Renal Denervation for the Treatment of Hypertension: A Scientific Statement From the American Heart Association.

Hypertension is a leading risk factor for cardiovascular morbidity and mortality. Despite the widespread availability of both pharmacological and lifestyle therapeutic options, blood pressure control rates across the globe are worsening. In fact, only 23% of individuals with high blood pressure in the United States achieve treatment goals. In 2023, the US Food and Drug Administration approved renal denervation, a catheter-based procedure that ablates the renal sympathetic nerves, as an adjunctive treatment for patients in whom lifestyle modifications and antihypertensive medications do not adequately control blood pressure. This approval followed the publication of multiple randomized clinical studies using rigorous trial designs, all incorporating renal angiogram as the sham control. Most but not all of the new generation of trials reached their primary end point, demonstrating modest efficacy of renal denervation in lowering blood pressure across a spectrum of hypertension, from mild to truly resistant. Individual patient responses vary, and further research is needed to identify those who may benefit most. The initial safety profile appears favorable, and multiple ongoing studies are assessing longer-term efficacy and safety. Multidisciplinary teams that include hypertension specialists and adequately trained proceduralists are crucial to ensure that referrals are made appropriately with full consideration of the potential risks and benefits. Incorporating patient preferences and engaging in shared decision-making conversations will help patients make the best decisions given their individual circumstances. Although further research is clearly needed, renal denervation presents a novel treatment strategy for patients with uncontrolled blood pressure.

Intracerebroventricular insulin injection acutely normalizes the augmented exercise pressor reflex in male rats with type 2 diabetes mellitus.

The exercise pressor reflex (EPR) is exaggerated in type 2 diabetes mellitus (T2DM), but the underlying central nervous system aberrations have not been fully delineated. Stimulation of muscle afferents within working skeletal muscle activates the EPR, by sending information to neurons in the brainstem, where it is integrated and results in reflexively increased mean arterial pressure (MAP) and sympathetic nerve activity. Brain insulin is known to regulate neural activity within the brainstem. We hypothesize that brain insulin injection in T2DM rats attenuates the augmented EPR, and that T2DM is associated with decreased brain insulin. Using male Sprague-Dawley rats, T2DM and control rats were generated via an induction protocol with two low doses of streptozotocin (35 and 25 mg/kg, i.p.) in combination with a 14-23-week high-fat diet or saline injections and a low-fat diet, respectively. After decerebration, MAP and renal sympathetic nerve activity (RSNA) were evaluated during EPR stimulation, evoked by electrically induced muscle contraction via ventral root stimulation, before and after (1 and 2 h post) intracerebroventricular (i.c.v.) insulin microinjections (500 mU, 50 nl). i.c.v. insulin decreased peak MAP (ΔMAP Pre (36 ± 14 mmHg) vs. 1 h (21 ± 14 mmHg) vs. 2 h (11 ± 6 mmHg), P < 0.05) and RSNA (ΔRSNA Pre (107.5 ± 40%), vs. 1 h (75.4 ± 46%) vs. 2 h (51 ± 35%), P < 0.05) responses in T2DM, but not controls. In T2DM rats, cerebrospinal fluid insulin was decreased (0.41 ± 0.19 vs. 0.11 ± 0.05 ng/ml, control (n = 14) vs. T2DM (n = 4), P < 0.01). The results demonstrated that insulin injections into the brain normalized the augmented EPR in brain hypoinsulinaemic T2DM rats, indicating that the EPR can be regulated by brain insulin. KEY POINTS: The reflexive increase in blood pressure and sympathetic nerve activity mediated by the autonomic nervous system during muscle contractions is also known as the exercise pressor reflex. The exercise pressor reflex is dangerously augmented in type 2 diabetes, in both rats and humans. In type 2 diabetic rats both cerebrospinal fluid insulin and phosphoinositide 3-kinase signalling within cardiovascular brainstem neurons decrease in parallel. Brain insulin injections decrease the magnitude of the reflexive pressor and sympathetic responses to hindlimb muscle contraction in type 2 diabetic rats. Partial correction of low insulin within the central nervous system in type 2 diabetes may treat aberrant exercise pressor reflex function.

