Lack of Association Between Neurohormonal Blockade and Survival in Transthyretin Cardiac Amyloidosis

Background Despite the belief that heart failure therapies are not effective in transthyretin cardiac amyloidosis, data are limited. We tested the association of neurohormonal blockade use with survival. Methods and Results A total of 309 consecutive patients with transthyretin cardiac amyloidosis were identified. Medication inventory was obtained at baseline and subsequent visits. Exposure included a neurohormonal blockade class (β‐blocker [βB], angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, and mineralocorticoid antagonist) at baseline and subsequent visits. βB was modeled as baseline use, time‐varying use, and in an inverse probability treatment weighted model. Primary outcome was all‐cause mortality analyzed with adjusted Cox proportional hazards models. Continuing compared with stopping βB during follow‐up was tested. Mean age was 73.2 years, 84.1% were men, and 17.2% had atrial fibrillation/flutter at baseline. At the time of study entry, 49.8% were on βBs, 35.0% were on angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, and 23.9% were on mineralocorticoid antagonists. For the total cohort, there was a trend toward harm in the unadjusted model for baseline βB use, but this was neutral after adjustment. When βB use was analyzed as a time‐varying exposure, there was no association with mortality. βB discontinuation was associated with decreased mortality for the total cohort. Findings were consistent in inverse probability treatment weighted models. For angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker or mineralocorticoid antagonist use, there was no association with mortality after adjustment for the total cohort. Conclusions There was no association of neurohormonal blockade use with survival in transthyretin cardiac amyloidosis. For the total cohort, deprescribing βB may be associated with improved survival. Additional studies are needed to confirm these findings.

Treatment of Primary Aldosteronism Increases Plasma Epoxyeicosatrienoic Acids

Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules formed from arachidonic acid by the action of CYP450s. EETs cause vasodilation, exert anti-inflammatory effects, and enhance insulin secretion and sensitivity in rodents. EETs are metabolized to less active dihydroxyeicosatrienoic acids (DHETs) by sEH (soluble epoxide hydrolase), and 14,15-DHET has been reported to be increased in patients with primary aldosteronism, but the effects of aldosterone on EET concentrations and sEH activity are unknown. We tested the hypothesis that treatment of primary aldosteronism would alter EET concentrations in humans. We studied 9 patients with primary aldosteronism before and at least 3 months after unilateral adrenalectomy (6) or treatment with a mineralocorticoid antagonist (3). Circulating total EET concentrations increased to 18.5±12.6 from 11.9±5.9 nmol/L with treatment of primary aldosteronism ( P =0.027). Among the regioisomers of EETs, 14,15-EET significantly increased after treatment, whereas 11,12-EET and 8,9 EET were unaltered. Total DHET concentrations and specific regioisomers of DHET did not change significantly. Circulating total EETs (ρ=−0.52, P =0.026), 14,15-EET ( ρ =−0.56, P =0.015), and 11,12-EET ( ρ =−0.48, P =0.042) correlated inversely with aldosterone. We also assessed EETs after a 12-hour aldosterone or vehicle infusion in a randomized cross-over study in healthy volunteers. Plasma EETs were similar after 12-hour aldosterone or vehicle infusion. Lastly, 3-day infusion of aldosterone in mice decreased EET concentrations in adipose and muscle and increased sEH expression as determined by molar ratio of DHETs to EETs and soluble epoxide hydrolase ( Ephx2 ) mRNA expression in adipose tissue. These studies suggest that prolonged exposure to increased aldosterone decreases EET concentrations.

