 38% to the septum and only 9% to the inflow cannula region). Non-inducibility of any VT was reached in 11 patients (58%). Over a follow-up of 429 (interquartile range 101-692) days, 5 (26%) patients underwent a redo VT ablation due to recurrent VTA and 2 (11%) patients died. CONCLUSIONS: Ventricular tachycardia ablation in patients with HM3 is feasible and safe when done in the appropriate setup. Long-term arrhythmia-free survival is acceptable but not well predicted by non-inducibility at the end of the procedure.

Bicuspid aortic valve area in normal heart.

INTRODUCTION: Bicuspid aortic valve (BAV) is a common congenital valve abnormality. There are no data in the literature regarding the range of aortic valve area (AVA) in normal functioning BAV. We aimed to evaluate the normal range of BAV area and to compare it to subjects with tricuspid aortic valve (TAV). METHODS: Bicuspid aortic valve subjects were identified from Sheba medical center echocardiographic database and were compared with TAV subjects. Inclusion criteria were normal tissue leaflets appearance and normal functioning valve in the presence of normal echocardiogram. Echocardiographic data, patients hemodynamics, and size were collected. AVA was measured with both planimetry and the continuity equation. RESULTS: Fifty BAV and 50 control subjects were studied (37 men, age 40 ± 13 years). All studies were performed with normal hemodynamics. Fusion between the coronary leaflets was the most common morphology (82%), followed by fusion between the right coronary leaflet with the noncoronary leaflet (18%). The left ventricular outflow tract (LVOT) diameter in BAV group was significantly larger (2.3 ± 0.3 cm vs 2.1 ± 0.2; P < .001). The BAV group presented with a larger AVA planimetry (3.8 ± 0.9 vs 3.3 ± 0.6; P < .001). However, measuring AVA using continuity equation has shown no differences between groups. If using the principles of coefficient of contraction, it seems that measuring AVA by planimetry overestimates the real anatomic AVA. CONCLUSION: This data provide normal values for echocardiographically determined AVA in BAV subjects. This population was characterized by large LVOT diameter and large AVA. The larger AVA measured with the planimetry emphasizes the limitation of this method in BAV population.

Risk of early, intermediate, and late rejection following heart transplantation: Trends over the past 25 years and relation to changes in medical management. Tertiary center experience: The Sheba Heart Transplantation Registry.

AIM: To explore the trends in the risk for rejection following heart transplantation (HT) over the past 25 years, and their relation to changes in medical management. METHODS: The study population comprised 216 HT patients. Rejection periods were defined as follows: 0-3 months (early), 3-12 months (intermediate), and 12+ months (late). HT era was dichotomized as follows: 1991-1999 (remote era) and 2000-2016 (recent era). Medication combination was categorized as newer (TAC, MMF, and everolimus) vs older therapies (AZA, CSA). RESULTS: Multivariate analysis showed that patients who underwent HT during the recent era experienced a significant reduction in the risk for major rejection. These findings were consistent for early (OR = 0.44 [95% CI 0.22-0.88]), intermediate (OR = 0.02 [95% CI 0.003-0.11]), and late rejections (OR = 0.18 [95% CI 0.05-0.52]). Using the year of HT as a continuous measure showed that each 1-year increment was independently associated with a significant reduction in the risk for early, intermediate, and late rejections (5%, 21%, 18%, respectively). In contrast, the risk reduction associated with newer types of immunosuppressive therapies was not statistically significant after adjustment for the treatment period. CONCLUSIONS: Major rejection rates following HT have significantly declined over the past 2 decades even after adjustment for changes in immunosuppressive therapies, suggesting that other factors may also play a role in the improved outcomes of HT recipients.

Early aspirin initiation following heart transplantation is associated with reduced risk of allograft vasculopathy during long-term follow-up.

AIM: Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality after heart transplantation (HT). Enhanced platelet reactivity is a contributing factor. We aimed to investigate the association between early initiation of aspirin therapy post-HT and the 15-year risk of the development of CAV. METHODS: We studied 206 patients who underwent HT between 1991 and 2016. Multivariate Cox proportional hazards regression modeling was employed to evaluate the association between early aspirin initiation and the long-term risk of CAV. RESULTS: Ninety-seven patients (47%) received aspirin therapy. At 15 years of follow-up, the rate of CAV was lowered by sixfold in patients treated with aspirin compared with the non-treated patients: 7% vs 37% (log-rank P-value<.001). The corresponding rates of the combined end-point of CAV or death were also lower in patients treated with aspirin, compared with the non-treated patients: 42% vs 78% (log-rank P < .001). Consistently, multivariate analysis showed that early aspirin therapy was associated with a significant 84% (P < .001) reduction in CAV risk, and with a corresponding 68% (P < .0001) reduction in the risk of the combined end-point of CAV or death. We further validated these results using a propensity score-adjusted Cox model. CONCLUSIONS: Early aspirin initiation is independently associated with a significant reduction in the risk of CAV.