Associations Between Cardiac Function and Brain Health in Diverse Middle-Aged Adults: The Dallas Heart Study-2.

Background: Previous studies have linked cardiovascular risk factors during midlife to cognitive function in later life. However, few studies have looked at the association between cardiac function, brain structure, and cognitive function and even less have included diverse middle-aged populations. Objectives: The objective of this study was to determine associations between cardiac and brain structure and function in a multiethnic cohort of middle-aged adults. Methods: A cross-sectional study was conducted in participants of the Dallas Heart Study phase 2 (N = 1,919; 46% Black participants). Left ventricular (LV) mass, LV ejection fraction, LV concentricity, and peak systolic strain (LV Ecc) were assessed by cardiac magnetic resonance imaging. White matter hyperintensities (WMH) volume was measured by fluid attenuated inversion recovery magnetic resonance imaging. The Montreal Cognitive Assessment was used to measure cognitive functioning. Associations between cardiac and brain measures were determined using multivariable linear regression after adjusting for cardiovascular risk factors, education level, and physical activity. Results: LV ejection fraction was associated with total Montreal Cognitive Assessment score (ß = 0.06 [95% CI: 0.003-0.12], P = 0.042) and LV Ecc was associated with WMH volume (ß = 0.08 [95% CI: 0.01-0.14], P = 0.025) in the overall cohort without significant interaction by race/ethnicity. Higher LV mass and concentricity were associated with larger WMH volume in the overall cohort (ß = 0.13 [95% CI: 0.03-0.23], P = 0.008 and 0.10 [95% CI: 0.03-0.17], P = 0.005). These associations were more predominant in Black than White participants (ß = 0.17 [95% CI: 0.04-0.30] vs ß = -0.009 [95% CI: -0.16 to 0.14], P = 0.036 and ß = 0.22 [95% CI: 0.13-0.32] vs ß = -0.11 [95% CI: -0.21 to -0.01], P < 0.0001, for LV mass and concentricity, respectively). Conclusions: Subclinical cardiac dysfunction indicated by LVEF was associated with lower cognitive function. Moreover, LV mass and concentric remodeling were associated with higher WMH burden, particularly among Black individuals.

High Blood Pressure Is Associated with Lower Brain Volume and Cortical Thickness in Healthy Young Adults.

BACKGROUND: High blood pressure (BP) in middle-aged and older adults is associated with lower brain volume and cortical thickness assessed with structural MRI. However, little evidence is available in young adults. We investigated the associations of high BP with brain volumes and cortical thickness in healthy young adults. METHODS: This cross-sectional study included 1095 young adults (54% women, 22-37 years) from the Human Connectome Project (HCP) who self-reported not having a history of hypertension or taking antihypertensive medications. Brachial systolic (SBP) and diastolic BP (DBP) were measured with semi-automatic or manual sphygmomanometer during study visits. Structural MRI was used to measure gray matter (GM) and white matter (WM) volume and mean cortical thickness. Associations of BP and hypertension stage with total and regional brain volumes and cortical thickness were analyzed using linear regression and analysis of covariance (ANCOVA) after adjusting for age, sex, education years, body mass index (BMI), smoking, alcohol consumption history, zygosity, and total intracranial volume. RESULTS: SBP and DBP were (mean ± SD) 123.6 ± 14.2 and 76.5 ± 10.6 mmHg, respectively (n = 1095). High DBP was associated with lower total GM (p = 0.012), cortical GM (p = 0.004), subcortical GM (p = 0.012), and total WM volumes (p = 0.031). High SBP and DBP were associated with lower regional cortical volume and cortical thickness. CONCLUSION: These findings suggest that high BP may have deleterious effects on brain health at the early stage of adulthood.