Clinical Phenotypes and Age-Related Differences in Presentation, Treatment, and Outcome of Heart Failure with Preserved Ejection Fraction: A Vietnamese Multicenter Research

Background. Heart failure with preserved ejection fraction (HFpEF) is a rising health problem with heterogeneous presentation and no evidence-based treatment. While Southeast Asia reported the highest mortality and morbidity among Asian population, little is known about the Vietnamese population, including patient characteristics, prescribing pattern and mortality rate. Methods. We conducted an observational study on 477 patients diagnosed with HFpEF from seven hospitals in Southern Vietnam from January 2019 to December 2019. Results. Mean age was 67.6 (40.9% < 65 years). 62.3% were female. 82.4% were diagnosed within 5 years. Dyspnea, congestion, and hypoperfusion on admission were noted in 63.9%, 48.8%, and 4.6% of the patients, respectively. Median ejection fraction was 63%. Valvular heart disease (VHD) was the leading cause of heart failure (35.9%). 78.6% had at least two comorbidities, mostly hypertension (68.6%). 30.6% of the patients were hospitalized, with a median stay of 7.0 (4.0–10.0) days and inhospital mortality of 4.8%. Older patients (≥65 years) were more likely to be females (OR = 1.52); had multimorbid conditions (OR = 3.14), including hypertension (OR = 4.28), diabetes (OR = 1.73), coronary artery disease (CAD) (OR = 2.50), dyslipidemia (OR = 1.94), and chronic kidney disease (OR = 2.44); and were more frequently prescribed statin (OR = 3.15). Younger individuals (<65 years) were associated with higher mineralocorticoid antagonist uptake (OR = 0.52) and VHD (OR = 0,40). Prescription rate for renin-angiotensin-aldosterone system inhibitor, beta blocker, mineralocorticoid antagonist, and loop diuretic was 72.5%, 59.1%, 43.0%, and 60.6%, respectively. Four phenotypes were identified, including the lean/elderly/multimorbid; congestive/metabolic; CAD-induced; and younger/atrial fibrillation (AF)/VHD. The novel phenotype “younger/AF/VHD” exhibited high symptom burden and poor functional capacity despite being the youngest and least multimorbid. The “lean/elderly/multimorbid” phenotype demonstrated the highest symptom severity and inhospital mortality. Conclusions. Our research highlights a younger, predominantly female population with high disease burden. The four novelly identified phenotypes provide contemporary and pragmatic insights into a phenotype-guided approach, exclusively targeting the Vietnamese population.

The Impact of Glucocorticoid Co-Secretion in Primary Aldosteronism on Thyroid Autoantibody Titers During the Course of Disease

Excess aldosterone is associated with the increased risk of cardio-/cerebrovascular events as well as metabolic comorbidities not only due to its hypertensive effect but also due to its proinflammatory action. Autonomous cortisol secretion (ACS) in the setting of primary aldosteronism (PA) is known to worsen cardiovascular outcome and potentially exhibit immunosuppressive effects. The aim of this study was to determine the impact of ACS status in patients with PA on kinetics of thyroid autoantibodies (anti-TPO, anti-TG) pre and post therapy initiation. Ninety-seven PA patients (43 unilateral, 54 with bilateral PA) from the database of the German Conn’s Registry were included. Anti-TPO and anti-TG levels were measured pre and 6–12 months post therapeutic intervention. Patients were assessed for ACS according to their 24- hour urinary cortisol excretion, late night salivary cortisol and low-dose dexamethasone suppression test. Abnormal test results in line with ACS were identified in 74.2% of patients with PA. Following adrenalectomy, significant increases in anti-TPO levels were observed in patients with at least one abnormal test (p = 0.049), adrenalectomized patients with at least two pathological ACS tests (p = 0.015) and adrenalectomized patients with pathologic dexamethasone suppression tests (p = 0.018). No antibody increases were observed in unilateral PA patients without ACS and in patients with bilateral PA receiving mineralocorticoid antagonist therapy (MRA). Our data are in line with an immunosuppressive effect of mild glucocorticoid excess in PA on thyroid autoantibody titers. This effect is uncovered by adrenalectomy, but not by MRA treatment.

