(1) Background: Arterial hypertension (HTN) is one of the most relevant cardiovascular risk factors. Nowadays multiple pharmaceutical treatment options exist with novel interventional methods (e.g., baroreflex activation therapy (BAT)) as a last resort to treat patients with resistant HTN. Although pathophysiology behind resistant HTN is still not fully understood. There is evidence that selected biomarkers may be involved in the pathophysiology of HTN. (2) Methods: We investigated serum SDC4-levels in patients suffering from resistant HTN before and 6 months after BAT implantation. We collected 19 blood samples from patients with resistant HTN and blood pressure above target and measured serum SDC4-levels. (3) Results: Our results showed high serum SDC4-levels in patients with resistant HTN as compared to a healthy population. Patients with both, resistant HTN and diabetes mellitus type II, demonstrated higher serum SDC4-levels. β-blockers had lowering effects on serum SDC4-levels, whereas calcium channel blockers were associated with higher levels of serum SDC4. BAT implantation did not lead to a significant difference in serum SDC4-levels after 6 months of therapy. (4) Conclusion: Based on our results we propose SDC4 is elevated in patients suffering from resistant HTN. Thus, SDC4 might be a potential marker for endothelial dysfunction in patients with resistant hypertension.

Patients with resistant hypertension (HTN) demonstrate an increased risk of chronic kidney disease and progression to end-stage renal disease; however, the individual course of progression is hard to predict. Assessing the stress-induced, urinary glycoprotein Dickkopf-3 (uDKK3) may indicate ongoing renal damage and consecutive estimated glomerular filtration rate (eGFR) decline. The present study aimed to determine the association between uDKK3 levels and further eGFR changes in patients with resistant HTN. In total, 31 patients with resistant HTN were included. Blood pressure and renal function were measured at baseline and up to 24 months after (at months 12 and 24). uDKK3 levels were determined exclusively from the first available spot urine sample at baseline or up to a period of 6 months after, using a commercial ELISA kit. Distinctions between different patient groups were analyzed using the unpaired t-test or Mann–Whitney test. Correlation analysis was performed using Spearman’s correlation. The median uDKK3 level was 303 (interquartile range (IQR) 150–865) pg/mg creatinine. Patients were divided into those with high and low eGFR loss (≥3 vs. <3 mL/min/1.73 m²/year). Patients with high eGFR loss showed a significantly higher median baseline uDKK3 level (646 (IQR 249–2555) (n = 13) vs. 180 (IQR 123–365) pg/mg creatinine (n = 18), p = 0.0412 (Mann–Whitney U)). Alternatively, patients could be classified into those with high and low uDKK3 levels (≥400 vs. <400 pg/mg creatinine). Patients with high uDKK3 levels showed significantly higher eGFR loss (−6.4 ± 4.7 (n = 11) vs. 0.0 ± 7.6 mL/min/1.73 m²/year (n = 20), p = 0.0172 (2-sided, independent t-test)). Within the entire cohort, there was a significant correlation between the uDKK3 levels and change in eGFR at the latest follow-up (Spearman’s r = −0.3714, p = 0.0397). In patients with resistant HTN, high levels of uDKK3 are associated with higher eGFR loss up to 24 months later.

Uncontrolled hypertension is a main risk factor for cardiovascular morbidity. Baroreflex activation therapy (BAT) is an effective therapy option addressing true resistant hypertension. We evaluated patients’ eligibility for BAT in a staged assessment as well as adherence to antihypertensive drug therapy. Therefore, we analyzed files of 345 patients, attending the hypertension clinic at University Medicine Göttingen. Additionally, gas chromatographic-mass spectrometric urine analyses of selected individuals were performed evaluating their adherence. Most common cause for a revoked BAT recommendation was blood pressure (BP) control by drug adjustment (54.2%). Second leading cause was presence of secondary hypertension (31.6%). Patients to whom BAT was recommended (59 (17.1%)) were significantly more often male (67.8% vs. 43.3%, P = .0063), had a higher body mass index (31.8 ± 5.8 vs. 30.0 ± 5.7 kg/m², P = .0436), a higher systolic office (168.7 ± 24.7 vs. 147.7 ± 24.1 mmHg, P < .0001), and 24h ambulatory BP (155.0 ± 14.6 vs. 144.4 ± 16.8 mmHg, P = .0031), took more antihypertensive drugs (5.8 ± 1.3 vs. 4.4 ± 1.4, P < .0001), and suffered more often from numerous concomitant diseases. Eventually, 27 (7.8%) received a BAT system. In the toxicological analysis of 75 patients, mean adherence was 75.1%. 16 patients (21.3%) showed non-adherence. Thus, only a small number of patients eventually received a BAT system, as treatable reasons for apparently resistant hypertension could be identified frequently. This study is—to our knowledge—the first report of a staged assessment of patients’ suitability for BAT and underlines the need for a careful examination and indication. Non-adherence was proven to be a relevant issue concerning apparently resistant hypertension and therefore non-eligibility for interventional antihypertensive therapy.