Conduction velocity is reduced in the posterior wall of hypertrophic cardiomyopathy patients with normal bipolar voltage undergoing ablation for paroxysmal atrial fibrillation.

OBJECTIVES: We investigated characteristics of left atrial conduction in patients with HCM, paroxysmal AF and normal bipolar voltage. BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) exhibit abnormal cardiac tissue arrangement. The incidence of atrial fibrillation (AF) is increased fourfold in patients with HCM and confers a fourfold increased risk of death. Catheter ablation is less effective in HCM, with twofold increased risk of AF recurrence. The mechanisms of AF perpetuation in HCM are poorly understood. METHODS: We analyzed 20 patients with HCM and 20 controls presenting for radiofrequency ablation of paroxysmal AF normal left atrial voltage(> 0.5 mV). Intracardiac electrograms were extracted from the CARTO mapping system and analyzed using Matlab/Python code interfacing with Core OpenEP software. Conduction velocity maps were calculated using local activation time gradients. RESULTS: There were no differences in baseline demographics, atrial size, or valvular disease between HCM and control patients. Patients with HCM had significantly reduced atrial conduction velocity compared to controls (0.44 ± 0.17 vs 0.56 ± 0.10 m/s, p = 0.01), despite no significant differences in bipolar voltage amplitude (1.23 ± 0.38 vs 1.20 ± 0.41 mV, p = 0.76). There was a statistically significant reduction in conduction velocity in the posterior left atrium in HCM patients relative to controls (0.43 ± 0.18 vs 0.58 ± 0.10 m/s, p = 0.003), but not in the anterior left atrium (0.46 ± 0.17 vs 0.55 ± 0.10 m/s, p = 0.05). There was a significant association between conduction velocity and interventricular septal thickness (slope = -0.013, R2 = 0.13, p = 0.03). CONCLUSIONS: Atrial conduction velocity is significantly reduced in patients with HCM and paroxysmal AF, possibly contributing to arrhythmia persistence after catheter ablation.

Risk of malignant ventricular arrhythmias in patients with mildly to moderately reduced ejection fraction after permanent pacemaker implantation.

BACKGROUND: Many patients with mildly to moderately reduced left ventricular ejection fraction (LVEF) who require permanent pacemaker (PPM) implantation do not have a concurrent indication for implantable cardioverter-defibrillator (ICD) therapy. However, the risk of ventricular tachycardia/ventricular fibrillation (VT/VF) in this population is unknown. OBJECTIVE: The aim of this study was to describe the risk of VT/VF after PPM implantation in patients with mildly to moderately reduced LVEF. METHODS: Retrospective analysis was performed of 243 patients with LVEF between 35% and 49% who underwent PPM placement and did not meet indications for an ICD. The primary end point was occurrence of sustained VT/VF. Competing risks regression was performed to calculate subhazard ratios for the primary end point. RESULTS: Median follow-up was 27 months; 73% of patients were male, average age was 79 ± 10 years, average LVEF was 42% ± 4%, and 70% were New York Heart Association class II or above. Most PPMs were implanted for sick sinus syndrome (34%) or atrioventricular block (50%). Of 243 total patients, 11 (4.5%) met the primary end point of VT/VF. Multivessel coronary artery disease (CAD) was associated with significantly higher rates of VT/VF, with a subhazard ratio of 5.4 (95% CI, 1.5-20.1; P = .01). Of patients with multivessel CAD, 8 of 82 (9.8%) patients met the primary end point for an annualized risk of 4.3% per year. CONCLUSION: Patients with mildly to moderately reduced LVEF and multivessel CAD undergoing PPM implantation are at increased risk for the development of malignant ventricular arrhythmias. Patients in this population may benefit from additional risk stratification for VT/VF and consideration for upfront ICD implantation.

A membrane-associated phosphoswitch in Rad controls adrenergic regulation of cardiac calcium channels.