SAT-LB76 Impact of Glucocorticoid Cosecretion in Primary Aldosteronism on Thyroid Autoantibody Titers During the Course of Disease

Context: Excess aldosterone is associated with the increased risk of cardio- and cerebrovascular events as well as metabolic comorbidities not only due to its hypertensive effect but also due to its proinflammatory action. Autonomous cortisol secretion (ACS) in the setting of primary aldosteronism (PA) is known to worsen cardiovascular outcome and potentially exhibit immunosuppressive effects.The aim of this study was to determine the impact of ACS status in patients with PA on kinetics of thyroid autoantibodies (anti-TPO, anti-TG) pre and post therapy initiation. Patients and Methods: 97 PA patients (43 with unilateral, 54 with bilateral PA) from the database of the German Conn’s Registry were included. Anti-TPO and anti-TG levels were measured pre and 6 to 12 months post therapeutic intervention. Patients were assessed for ACS according to their 24h urinary cortisol excretion, late night salivary cortisol and low-dose dexamethason suppression test. Results: Abnormal test results in line with ACS were identified in 74.2% of patients. Significant increases in anti-TPO levels were observed in adrenalectomized patients with at least one abnormal test (p = 0.049), adrenalectomized patients with at least two pathological ACS tests (p = 0.015) and adrenalectomized patients with pathologic dexamethasone suppression tests (p = 0.018). No antibody increases were observed in unilateral PA patients without ACS and in patients with bilateral PA receiving mineralocorticoid antagonist therapy. Conclusion: ACS appears to be a relevant factor in PA affecting thyroid autoimmune disease. The biochemical and clinical course maybe be exacerbated after resolution of hypercortisolism by adrenalectomy in PA.

Predictive factors of selective mineralocorticoid antagonist treatment in chronic central serous chorioretinopathy

Purpose: To compare the macular morphology of good and poor responders to eplerenone treatment in chronic central serous chorioretinopathy (CSCR) patients. Methods: 30 eyes of 29 patients with chronic CSCR were treated with 50 mg/day oral eplerenone and followed up for one year. The integrity of outer retinal layers at baseline was assessed using optical coherence tomography. Patients who showed complete resolution of subretinal fluid at one year were assigned to the good responder group (Group 1), whilst those who showed moderate or no resolution were classified as poor responders (Group 2). Results: In Group 2 hyperreflective foci in outer segment and outer nuclear layer were significantly more frequent, while ellipsoid zone interruption was significantly more frequent than in Group 1 (p=0.006 and p<0.001 respectively). The multivariable regression analysis showed that intact ellipsoid zone at baseline is an independent predictor of good therapeutic response, with an odds ratio of 26.00 (95% CI: 3.69–183.45; p=0.001). Conclusion: The resolution of subretinal fluid after eplerenone treatment is associated with the integrity of outer retinal layers in CSCR patients. Baseline morphologic evaluation of these layers can be useful in predicting the response to mineralocorticoid antagonist therapy.

Resistant and refractory hypertension: two sides of the same disease?

Refractory hypertension (RfH) is an extreme phenotype of resistant hypertension (RH), being considered an uncontrolled blood pressure besides the use of 5 or more antihypertensive medications, including a long-acting thiazide diuretic and a mineralocorticoid antagonist. RH is common, with 10-20% of the general hypertensives, and its associated with renin angiotensin aldosterone system hyperactivity and excess fluid retention. RfH comprises 5-8% of the RH and seems to be influenced by increased sympathetic activity. RH patients are older and more obese than general hypertensives. It is strongly associated with diabetes, obstructive sleep apnea, and hyperaldosteronism status. RfH is more frequent in women, younger patients and Afro-americans compared to RFs. Both are associated with increased albuminuria, left ventricular hypertrophy, chronic kidney diseases, stroke, and cardiovascular diseases. The magnitude of the white-coat effect seems to be higher among RH patients. Intensification of diuretic therapy is indicated in RH, while in RfH, therapy failure imposes new treatment alternatives such as the use of sympatholytic therapies. In conclusion, both RH and RfH constitute challenges in clinical practice and should be addressed as distinct clinical entities by trained professionals who are capable to identify comorbidities and provide specific, diversified, and individualized treatment.