A randomized, multicenter, open-label, blinded end point trial comparing the effects of spironolactone to chlorthalidone on left ventricular mass in patients with early-stage chronic kidney disease: Rationale and design of the SPIRO-CKD trial.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased left ventricular (LV) mass and arterial stiffness. In a previous trial, spironolactone improved these end points compared with placebo in subjects with early-stage CKD, but it is not known whether these effects were specific to the drug or secondary to blood pressure lowering. AIM: The aim was to investigate the hypothesis that spironolactone is superior to chlorthalidone in the reduction of LV mass while exerting similar effects on blood pressure. DESIGN: This is a multicenter, prospective, randomized, open-label, blinded end point clinical trial initially designed to compare the effects of 40weeks of treatment with spironolactone 25mg once daily to chlorthalidone 25mg once daily on the co-primary end points of change in pulse wave velocity and change in LV mass in 350 patients with stages 2 and 3 CKD on established treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Because of slow recruitment rates, it became apparent that it would not be possible to recruit this sample size within the funded time period. The study design was therefore changed to one with a single primary end point of LV mass requiring 150 patients. Recruitment was completed on 31 December 2016, at which time 154 patients had been recruited. Investigations included cardiac magnetic resonance imaging, applanation tonometry, 24-hour ambulatory blood pressure monitoring, and laboratory tests. Subjects are assessed before and after 40weeks of randomly allocated drug therapy and at 46weeks after discontinuation of the study drug.

Remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment?

BACKGROUND: We assessed whether remote ischemic preconditioning (RIPC) improves myocardial, renal, and lung protection after on-pump coronary surgery. METHODS AND RESULTS: This was a single-center, prospective, randomized (1:1), placebo-controlled trial. Patients, investigators, anesthetists, surgeons, and critical care teams were blinded to group allocation. Subjects received RIPC (or placebo) stimuli (×3 upper limb (or dummy arm), 5-minute cycles of 200 mm Hg cuff inflation/deflation) before aortic clamping. Anesthesia, perfusion, cardioplegia, and surgical techniques were standardized. The primary end point was 48-hour area under the curve (AUC) troponin T (cTnT) release. Secondary end points were 6-hour and peak cTnT, ECG changes, cardiac index, inotrope and vasoconstrictor use, renal dysfunction, and lung injury. Hospital survival was 99.4%. Comparing placebo and RIPC, median (interquartile range) AUC 48-hour cTnT (ng/mL(-1)/48 h(-1)); 28 (19, 39) versus 30 (22, 38), 6-hour cTnT (ng/mL(-1)); 0.93(0.59, 1.35) versus 1.01(0.72, 1.43), peak cTnT (ng/mL(-1)); 1.02 (0.74, 1.44) versus 1.04 (0.78, 1.51), de novo left bundle-branch block (4% versus 0%) and Q waves (5.3% versus 5.5%), serial cardiac indices, intraaortic balloon pump usage (8.5% versus 7.5%), inotrope (39% versus 50%) and vasoconstrictor usage (66% versus 64%) were not different. Dialysis requirement (1.2% versus 3.8%), peak creatinine (median [interquartile range], 1.2 mg/dL(-1) (1.1, 1.4) versus 1.2 (1.0, 1.4)), and AUC urinary albumin-creatinine ratios 69 (40, 112) versus 58 (32, 85) were not different. Intubation times; median (interquartile range), 937 minutes(766, 1402) versus 895(675, 1180), 6-hour; 278 (210, 338) versus 270 (218, 323) and 12-hour pO(2):FiO(2) ratios 255 (195, 323) versus 263 (210, 308) were similar. CONCLUSIONS: In contrast to prior smaller studies, RIPC did not reduce troponin release, improve hemodynamics, or enhance renal or lung protection. Clinical Trial Registration-URL: http://www.ukcrn.org.uk. Unique identifier: 4659.

