Massimo Nardone

Background: Clinical guidelines recommend combined use of renin-angiotensin system inhibitors (RASi), sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1RA) and nonsteroidal mineralocorticoid receptor antagonists (nsMRA) to reduce cardiorenal risk. However, eligibility for combination treatment and the potential effects of implementation on preventing mortality remain unclear. Methods: We conducted a microsimulation study using data from the National Health and Nutrition Examination Survey (NHANES 2007–2016 and 2017–2020). The model incorporated acute treatment effects of RASi, SGLT2i, GLP1RA, and nsMRA on estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and serum potassium. Eligibility for combination treatment was assessed for each participant according to 73 clinical practice guideline recommendations and inclusion criteria from recently published clinical trials. Primary outcomes included: 1) the percentage of participants eligible for single or combination treatment with RASi, SGLT2i, GLP1RA, and nsMRA, and 2) the projected potential number of annually averted all-cause and cardiovascular deaths. Results: Of 8,152 adults, 15% had type 2 diabetes (DM), 14% had chronic kidney disease (CKD) and 5% had DM and CKD (DKD). Among all U.S. adults, 19% were treated with RASi, 1% with SGLT2i, 1% with GLP1RA and none with nsMRA. The dual-therapy associated with the highest eligibility was RASi+SGLT2i, with 15% of the U.S. population eligible (DM subgroup: 70%; CKD subgroup: 50%; DKD subgroup: 84%). The triple-therapy with the highest eligibility was RASi+SGLT2i+GLP1RA, with 11% overall eligibility (DM: 69%; CKD: 33%; DKD: 83%). Eligibility for quadruple-therapy was 4% overall (DM: 22%; CKD: 17%; DKD: 40%). Based on our microsimulation model, fewer individuals with diabetes were eligible for triple-therapy with RASi+SGLT2i+GLP1RA compared to dual-therapy with RASi+SGLT2i, but triple-therapy was projected to prevent 2-fold more potential all-cause and cardiovascular deaths versus dual-therapy. Conclusions: Under the assumptions of our microsimulation model, eligibility for combined treatment with cardiorenal protective therapies was prevalent, particularly in adults with type 2 diabetes and/or CKD.

Sympathetic neurovascular transduction to mean arterial pressure (MAP), superficial femoral artery (SFA), and femoral vein (FV) flow were quantified at baseline and during slow deep breathing (SDB). MAP was unchanged during SDB, whereas MSNA was decreased, and sympathetic transduction to MAP, SFA flow, and FV flow (tendency) were increased. Respiratory-coupled oscillations in MSNA, SFA flow, and FV flow appear to work synergistically with the respiratory muscle pump to facilitate venous return during SDB.

Peripheral or central chemoreceptor sensitization is a well-documented cause of reflex sympathetic excitation in patients with heart failure and reduced ejection fraction (HFrEF).¹ In one series, augmented ventilatory responsiveness to hypercapnia and hypoxia, present in ∼half the patient cohort, predicted a 4-year survival of 49%.² The carotid body has been identified as a target for surgical or percutaneous intervention with the aim of benefiting such individuals by restoring autonomic equilibrium.^3,4 Importantly, this strategy is predicated on the assumption that transient intermittent hypoxic tests can accurately characterize a sensitized peripheral chemoreflex, with the conjecture that the slope or sensitivity of the efferent sympathetic response then parallels that of ventilation. However, chemoreceptor-mediated regulation of breathing and autonomic outflow engage different brainstem circuits.⁵ To date, selection of patients for peripheral chemoreflex intervention has involved quantification of ventilatory responses to intermittent hypoxia³: 100% nitrogen is inhaled over a short duration (∼2–8 breaths) to achieve a range of oxygen saturations (70%–100% S_aO₂). The peak of ventilation (V̇_E) elicited by each exposure is inversely related to the prior nadir in S_aO₂, generating a V̇_E–S_aO₂ slope for peripheral chemoreflex sensitivity with units of L·min⁻¹·%S_aO₂⁻¹. This measure is often called the ‘hypoxic ventilatory response’ (HVR).⁶ In patients with HFrEF, a value ≥0.75 L·min⁻¹·%S_aO₂⁻¹ is considered an ‘exaggerated’ HVR and used as an indication for carotid body intervention.⁷

Luxcia Kugathasan, Vikas S. Sridhar, Michael J. Davies, Manon Girard, Belinda Hardin, David J.T. Campbell, Anita T. Layton, Bruce A. Perkins, Sean Barbour,