The ability to fight or flee from a threat relies on an acute adrenergic surge that augments cardiac output, which is dependent on increased cardiac contractility and heart rate. This cardiac response depends on ß-adrenergic-initiated reversal of the small RGK G protein Rad-mediated inhibition of voltage-gated calcium channels (CaV) acting through the Cavß subunit. Here, we investigate how Rad couples phosphorylation to augmented Ca2+ influx and increased cardiac contraction. We show that reversal required phosphorylation of Ser272 and Ser300 within Rad's polybasic, hydrophobic C-terminal domain (CTD). Phosphorylation of Ser25 and Ser38 in Rad's N-terminal domain (NTD) alone was ineffective. Phosphorylation of Ser272 and Ser300 or the addition of 4 Asp residues to the CTD reduced Rad's association with the negatively charged, cytoplasmic plasmalemmal surface and with CaVß, even in the absence of CaVα, measured here by FRET. Addition of a posttranslationally prenylated CAAX motif to Rad's C-terminus, which constitutively tethers Rad to the membrane, prevented the physiological and biochemical effects of both phosphorylation and Asp substitution. Thus, dissociation of Rad from the sarcolemma, and consequently from CaVß, is sufficient for sympathetic upregulation of Ca2+ currents.

"Body packers" in Israel: a case series.

BACKGROUND: "Body packers" swallow multiple packets filled with illicit drugs, mainly cocaine, in order to smuggle them across international borders. In recent years, an increasing number of body packers have been hospitalized after their detention by the police upon arrival in Israel. OBJECTIVES: To characterize the clinical features and outcomes of body packers hospitalized at the Sheba Medical Center. METHODS: We conducted a retrospective case series of body packers hospitalized between January 2010 and October 2012 in our medical center. Electronic medical records and imaging files were reviewed to extract clinical, laboratory and radiological data as well as details on medical treatments. RESULTS: We identified 23 body packers (mean age 38 +/- 10 years), 20 of whom smuggled cocaine from South America. The number of packets transported ranged from 1 to 242 (median 42) and duration of hospitalization from 1 to 14 days (median 2). Two subjects required surgical intervention. All others were treated conservatively by polyethylene glycol-electrolyte lavage solution, laxatives, or watchful waiting. Ten patients underwent a urinary screen for illicit drugs, 7 of whom tested positive for cocaine and 2 for cannabinoids. Abdominal X-rays were performed in all patients at admission, and 14 had follow-up imaging, including abdominal CT scans without contrast media in 8. CONCLUSIONS: The main treatment goals for body packers are the rapid excretion of drug packets and early detection of complications, i.e., drug intoxication and bowel obstruction. We suggest the use of a structured treatment approach for the in-hospital management of body packers.

Long-Term Outcomes of Tachycardia-Induced Cardiomyopathy Compared with Idiopathic Dilated Cardiomyopathy.

BACKGROUND: data on the natural course and prognosis of tachycardia-induced cardiomyopathy (TICMP) and comparison with idiopathic dilated cardiomyopathies (IDCM) are scarce. OBJECTIVE: To compare the clinical presentation, comorbidities, and long-term outcomes of TICMP patients with IDCM patients. METHODS: a retrospective cohort study of patients hospitalized with new-onset TICMP or IDCM. The primary endpoint was a composite of death, myocardial infarction, thromboembolic events, assist device, heart transplantation, and ventricular tachycardia or fibrillation (VT/VF). The secondary endpoint was recurrent hospitalization due to heart failure (HF) exacerbation. RESULTS: the cohort was comprised of 64 TICMP and 66 IDCM patients. The primary composite endpoint and all-cause mortality were similar between the groups during a median follow-up of ~6 years (36% versus 29%, p = 0.33 and 22% versus 15%, p = 0.15, respectively). Survival analysis showed no significant difference between TICMP and IDCM groups for the composite endpoint (p = 0.75), all-cause mortality (p = 0.65), and hospitalizations due to heart failure exacerbation. Nonetheless, the incidence of recurrent hospitalization was significantly higher in TICMP patients (incidence rate ratio 1.59; p = 0.009). CONCLUSIONS: patients with TICMP have similar long-term outcomes as those with IDCM. However, it portends a higher rate of HF readmissions, mostly due to arrhythmia recurrences.

Reply to Kataoka, N.; Imamura, T. How to Improve Clinical Outcomes in Patients with Tachycardia-Induced Cardiomyopathy. Comment on "Katz et al. Long-Term Outcomes of Tachycardia-Induced Cardiomyopathy Compared with Idiopathic Dilated Cardiomyopathy. J. Clin. Med. 2023, 12, 1412".