Association between dietary phosphate intake and skeletal muscle energetics in adults without cardiovascular disease.

Highly bioavailable inorganic phosphate (Pi) is present in large quantities in the typical Western diet and represents a large fraction of total phosphate intake. Dietary Pi excess induces exercise intolerance and skeletal muscle mitochondrial dysfunction in normal mice. However, the relevance of this to humans remains unknown. The study was conducted on 13 individuals without a history of cardiopulmonary disease (46% female, 15% Black participants) enrolled in the pilot-phase of the Dallas Heart and Mind Study. Total dietary phosphate was estimated from 24-h dietary recall (ASA24). Muscle ATP synthesis was measured at rest, and phosphocreatinine (PCr) dynamics was measured during plantar flexion exercise using 7-T 31P magnetic resonance (MR) spectroscopy in the calf muscle. Correlation was assessed between dietary phosphate intake normalized to total caloric intake, resting ATP synthesis, and PCr depletion during exercise. Higher dietary phosphate intake was associated with lower resting ATP synthesis (r = -0.62, P = 0.03), and with higher levels of PCr depletion during plantar flexion exercise relative to the resting period (r = -0.72; P = 0.004). These associations remain significant after adjustment for age and estimated glomerular filtration rate (both P < 0.05). High dietary phosphate intake was also associated with lower serum Klotho levels, and Klotho levels are in turn associated with PCr depletion and higher ADP accumulation post exercise. Our study suggests that higher dietary phosphate is associated with reduced skeletal muscle mitochondrial function at rest and exercise in humans providing new insight into potential mechanisms linking the Western diet to impaired energy metabolism.NEW & NOTEWORTHY This is the first translational research study directly demonstrating the adverse effects of dietary phosphate on muscle energy metabolism in humans. Importantly, our data show that dietary phosphate is associated with impaired muscle ATP synthesis at rest and during exercise, independent of age and renal function. This is a new biologic paradigm with significant clinical dietary implications.

HDL-C and apolipoprotein A-I are independently associated with skeletal muscle mitochondrial function in healthy humans.

Prior animal and cell studies have demonstrated a direct role of high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-I) in enhancing skeletal muscle mitochondrial function and exercise capacity. However, the relevance of these animal and cell investigations in humans remains unknown. Therefore, a cross-sectional study was conducted in 48 adults (67% female, 8% Black participants, age 39 ± 15.4 yr old) to characterize the associations between HDL measures, ApoA-I, and muscle mitochondrial function. Forearm muscle oxygen recovery time (tau) from postexercise recovery kinetics was used to assess skeletal muscle mitochondrial function. Lipoprotein measures were assessed by nuclear magnetic resonance. HDL efflux capacity was assessed using J774 macrophages, radiolabeled cholesterol, and apolipoprotein B-depleted plasma both with and without added cyclic adenosine monophosphate. In univariate analyses, faster skeletal muscle oxygen recovery time (lower tau) was significantly associated with higher levels of HDL cholesterol (HDL-C), ApoA-I, and larger mean HDL size, but not HDL cholesterol efflux capacity. Slower recovery time (higher tau) was positively associated with body mass index (BMI) and fasting plasma glucose (FPG). In multivariable linear regression analyses, higher levels of HDL-C and ApoA-I, as well as larger HDL size, were independently associated with faster skeletal muscle oxygen recovery times that persisted after adjusting for BMI and FPG (all P < 0.05). In conclusion, higher levels of HDL-C, ApoA-I, and larger mean HDL size were independently associated with enhanced skeletal muscle mitochondrial function in healthy humans.NEW & NOTEWORTHY Our study provides the first direct evidence supporting the beneficial role of HDL-C and ApoA-I on enhanced skeletal muscle mitochondrial function in healthy young to middle-aged humans without cardiometabolic disease.

Management of Resistant Hypertension-An Update.