Diastolic dysfunction on echocardiography does not predict survival after transjugular intrahepatic portosystemic stent-shunt in patients with cirrhosis.

BACKGROUND: Cardiac dysfunction is frequently observed in patients with cirrhosis. There remains a paucity of data from routine clinical practice regarding the role of echocardiography in the pre-assessment of transjugular intrahepatic portosystemic stent-shunt. AIM: Our study aimed to investigate if echocardiography parameters predict outcomes after transjugular intrahepatic portosystemic stent-shunt insertion in cirrhosis. METHODS: Patients who underwent echocardiography and transjugular intrahepatic portosystemic stent-shunt insertion at the liver unit (Birmingham, UK) between 1999 and 2016 were included. All echocardiography measures (including left ventricle ejection fraction; early maximal ventricular filling/late filling velocity ratio, diastolic dysfunction as per British Society of Echocardiography guidelines) were independently reviewed by a cardiologist. Predictors of 30-day and overall transplant free-survival were assessed. RESULTS: One Hundred and Seventeen patients with cirrhosis (median age 56 years; 54% alcohol; Child-Pugh B/C 71/14.5%; Model For End-Stage Liver Disease 12) underwent transjugular intrahepatic portosystemic stent-shunt for ascites (n = 78) and variceal haemorrhage (n = 39). Thirty-day and overall transplant-free survival was 90% (n = 105) and 31% (n = 36), respectively, over a median 663 (IQR 385-2368) days follow-up. Model for End-Stage Liver Disease (P < 0.001) and Child-Pugh Score (P = 0.002) significantly predicted 30-day and overall transplant-free survival. Model for End-Stage Liver Disease ≥15 implied three-fold risk of death. Six per cent (n = 7) of patients pre-transjugular intrahepatic portosystemic stent-shunt had a history of ischaemic heart disease and 34% (n = 40) had 1 or more cardiovascular disease risk factors. Fifty per cent (n = 59) had an abnormal echocardiogram and 33% (n = 39) had grade 1-3 diastolic dysfunction. On univariate analysis none of the echocardiography measures pre-intervention were related to 30-day or overall transplant-free survival post-transjugular intrahepatic portosystemic stent-shunt. CONCLUSIONS: Ventricular, in particular diastolic dysfunction in patients with cirrhosis does not predict survival after transjugular intrahepatic portosystemic stent-shunt insertion. Model for End-Stage Liver Disease and Child-Pugh scores remain the best predictors of survival. Further prospective study is required to clarify the role of routine echocardiography prior to transjugular intrahepatic portosystemic stent-shunt insertion.

A Follow-Up Study of the Prevalence of Valvular Heart Abnormalities in Hyperprolactinemic Patients Treated With Cabergoline.

CONTEXT: Uncertainty exists whether the long-term use of ergot-derived dopamine agonist (DA) drugs for the treatment of hyperprolactinemia may be associated with clinically significant valvular heart disease and whether current regulatory authority guidelines for echocardiographic screening are clinically appropriate. OBJECTIVE: Our objective was to provide follow-up echocardiographic data on a previously described cohort of patients treated with DA for lactotrope pituitary tumors and to explore possible associations between structural and functional valve abnormalities with the cumulative dose of drug used. DESIGN: Follow-up echocardiographic data were collected from a proportion of our previously reported cohort of patients; all had received continuous DA therapy for at least 2 years in the intervening period. Studies were performed according to British Society of Echocardiography minimum standards for adult transthoracic echocardiography. Generalized estimating equations with backward selection were used to determine odds ratios of valvular heart abnormalities according to tertiles of cumulative cabergoline dose, using the lowest tertile as the reference group. SETTING: Thirteen centers of secondary/tertiary endocrine care across the United Kingdom were included. RESULTS: There were 192 patients (81 males; median age, 51 years; interquartile range [IQR], 42-62). Median (IQR) cumulative cabergoline doses at the first and second echocardiograms were 97 mg (20-377) and 232 mg (91-551), respectively. Median (IQR) duration of uninterrupted cabergoline therapy between echocardiograms was 34 months (24-42). No associations were observed between cumulative doses of dopamine agonist used and the age-corrected prevalence of any valvular abnormality. CONCLUSION: This large UK follow-up study does not support a clinically significant association between the use of DA for the treatment of hyperprolactinemia and cardiac valvulopathy.