Aims: Arterial hypertension (aHTN) plays a fundamental role in the pathogenesis and prognosis of heart failure with preserved ejection fraction (HFpEF). The risk of heart failure increases with therapy-resistant arterial hypertension (trHTN), defined as inadequate blood pressure (BP) control ≥140/90 mmHg despite taking ≥3 antihypertensive medications including a diuretic. This study investigates the effects of the BP lowering baroreflex activation therapy (BAT) on cardiac function and morphology in patients with trHTN with and without HFpEF. Methods: Sixty-four consecutive patients who had been diagnosed with trHTN and received BAT implantation between 2012 and 2016 were prospectively observed. Office BP, electrocardiographic and echocardiographic data were collected before and after BAT implantation. Results: Mean patients' age was 59.1 years, 46.9% were male, and mean body mass index (BMI) was 33.2 kg/m2. The prevalence of diabetes mellitus was 38.8%, atrial fibrillation was 12.2%, and chronic kidney disease (CKD) stage ≥3 was 40.8%. Twenty-eight patients had trHTN with HFpEF, and 21 patients had trHTN without HFpEF. Patients with HFpEF were significantly older (64.7 vs. 51.6 years, P < 0.0001), had a lower BMI (30.0 vs. 37.2 kg/m2, P < 0.0001), and suffered more often from CKD-stage ≥3 (64 vs. 20%, P = 0.0032). After BAT implantation, mean office BP dropped in patients with and without HFpEF (from 169 ± 5/86 ± 4 to 143 ± 4/77 ± 3 mmHg [P = 0.0019 for systolic BP and 0.0403 for diastolic BP] and from 170 ± 5/95 ± 4 to 149 ± 6/88 ± 5 mmHg [P = 0.0019 for systolic BP and 0.0763 for diastolic BP]), while a significant reduction of the intake of calcium-antagonists, α2-agonists and direct vasodilators, as well as a decrease in average dosage of ACE-inhibitors and α2-agonists could be seen. Within the study population, a decrease in heart rate from 74 ± 2 to 67 ± 2 min−1 (P = 0.0062) and lengthening of QRS-time from 96 ± 3 to 106 ± 4 ms (P = 0.0027) and QTc-duration from 422 ± 5 to 432 ± 5 ms (P = 0.0184) were detectable. The PQ duration was virtually unchanged. In patients without HF, no significant changes of echocardiographic parameters could be seen. In patients with HFpEF, posterior wall diameter decreased significantly from 14.0 ± 0.5 to 12.7 ± 0.3 mm (P = 0.0125), left ventricular mass (LVM) declined from 278.1 ± 15.8 to 243.9 ± 13.4 g (P = 0.0203), and e′ lateral increased from 8.2 ± 0.4 to 9.0 ± 0.4 cm/s (P = 0.0471). Conclusions: BAT reduced systolic and diastolic BP and was associated with morphological and functional improvement of HFpEF.