This JAMA Internal Medicine Clinical Insights review provides an update on the current recommendations for resistant hypertension management.

Preventing cognitive decline by reducing BP target (PCOT): A randomized, pragmatic, multi-health systems clinical trial.

BACKGROUND: Growing evidence suggests that intensive lowering of systolic blood pressure (BP) may prevent mild cognitive impairment (MCI) and dementia. However, current guidelines provide inconsistent recommendations regarding optimal BP targets, citing safety concerns of excessive BP lowering in the diverse population of older adults. We are conducting a pragmatic trial to determine if an implementation strategy to reduce systolic BP to <130 and diastolic BP to <80 mmHg will safely slow cognitive decline in older adults with hypertension when compared to patients receiving usual care. METHODS: The Preventing Cognitive Decline by Reducing BP Target Trial (PCOT) is an embedded randomized pragmatic clinical trial in 4000 patients from two diverse health-systems who are age ≥ 70 years with BP >130/80 mmHg. Participants are randomized to the intervention arm or usual care using a permuted block randomization within each health system. The intervention is a combination of team-based care with clinical decision support to lower home BP to <130/80 mmHg. The primary outcome is cognitive decline as determined by the change in the modified Telephone Interview for Cognitive Status (TICS-m) scores from baseline. As a secondary outcome, patients who decline ≥3 points on the TICS-m will complete additional cognitive assessments and this information will be reviewed by an expert panel to determine if they meet criteria for MCI or dementia. CONCLUSION: The PCOT trial will address the effectiveness and safety of hypertension treatment in two large health systems to lower BP targets to reduce risk of cognitive decline in real-world settings.

Recruitment methods and yield rates for a multisite clinical trial exploring risk reduction for Alzheimer's disease (rrAD).

INTRODUCTION: The risk reduction for Alzheimer's disease (rrAD) trial was a multisite clinical trial to assess exercise and intensive vascular pharmacological treatment on cognitive function in community-dwelling older adults at increased risk for Alzheimer's disease. METHODS: Eligibility, consent, and randomization rates across different referral sources were compared. Informal interviews conducted with each site's project team were conducted upon study completion. RESULTS: Initially, 3290 individuals were screened, of whom 28% were eligible to consent, 805 consented to participate (87.2% of those eligible), and 513 (36.3% of those consented) were randomized. Emails sent from study site listservs/databases yielded the highest amount (20.9%) of screened individuals. Professional referrals from physicians yielded the greatest percentage of consented individuals (57.1%). Referrals from non-professional contacts (ie, friends, family; 75%) and mail/phone contact from a site (73.8%) had the highest yield of randomization. DISCUSSION: Professional referrals or email from listservs/registries were most effective for enrolling participants. The greatest yield of eligible/randomized participants came from non-professional and mail/phone contacts. Future trials should consider special efforts targeting these recruitment approaches. Highlights: Clinical trial recruitment is commonly cited as a significant barrier to advancing our understanding of cognitive health interventions.The most cited referral source was email, followed by interviews/editorials on the radio, television, local newspapers, newsletters, or magazine articles.The referral method that brought in the largest number of contacts was email but did not result in the greatest yield of consents or eligible participants.The sources that yielded the greatest likelihood of consent were professional referrals (ie, physician), social media, and mail/phone contact from study site.The greatest yield of eligible/randomized participants came from non-professional contacts and mail/phone contact from a site.Findings suggest that sites may need to focus on more selective referral sources, such as using contact mailing and phone lists, rather than more widely viewed recruitment sources, such as social media or TV/radio advertisements.

Potassium Magnesium Citrate Is Superior to Potassium Chloride in Reversing Metabolic Side Effects of Chlorthalidone.