In a letter to the editor titled "How to improve clinical outcomes in patients with tachycardia-induced cardiomyopathy", Dr. Naoya Kataoka and Dr. Teruhiko Imamura [...].

The clinical outcomes of patients who developed typical atrial flutter on class 1C anti arrhythmic medications treated with hybrid approach.

INTRODUCTION: A common approach to patients, who developed atrial flutter secondary to treatment with class 1C anti-arrhythmic drugs for atrial fibrillation (AF) (1C flutter), is a hybrid approach: ablation of the Cavo-Tricuspid isthmus (CTI) and continuation 1C medical treatment to prevent recurrence of AF. We aim to explore the clinical outcome of patients treated in this approach. METHODS AND RESULTS: Two hundred and four consecutive patients who underwent ablation for typical AFL at a tertiary medical center between 2010 and 2016 were enrolled and followed up. The clinical outcome of patient treated by the hybrid approach (treatment group; n = 67) was compared to patient without history of AF (control group; n = 137). The primary endpoint was time to occurrence of AF. Twenty-eight (41.8%) patients in treatment group had AF occurrence in 1 year, including 9 (13.4%) patients who needed to escalate anti-arrhythmic drug treatment to class III, and 11 (16.4%) patients who underwent AF ablation. In comparison, only 21 (15.3%) patients in control group had occurrence during the first year after ablation. The median time from ablations till AF occur was 106 ± 481 days in treatment group, and 403 ± 668 days in control group (P < .01). CONCLUSIONS: There is a relatively high rate of AF recurrence in patients treated with the hybrid approach during the first year after CTI ablation. An alternative approach should be considered in this selected population.

The impact of gender mismatching on early and late outcomes following heart transplantation.

AIMS: The role of donor/recipient gender matching on the long-term rejection process and clinical outcomes following heart transplantation (HT) outcomes is still controversial. We aim to investigate the impact of gender matching on early and long-term outcome HT. METHODS AND RESULTS: The study population comprised 166 patients who underwent HT between 1991 and 2013 and were prospectively followed up in a tertiary referral centre. Early and late outcomes were assessed by the type of donor-recipient gender match (primary analysis: female donor-male recipient [FD-MR, n = 36] vs. male donor-male recipient [MD-MR, n = 109]). Early mortality, need for inotropic support, length of hospital stay, and major perioperative adverse events did not differ between the FD-MR and MD-MR groups. However, the FD-MR group experienced significantly higher rates of early major rejections per patient as compared with the MD-MR group (1.2 ± 1.6 vs. 0.4 ± 0.8; P = 0.001), higher rates of overall major rejections (16 vs. 5.5 per 100 person years; P < 0.05), and higher rate of cardiac allograft vasculopathy (43% vs. 20%; P = 0.01). Kaplan-Meier survival analysis showed that the cumulative probabilities of survival free of rejections and major adverse events were significantly higher in MD-MR group (P = 0.002 and 0.001, respectively). Multivariate analysis showed that FD-MR status was associated with >2.5-fold (P = 0.03) increase in the risk for rejections and with a >3-fold (P = 0.01) increase in the risk for major adverse events during follow-up. CONCLUSIONS: Donor-recipient gender mismatch is a powerful independent predictor of early and late rejections and long-term major adverse events following HT.

Metformin therapy reduces the risk of malignancy after heart transplantation.

BACKGROUND: Malignancy and diabetes mellitus (DM) cause significant morbidity and mortality after heart transplantation (HTx). Metformin, one of the most commonly used anti-diabetic drugs worldwide, has also been shown to exhibit anti-tumor activity. We therefore investigated the association between metformin therapy and malignancy after HTx. METHODS: The study population comprised 237 patients who underwent HTx between 1991 and 2016 and were prospectively followed-up. Clinical data were recorded on prospectively designed forms. The primary outcome was any cancer recorded during 15 years of follow-up. Treatment with metformin and the development of DM after HTx were assessed as time-dependent factors in the analyses. RESULTS: Of the 237 study patients, 85 (36%) had diabetes. Of the DM patients, 48 (56%) were treated with metformin. Kaplan-Meier survival analysis showed that, at 15 years after HTx, malignancy rate was 4% for DM patients treated with metformin, 62% for those who did not receive metformin and 27% for non-DM patients (log-rank test, p < 0.0001). Consistently, multivariate analysis showed that for DM patients, metformin therapy was independently associated with a significant 90% reduction (hazard ratio = 0.10; 95% confidence interval 0.02 to 0.40; p = 0.001) in the risk of the development of a malignancy. DM patients who were treated with metformin had a markedly lower risk (65%; p = 0.001) for the development of a malignancy or death after HTx as compared with non-DM patients. CONCLUSIONS: Our findings suggest that metformin therapy is independently associated with a significant reduction in the risk of malignancy after HTx.