Endothelial nitric oxide synthase single nucleotide polymorphism and left ventricular function in early chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease and heart failure. Endothelial nitric oxide synthase (eNOS) Glu298Asp single nucleotide polymorphism (SNP) genotype has been associated with a worse phenotype amongst patients with established heart failure and in patients with progression of their renal disease. The association of a cardiac functional difference in non-dialysis CKD patients with no known previous heart failure, and eNOS gene variant is investigated. METHODS: 140 non-dialysis CKD patients, who had cardiac magnetic resonance (CMR) imaging and tissue doppler echocardiography as part of two clinical trials, were genotyped for eNOS Glu298Asp SNP retrospectively. RESULTS: The median estimated glomerular filtration rate (eGFR) was 50 mls/min and left ventricular ejection fraction (LVEF) was 74% with no overt diastolic dysfunction in this cohort. There were significant differences in LVEF across eNOS genotypes with GG genotype being associated with a worse LVEF compared to other genotypes (LVEF: GG 71%, TG 76%, TT 73%, p = 0.006). After multivariate analysis, (adjusting for age, eGFR, baseline mean arterial pressure, contemporary CMR heart rate, total cholesterol, high sensitive C-reactive protein, body mass index and gender) GG genotype was associated with a worse LVEF, and increased LV end-diastolic and systolic index (p = 0.004, 0.049 and 0.009 respectively). CONCLUSIONS: eNOS Glu298Asp rs1799983 polymorphism in CKD patients is associated with relevant sub-clinical cardiac remodelling as detected by CMR. This gene variant may therefore represent an important genetic biomarker, and possibly highlight pathways for intervention, in these patients who are at particular risk of worsening cardiac disease as their renal dysfunction progresses.

Does immunosuppressant medication lower blood pressure and arterial stiffness in patients with chronic kidney disease? An observational study.

Chronic kidney disease is a proinflammatory state associated with increased arterial stiffness. We hypothesized that chronic kidney disease patients on long-term immunosuppression would have lower arterial stiffness and require treatment with less antihypertensive medication compared with non-immunosuppressed patients. A total of 254 patients (97 on immunosuppression) with chronic kidney disease were recruited from specialist renal clinics. Brachial blood pressure, central aortic pressure and waveform and pulse wave velocity were measured. Age, peripheral blood pressure and pulse wave velocity increased with worsening renal function but were not different between immunosuppressed and non-immunosuppressed patients. Central systolic (P < 0.001) and pulse pressure (P = 0.003) and the number of antihypertensive medications (P < 0.001) increased with worsening renal function and were higher in non-immunosuppressed patients (P = 0.02, P = 0.004 and P < 0.001, respectively). Age, mean arterial pressure, number of antihypertensive medications and a diagnosis of diabetes were found to be independent predictors of pulse wave velocity (R(2) = 0.375; P < 0.001). In a subgroup of 30 patient pairs without diabetes mellitus and cardiovascular disease and with a proven renal diagnosis, carefully matched for age, gender, renal function and systolic pressure, the prescribed antihypertensive medication remained lower in the immunosuppressed patients compared with non-immunosuppressed patients (P = 0.04). Pulse wave velocity was lower in the immunosuppressed group (7.5 ± 1.8 vs. 8.8 ± 1.9 m s(-1); P = 0.02). This study suggests that immunosuppression might be a method of reducing blood pressure and arterial stiffness in patients with chronic kidney disease.