BACKGROUND: Thiazide diuretics (TD) are the first-line treatment of hypertension because of its consistent benefit in lowering blood pressure and cardiovascular risk. TD is also known to cause an excess risk of diabetes, which may limit long-term use. Although potassium (K) depletion was thought to be the main mechanism of TD-induced hyperglycemia, TD also triggers magnesium (Mg) depletion. However, the role of Mg supplementation in modulating metabolic side effects of TD has not been investigated. Therefore, we aim to determine the effect of potassium magnesium citrate (KMgCit) on fasting plasma glucose and liver fat by magnetic resonance imaging during TD therapy. METHODS: Accordingly, we conducted a double-blinded RCT in 60 nondiabetic hypertension patients to compare the effects of KCl versus KMgCit during chlorthalidone treatment. Each patient received chlorthalidone alone for 3 weeks before randomization. Primary end point was the change in fasting plasma glucose after 16 weeks of KCl or KMgCit supplementation from chlorthalidone alone. RESULTS: The mean age of subjects was 59±11 years (30% Black participants). Chlorthalidone alone induced a significant rise in fasting plasma glucose, and a significant fall in serum K, serum Mg, and 24-hour urinary citrate excretion (all P<0.05). KMgCit attenuated the rise in fasting plasma glucose by 7.9 mg/dL versus KCl (P<0.05), which was not observed with KCl. There were no significant differences in liver fat between the 2 groups. CONCLUSIONS: KMgCit is superior to KCl, the common form of K supplement used in clinical practice, in preventing TD-induced hyperglycemia. This action may improve tolerability and cardiovascular safety in patients with hypertension treated with this drug class.

Diagnostic performance of the adrenal vein to inferior vena cava aldosterone ratio in classifying the subtype of primary aldosteronism.

Adrenal vein sampling (AVS) is the standard procedure for distinguishing unilateral primary aldosteronism (PA) from bilateral PA. In cases where only one adrenal vein is successfully cannulated, it has been suggested that subtype classification can be determined based on the ratio of the concentration of aldosterone between the adrenal vein and the inferior vena cava (AV/IVC index). However, diagnostic performance of the ipsilateral versus contralateral AV/IVC index in predicting lateralization has not been directly compared. In a retrospective cohort of 133 patients with confirmed PA who underwent successful AVS, the performance of the AV/IVC index to predict laterality was evaluated and the area under the receiver operating characteristic (AUROC) curves was calculated. In detecting left unilateral PA (n = 47), the AUROC of the right AV/IVC index (RAV/IVC) was significantly higher than the AUROC of the left AV/IVC (LAV/IVC) index (0.967 vs. 0.871, p = 0.008). In detecting right unilateral PA (n = 30), the AUROC of the LAV/IVC index tended to be higher than that of the RAV/IVC index, but the difference did not reach statistical significance (0.966 vs. 0.906, p = 0.08). In detecting left unilateral PA, the sensitivities of the RAV/IVC and LAV/IVC indices were 83% and 46%, respectively, while the specificities of both were above 90%. In detecting right unilateral PA, the sensitivities of the LAV/IVC and RAV/IVC indices were 80% and 43%, respectively, while the specificities of both were above 90%. The AV/IVC index has superior diagnostic performance in detecting contralateral unilateral PA compared to ipsilateral unilateral PA.

Utility of standing office blood pressure in detecting hypertension in healthy adults.