Chewing versus Swallowing Ticagrelor to Accelerate Platelet Inhibition in Acute Coronary Syndrome - the CHEERS study. For The PLATIS (Platelets and Thrombosis in Sheba) Study Group.

It was the study objective to evaluate whether chewing a 180 mg loading dose of ticagrelor versus an equal dose of traditional oral administration, enhances inhibition of platelet aggregation 1 hour (h) after administering a ticagrelor loading dose in non-ST elevation myocardial infarction (NSTEMI) patients. Dual anti-platelet therapy represents standard care for treating NSTEMI patients. Ticagrelor is a direct acting P2Y12 inhibitor and, unlike clopidogrel and prasugrel, does not require metabolic activation. Fifty NSTEMI patients were randomised to receive either a chewing loading dose of 180 mg ticagrelor or an equal standard oral dose of ticagrelor. Platelet reactivity was evaluated by VerifyNow at baseline, 1 and 4 h post-loading dose. Results are reported in P2Y12 reaction units. Patients then continued to receive standard 90 mg oral ticagrelor twice daily. Baseline characteristics did not differ between the two groups. P2Y12 reaction units in the chewing group compared with the standard group at 0, 1 and 4 h after ticagrelor loading dose were: 245 vs 239 (p=0.59), 45 vs 130 (p=0.001) and 39 vs 60 (p=0.12), respectively, corresponding to a relative inhibition of platelet aggregation of 83 % vs only 47 % at 1 h (p< 0.001), and 84 % vs 77 % (p=0.59) at 4 h. Major adverse cardiac and cardiovascular events at 30 days were low (2 %), occurring in only one patient in the standard group. In conclusion, chewing a 180 mg ticagrelor loading dose is feasible and facilitates both faster and improved early inhibition of platelet aggregation in NSTEMI patients, compared with a standard oral-loading dose.

Effect of Chewing vs Swallowing Ticagrelor on Platelet Inhibition in Patients With ST-Segment Elevation Myocardial Infarction: A Randomized Clinical Trial.

Importance: Dual anti-platelet therapy represents standard care for treating patients with ST-segment elevation myocardial infarction (STEMI). Ticagrelor is a direct-acting P2Y12 inhibitor and, unlike clopidogrel and prasugrel, does not require metabolic activation. Objective: To evaluate whether chewing a loading dose (LD) of ticagrelor, 180 mg, vs traditional oral administration of an equal dose enhances platelet inhibition at 30 minutes and 1 hour after LD administration in patients with STEMI. Design, Setting, and Participants: A randomized clinical trial was conducted in adults aged 30 to 87 years from May to October 2016 in a large tertiary care center. Analyses were intention-to-treat. Interventions: Fifty patients with STEMI were randomized to either chewing an LD of ticagrelor, 180 mg, or standard oral administration of an equal dose. Main Outcomes and Measures: P2Y12 reaction units were evaluated using VerifyNow (Accumentrics) at baseline, 30 minutes, 1 hour, and 4 hours after LD. Results: Baseline characteristics were similar in both groups. The mean (SD) of P2Y12 reaction units in the chewing group compared with the standard group at baseline, 30 minutes, 1 hour, and 4 hours after ticagrelor LD were 224 (33) vs 219 (44) (95% CI, -16.77 to 27.73; P = .26), 168 (78) vs 230 (69) (95% CI, -103.77 to -19.75; P = .003), 106 (90) vs 181 (89) (95% CI, -125.15 to -26.29; P = .005), and 43 (41) vs 51 (61) (95% CI, -36.34 to 21.14; P = .30), respectively. Platelet reactivity in the chewing group was significantly reduced by 24% at 30 minutes after LD (95% CI, 19.75 to 103.77; P = .001). The relative inhibition of platelet aggregation in the chewing vs the standard group were 51% vs 10% (95% CI, 13.69 to 67.67; P = .005) at 1 hour and 81% vs 76% (95% CI, -12.32 to 16.79; P = .24) at 4 hours, respectively. Major adverse cardiac and cardiovascular event rate at 30 days was low (4%) and occurred in 1 patient in each group (95% CI, 0.06 to 16.93; P > .99). Conclusions and Relevance: Chewing an LD of ticagrelor, 180 mg, in patients with STEMI is feasible and facilitates better early platelet inhibition compared with a standard oral LD. Larger studies are warranted to see if our preliminary findings translate into clinical outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT02725099.