BACKGROUND: We investigated the impact of 12 weeks of sodium-glucose cotransporter-2 inhibition (dapagliflozin 10 mg daily) on vascular stiffness, cardiac and kidney function, and neurohormonal pathways in participants at cardiovascular risk. METHODS: This randomized double-blind, parallel-group, placebo-controlled study enrolled 51 participants with at least 1 established cardiovascular condition or cardiovascular risk factor. Participants underwent 3 sequential assessments under clamped euglycemia (4–6 mmol/L): at baseline, at 1 week and 12 weeks of treatment. The primary outcome was vascular arterial stiffness, quantified as augmentation index and pulse-wave velocity. Secondary outcomes included: blood pressure, body fluid composition, noninvasive cardiac output monitoring, arterial vasodilatation tests, heart rate variability, echocardiography, iohexol-measured glomerular filtration rate, and natriuresis. RESULTS: Dapagliflozin decreased vascular arterial stiffness, as measured by aortic augmentation index (placebo-adjusted change of –7.4±2.8%, P =0.01) after 12 weeks. Dapagliflozin acutely decreased extracellular fluid (–0.8±0.3 L, P =0.004), with sustained reductions in thoracic fluid content at 12 weeks (–3.3±1.5 kΩ ⁻¹ , P =0.03). Reductions in measured glomerular filtration rate (–5.8±2.1 mL/min per 1.73m ² , P =0.008) were accompanied by acute increases in proximal sodium excretion (5.1±2.2%, P =0.03), absolute fractional distal sodium reabsorption (4.4±2.1%, P =0.04), and urine adenosine (0.21±0.08 mmol/L per μmol Cr, P =0.01). CONCLUSIONS: Dapagliflozin induced early cardiorenal changes in individuals at varying levels of cardiovascular risk in whom evidence of clinical protection is lacking. Clinical trials in lower-risk populations, particularly in the context of primary prevention, are needed to determine whether these effects of sodium-glucose cotransporter-2 inhibition translate into improved clinical cardiorenal outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04258371.

Key Points: The effIcacy, mechaNisms and saFety of SGLT2 INhibitors in kIdney Transplant recIpients trial assessed the physiologic effects of sodium-glucose cotransporter-2 inhibitors in kidney transplant recipients. In kidney transplant recipients, sodium-glucose cotransporter-2 inhibitors lowered mean arterial pressure after 1 week, reduced GFR, increased glucosuria, and were safe. Dapagliflozin was well tolerated in kidney transplant recipients, showing similar cardio-kidney effects seen in other groups; outcome trials in kidney transplant recipients are now needed. Background: Cardiovascular and kidney protective mechanisms with 12 weeks of sodium-glucose cotransporter-2 inhibitor treatment (dapagliflozin 10 mg daily) were assessed in kidney transplant recipients (KTR) with and without type 2 diabetes. Methods: This randomized double-blind, parallel-group, placebo-controlled study enrolled 52 KTR and comprised three sequential physiologic assessments under clamped euglycemia (4–6 mmol/L): baseline, at 1, and 12 weeks of treatment. The primary objective was to evaluate BP lowering with dapagliflozin. Secondary outcomes were iohexol-measured GFR, natriuresis, body composition, noninvasive cardiac output monitoring, arterial stiffness, heart rate variability, neurohormones, and safety. Results: Fifty-one KTR completed the study—mean age 53±13 years, 62% with hypertension, 57% with type 2 diabetes, 50% on renin-angiotensin-aldosterone system inhibitors, and mean eGFR 68.2±24.4 ml/min per 1.73 m ² . Compared with placebo, dapagliflozin did not lower systolic BP at 1 or 12 weeks, although it did reduce mean arterial pressure after 1 week (3.9 mm Hg; 95% confidence interval [CI], −7.5 to −0.2). Dapagliflozin led to significant, placebo-adjusted reductions in iohexol-measured GFR from baseline to 1 week (4.2 ml/min per 1.73 m ² ; 95% CI, −7.14 to −1.24 ml/min per 1.73 m ² ) and 12 weeks (−3.49 ml/min per 1.73 m ² ; 95% CI, −6.33 to −0.64). Dapagliflozin significantly increased glucosuria without altering proximal sodium handling or evidence of sympathetic activation. Acute decreases in arterial stiffness (carotid augmentation index, −3.5%; 95% CI, −6.0 to −1.1) were observed in the dapagliflozin group after 12 weeks, although this was not significant compared with placebo. Dapagliflozin was generally safe and well tolerated. No episodes of urinary tract or genitourinary infections were observed in either treatment group throughout the trial. Conclusions: Dapagliflozin activated expected physiologic pathways, although key differences observed in KTR might suggest mechanistic heterogeneity compared with nontransplant populations. Clinical trials evaluating sodium-glucose cotransporter-2 inhibitors in KTR are important to determine whether these mechanistic effects translate to improvements in kidney and cardiovascular outcomes. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT04965935. Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3//www.asn-online.org/media/podcast/JASN/2026_02_09_KTS_February2026.mp3