Current guidelines recommend office blood pressures (BP) be taken in a seated position when screening for hypertension (HTN). Seated BP is known to have limited accuracy in detecting high BP, while the utility of standing BP in diagnosing HTN is unknown. We conducted a cross-sectional study to determine the incremental value of standing BP in diagnosing HTN. Seated, standing, and 24-h ambulatory BPs (ABPM) were obtained in adults without known cardiovascular disease, HTN, or BP medication use. Presence of HTN was defined by the 2017 ACC/AHA and the 2023 ESH HTN guidelines based on ABPM. Area under the receiver-operating-characteristic curve (AUROC) was used to evaluate the diagnostic accuracy of seated and standing BP. Sensitivity and specificity of standing BP was determined using cut-offs derived from Youden's Index, while sensitivity and specificity of seated BP was determined using the cut-off of 130/80 mmHg and by 140/90 mmHg. Among 125 participants (mean age 49 ± 17 years; 62% female; 24% Black), 33.6% of them had HTN. Sensitivity and specificity of seated systolic BP (SBP) was 43% and 92%, respectively. Cut-offs selected by Youden's index for standing SBP/diastolic BP (DBP) were 124/81 mmHg according to the 2017 ACC/AHA HTN guidelines, and 123.5/83.5 mmHg according to the 2023 ESH HTN guidelines. Sensitivity and specificity of standing SBP was 71% and 67%, respectively. The AUROC of standing SBP (0.81 [0.71-0.92]) was significantly higher than seated SBP (0.70 [0.49-0.91]), when HTN was defined as average 24-h SBP ≥ 125 mmHg. Moreover, the addition of standing to seated SBP (0.80 [0.68-0.92]) improved HTN detection when compared to seated SBP. These patterns were consistent for both the 2017 ACC/AHA and the 2023 ESH definitions for HTN. In summary, standing BP, alone or in combination with seated BP, outperformed seated BP alone in diagnosing HTN in adults.

Blockade of endogenous insulin receptor signaling in the nucleus tractus solitarius potentiates exercise pressor reflex function in healthy male rats.

Insulin not only regulates glucose and/or lipid metabolism but also modulates brain neural activity. The nucleus tractus solitarius (NTS) is a key central integration site for sensory input from working skeletal muscle and arterial baroreceptors during exercise. Stimulation of the skeletal muscle exercise pressor reflex (EPR), the responses of which are buffered by the arterial baroreflex, leads to compensatory increases in arterial pressure to supply blood to working muscle. Evidence suggests that insulin signaling decreases neuronal excitability in the brain, thus antagonizing insulin receptors (IRs) may increase neuronal excitability. However, the impact of brain insulin signaling on the EPR remains fully undetermined. We hypothesized that antagonism of NTS IRs increases EPR function in normal healthy rodents. In decerebrate rats, stimulation of the EPR via electrically induced muscle contractions increased peak mean arterial pressure (MAP) responses 30 min following NTS microinjections of an IR antagonist (GSK1838705, 100 µM; Pre: Δ16 ± 10 mmHg vs. 30 min: Δ23 ± 13 mmHg, n = 11, p = .004), a finding absent in sino-aortic baroreceptor denervated rats. Intrathecal injections of GSK1838705 did not influence peak MAP responses to mechano- or chemoreflex stimulation of the hindlimb muscle. Immunofluorescence triple overlap analysis following repetitive EPR stimulation increased c-Fos overlap with EPR-sensitive nuclei and IR-positive cells relative to sham operation (p < .001). The results suggest that IR blockade in the NTS potentiates the MAP response to EPR stimulation. In addition, insulin signaling in the NTS may buffer EPR stimulated increases in blood pressure via baroreflex-mediated mechanisms during exercise.

Hypertension in Patients Treated With In-Center Maintenance Hemodialysis: Current Evidence and Future Opportunities: A Scientific Statement From the American Heart Association.

Nearly 500 000 individuals are treated with maintenance hemodialysis for kidney failure in the United States, and roughly half will die of cardiovascular causes. Hypertension, an important and modifiable risk factor for cardiovascular disease, is observed in >80% of patients treated with maintenance hemodialysis. The pathophysiology of hypertension in patients treated with maintenance hemodialysis is multifactorial and differs from that seen in other patient populations. Factors that contribute to hypertension in patients treated with hemodialysis include volume overload, arterial stiffness, enhanced activity of the sympathetic nervous and renin-angiotensin-aldosterone systems, endothelial dysfunction, and use of erythropoietin-stimulating agents. This scientific statement reviews the current evidence on defining, diagnosing, and treating hypertension in patients treated with maintenance hemodialysis and highlights opportunities for future investigation, including studies on blood pressure targets and treatment strategies.