Exercise systolic blood pressure variability is associated with increased risk for new-onset hypertension among normotensive adults.

Both resting blood pressure (BP) variability and exercise BP previously showed association with incident hypertension. The aim of the present study was to examine whether visit-to-visit variability in exercise systolic blood pressure (SBP) can predict the risk for new-onset hypertension among normotensive adults. We investigated 6546 normotensive men and women who were annually screened in a tertiary medical center and completed treadmill exercise tests at each visit. Based on the initial three baseline annual visits, long-term intervisit variability of exercise SBP among the three tests was measured using standard deviation (SD) and coefficient of variation for each participant. The rate of newly diagnosed hypertension was measured in different variability levels during 6 ± 3 years of follow-up. Multivariate analysis adjusted for various clinical factors, including resting BP, showed that each 5 mm Hg rise in the SD of exercise SBP resulted in a significant 5% increase in the risk for the development of future hypertension (P = .015). Subjects in the upper exercise SBP SD variability tertile had a 28% (P = .007) increased risk for hypertension during follow-up, as compared with those in the lowest tertile. Similar results were achieved for the assessment of coefficient of variation of exercise SBP. In conclusion, visit-to-visit variability in exercise SBP can predict the development of future hypertension among normotensive individuals.

Programmed deep brain stimulation synchronizes VTA gamma band field potential and alleviates depressive-like behavior in rats.

Deep brain stimulation (DBS) significantly alleviates symptoms in various neurological disorders. Current research focuses on developing programmed stimulation protocols for customization to individual symptoms. However, the therapeutic mechanism of action of programmed DBS (pDBS) is poorly understood. We previously demonstrated that pDBS in the ventral tegmental area (VTA) normalizes molecular and behavioral abnormalities in the Flinders Sensitive Line (FSL) rat model for depression. Herein, we examined the effect of a short-duration, low-frequency DBS template on local field potential (LFP) synchronization patterns along the anterior-posterior axis of the VTA of FSL rats, and correlation of this effect with depressive-like behavior, as compared with non-programmed, continuous low-frequency DBS (npDBS). We used the wavelet phase coherence (WPC) measure for effective representation of time and frequency of LFP patterns, and the forced swim test to measure immobility (despair). Baseline WPC values were lower in FSLs as compared with SD controls, at the low and high gamma frequency range (above 30 Hz). Baseline immobility scores for FSL rats were higher than those of SD rats, while pDBS, and not npDBS, significantly reduced FSL immobility scores to control SD levels, up to day 14. pDBS also significantly increased the change (between baseline and day 14) in WPC values, in beta, low gamma and high gamma frequency ranges. The change in high gamma (60-100 Hz) WPC values correlated with improvement in depressive-like behavior. Our results suggest that programmed DBS of the VTA increases interaction among local neuronal populations, an effect that may underlie the normalization of depressive-like behavior.

Exercise blood pressure and the risk for future hypertension among normotensive middle-aged adults.

BACKGROUND: The aim of the present study was to examine whether exercise blood pressure can be used to predict the development of hypertension in normotensive middle-aged adults. METHODS AND RESULTS: We investigated 7082 normotensive subjects who were annually screened in a tertiary medical center and completed maximal treadmill exercise tests at each visit. After the initial 3 years, subjects were divided into approximate quartiles according to their average exercise systolic and diastolic blood pressure responses (≤158; 158 to 170; 170 to 183; ≥183 mm Hg for systolic blood pressure and ≤73; 73 to 77; 77 to 82; ≥82 mm Hg for diastolic blood pressure). Mean age of the study population was 48 ± 9 years and 73% were men. Average baseline resting blood pressure was 120/77 ± 12/7 mm Hg. During a follow-up of 5 ± 3 years, 1036 (14.6%) subjects developed hypertension. The cumulative probability of new-onset hypertension at 5 years was significantly increased with increasing quartiles of exercise systolic blood pressure (5%, 9%, 17%, and 35%, respectively; P<0.001), with a similar association shown for diastolic blood pressure. After adjustment for baseline resting blood pressure and clinical parameters, each 5-mm Hg increments in exercise either systolic or diastolic blood pressures were independently associated with respective 11% (P<0.001) and 30% (P<0.001) increased risk for the development of hypertension. CONCLUSIONS: In normotensive middle-aged individuals, blood pressure response to exercise is associated with future development of hypertension.