Exogenous ketone supplementation can impact cardiovascular regulation, but the effects on muscle sympathetic nerve activity (MSNA) remain unknown. In a randomized, crossover, double‐blind design, 19 participants (23 ± 4 years.; female: n = 9) ingested an oral ketone monoester (KME; 0.4 g/kg) or isocaloric, isovolumetric placebo. Blood pressure, heart rate, brachial artery blood flow, and MSNA (microneurography; n = 14) were assessed at rest before and after ingestion and during two laboratory stressors: 2‐min static handgrip exercise and 2‐min of mental arithmetic. Capillary β‐hydroxybutyrate increased 20 and 40 min post KME ingestion versus placebo (both, p < 0.001). Compared to placebo, KME had no effects on resting mean arterial pressure (Placebo: 78.3 ± 9.3 to 80.2 ± 10.5 mmHg; KME: 76.3 ± 8.3 to 79.5 ± 8.8 mmHg; interaction p = 0.32), heart rate (Placebo: 64.6 ± 12.3 to 69.6 ± 11.0 bpm; KME: 65.3 ± 10.6 to 72.6 ± 11.3 bpm; interaction p = 0.30), or MSNA burst frequency (Placebo: 17.7 ± 7.3 to 17.7 ± 6.7 bursts/minute; KME: 17.5 ± 6.1 to 18.2 ± 7.0 bursts/minute; interaction p = 0.72). Resting brachial artery blood flow and vascular conductance changed over time but did not differ between conditions (interactions, both p > 0.40). Neuro‐cardiovascular responses during exercise (interactions, all p > 0.72) or mental stress (interactions, all p > 0.44) did not differ between conditions. Compared to placebo, acute KME ingestion did not modulate neuro‐cardiovascular measures at rest or during stress in healthy young adults.

Elevated peak blood pressure (BP) during exercise is an independent risk factor for future hypertension, but the mechanisms responsible for inter-individual differences in exercise BP remain poorly studied. Forty-four participants (22±5 years; 18 female) completed a maximal exercise test (modified Bruce protocol) with brachial artery BP measured every 90-seconds (automated auscultation). On a subsequent visit, participants underwent measures of carotid-femoral pulse wave velocity (n=37), superficial femoral artery flow-mediated dilation (n=27), and muscle sympathetic nerve activity (MSNA; microneurography, n=44). Hemodynamic and MSNA data were collected at rest, during handgrip exercise (static and rhythmic), and post-exercise circulatory occlusion. Participants were separated by sex and grouped into tertiles based on peak exercise systolic BP (SBP). Peak exercise SBP differed between tertiles (Tertile 1: 168±16 vs. Tertile 2: 194±14 vs. Tertile 3: 223±17 mmHg, P<0.001), despite no differences in resting SBP ( P=0.12), diastolic BP ( P=0.17), heart rate ( P=0.12), superficial femoral artery flow-mediated dilation ( P=0.85), carotid-femoral pulse wave velocity ( P=0.15), or MSNA (17.8±5.9 vs. 16.8±5.8 vs. 19.0±4.5 bursts/min, P=0.56). MSNA was higher during the final 30-seconds of static handgrip in Tertile 3 compared to both Tertile 1 and 2 (28.8±8.0 vs. 29.3±9.0 vs. 43.7 ± 14.0 bursts/min, both P0.19). Normotensive adults with higher peak SBP during maximal treadmill exercise have augmented MSNA during activation of the muscle metaboreflex.

Following cycling exercise, leg vascular conductance increases, whereas sympathetic nerve traffic is unchanged in young healthy adults. Discordant vascular and sympathetic responses may reflect modulation in vasoconstrictor responsiveness. The current study demonstrated that signal-averaged sympathetic neurovascular transduction was increased by ∼75% following a single bout of cycling exercise. Secondary experiments using local heating suggest that potentiation in sympathetic neurovascular transduction after exercise may occur independent of changes in resting vascular conductance.