Background: Patients with chronic heart failure (HF) show an increased risk for the occurrence of chronic kidney disease and cardiorenal syndrome. Urinary Dickkopf‐3 (uDKK3), a stress‐induced, tubular profibrotic glycoprotein, may be elevated in HF as early as in New York Heart Association class I HF and may indicate subsequent decline in estimated glomerular filtration rate (eGFR). Methods and Results: uDKK3 levels in patients with HF and controls were measured by enzyme‐linked immunosorbent assay. eGFR was determined up to 5 years in HF. Change in eGFR was assessed with respect to baseline uDKK3 using (mixed‐effect) linear and logistic regression models. A total of 488 patients with chronic HF and 45 control patients were included. Patients with HF showed higher median uDKK3 levels than controls (259.6 pg/mg creatinine [interquartile range (IQR), 119.2–509.4 pg/mg creatinine] versus 107.5 pg/mg creatinine [IQR, 60.5–181.2 pg/mg creatinine], P <0.001). Regression models demonstrated a significant association between log uDKK3 and the decline in eGFR during a median of 13 months (IQR, 12–59 months) (estimated higher eGFR loss, 0.8039 mL/min per 1.73 m ² /year [95% CI, 0.002–1.606 mL/min per 1.73 m ² /year], P =0.049; odds ratio, 1.345 [95% CI, 1.049–1.741], P =0.021). uDKK3 levels ≥354 pg/mg creatinine were associated with a significantly higher risk for eGFR decline at 1‐year follow‐up (estimated higher eGFR loss, 4.538 mL/min per 1.73 m ² [95% CI, 1.482–9.593 mL/min per 1.73 m ² ]), P =0.004). Even patients with HF without chronic kidney disease (n=334) had higher uDKK3 levels compared with controls (233.4 [IQR, 109.0–436.9 pg/mg creatinine] versus 107.5 [IQR, 60.5–181.2 pg/mg creatinine], P <0.001). Conclusions: The present findings indicate that uDKK3 is a promising prognostic biomarker for subsequent eGFR decline in patients with HF, irrespective of the presence of chronic kidney disease and even in the early stages of HF. This potential allows for early intervention to mitigate the deterioration of kidney function. Further investigation is warranted to validate its clinical utility.

Sodium-glucose cotransporter-2 inhibitors (SGLT2I) are a standard of care treatment for chronic kidney disease (CKD). However, the effects of SGLT2I on tubular function and stress are rare. A monocentric, prospective, observational study. Patients with CKD who were referred to the outpatient clinic of the Department of Nephrology at Göttingen University Hospital and for whom SGLT2I therapy was indicated as part of standard treatment were prospectively included and treated with SGLT2I in accordance with current guidelines. Urine samples were collected, and the levels of urinary α1-microglobulin (uα-1-MG), urinary Dickkopf-3 (uDKK3), and urinary albumin creatinine ratio (UACR), each normalized to urinary creatinine, were measured at baseline and after 6 months of therapy. Total of 57 patients were included. The mean age was 66.4 ± 12.4 years; 42.1% were female. At baseline, mean estimated glomerular filtration rate was 42.0 ± 15.3 mL/min/1.73m². Within 6 months, the mean estimated glomerular filtration rate decreased by −2.1 ± 7.6 mL/min/1.73 m² (P = 0.04). While overall patients, UACR (P = 0.23) and uDKK3 (P = 0.87) remained unchanged, there was a significant increase in median uα-1-MG within 6-months (+9.7 mg/g creatinine [IQR 1.0-22.2]; P < 0.001). Although patients with A3 albuminuria (n = 14) showed only a numerical increase of median uα-1-MG level (+4.6 mg/g creatinine [IQR −7.1 to 20.8]; P = 0.30), there was a significant increase of median uα-1-MG in stage A1 (n=22, +11.5 mg/g creatinine [IQR 3.8-23.2]; P < 0.001) and A2 patients (n = 21, +7.2 mg/g creatinine [IQR 0.7-30.8]; P = 0.006). The small sample size, lack of a control group, and the short follow-up duration may restrict the findings. This study demonstrates an increase in uα-1-MG during SGLT2I treatment in patients with CKD, particularly in UACR stage A1, in which reduction of hyperfiltration is less pronounced. Because uDKK3 as a parameter of tubular damage remained stable, the increase in uα-1-MG may reflect a functional reduction of protein reabsorption and thus reduced intratubular protein overload as a potential nephroprotective effect.