The Cardiorenal Effects of Chronic Phosphodiesterase-V Inhibition in Preclinical Diastolic Dysfunction (Stage B Heart Failure).

OBJECTIVE: To determine whether chronic phosphodiesterase-V (PDEV) inhibition with tadalafil will improve urinary sodium excretion, glomerular filtration rate (GFR), plasma cyclic guanosine 3', 5'-monophosphate (cGMP), and urinary cGMP excretion in response to volume expansion (VE) in patients with preclinical diastolic dysfunction (PDD) or stage B heart failure. BACKGROUND: PDD is defined as abnormal diastolic function with normal systolic function, without clinical heart failure. PDD is predictive of development of heart failure and all-cause mortality. Impaired renal function and attenuated cGMP response to VE are hallmarks of PDD. METHODS: A double-blind, placebo-controlled, proof-of-concept study was conducted to compare 12 weeks of tadalafil 20 mg daily (n = 14) vs placebo (n = 7). Subjects underwent 2 study visits 12 weeks apart. Renal, neurohormonal and echocardiographic assessments were performed before and after intravascular VE (normal saline 0.25 mL/kg/min for 1 hour). RESULTS: Baseline characteristics were similar. There was no increase in GFR, plasma cGMP or urinary cGMP excretion in response to VE in either group at visit 1. At visit 2, tadalafil did not result in significant change in GFR but increased plasma cGMP and urinary cGMP excretion at baseline. In response to VE, tadalafil resulted in increased urine flow, urinary sodium excretion, GFR (7.00 [-1.0, 26.3] vs -9.00 [-24.5, 2.0] mL/min/1.73m2; P = 0.02) and plasma cGMP (0.50 [-0.1, 0.7] vs -0.25 [-0.6, -0.1] pmol/mL; P = 0.02). It did not improve urinary cGMP excretion after VE. CONCLUSION: In PDD, chronic PDEV inhibition with tadalafil improved renal response to VE through increased urine flow, urinary sodium excretion, GFR, and plasma cGMP. Further studies are required to determine whether this enhanced renal response can mitigate progression to clinical heart failure.

Sex-specific cut-off values for soluble suppression of tumorigenicity 2 (ST2) biomarker increase its cardiovascular prognostic value in the community.

BACKGROUND: Suppression of tumorigenicity 2 (ST2) has important cardiovascular prognostic value in community patients; however, previous analyses have utilized non-sex specific cut-off values. We assessed whether sex-specific ST2 cut-off values would improve the prognostic utility of ST2 in the asymptomatic community. METHODS: A total of 2042 participants underwent clinical assessment and echocardiographic evaluation. Baseline measurements of high sensitivity troponin, natriuretic peptides and ST2 were obtained in 1681 individuals. ST2, cardiac biomarkers and associated co-morbidities were evaluated by sex-specific ST2 quartile analysis. ST2 concentrations were also analysed as dichotomous variables defined as being above the sex-specific cut-off for each the outcomes of heart failure (HF), major adverse cardiac event (MACE) and mortality. RESULTS: Median ST2 concentration was 29.4 ng/mL in male subjects and 24.1 ng/mL in female subjects. Higher ST2 concentrations were associated with incident HF (p<0.001; preserved ejection fraction (EF) p<0.001, reduced EF p=0.23), MACE (p=0.003) and mortality (p<0.001) across sex-specific quartiles. Event-based, hazard ratio (HR) analysis revealed sex-specific ST2 cut-offs were significantly more predictive of incident HF, MACE and mortality compared to non-sex-specific analysis even following adjustment for cardiac co-morbidities and traditional biomarkers. CONCLUSIONS: These data suggest that sex-specific cut-offs, greater than non-sex specific cut-offs, significantly impact the prognostic value of the biomarker ST2 in the asymptomatic community cohort.Clinical SignificanceSuppression of tumorigenicity 2 (ST2) is a biomarker which has known associations with heart failure (HF), major adverse cardiac events (MACEs) and mortality in the general population.Recent data support the concept of sex-specific cut off values and individualized approaches based on sex to predict cardiovascular disease. Given the difference in pathobiology between the sexes, the fact that such approaches improve risk stratification is understandable. Thus, when sex-specific treatments are developed, this may similarly lead to improved outcomes.The use of sex-specific ST2 cut-off values significantly improved the prognostic value in predicting HF, MACE, and mortality in an asymptomatic community. This prognostication was particularly strong for HF with preserved ejection fraction and remained clinically significant following adjustment for cardiac co-morbidities and other traditional cardiac biomarkers (NTproBNP and hscTnI).

Neuroimaging utilization and findings in headache outpatients: Significance of red and yellow flags.

Background Neuroimaging for headache commonly exceeds published guideline recommendations and may be overutilized. Methods We conducted a retrospective cross-sectional study of all outpatient community patients at Mayo Clinic Rochester who underwent a neuroimaging study for a headache indication in 2015. We assessed the neuroimaging utilization pattern, clinical application of red flags, and concordance with neuroimaging guidelines. Results We identified 190 outpatients who underwent 304 neuroimaging studies for headache. The median age was 46.5 years (range 18-91 years), 65% were female, and most reported no prior history of headache (n = 97, 51%). A minority of patients had prior brain imaging studies (n = 44, 23%) and neurological consultations for headache (n = 29, 15%). Few studies were ordered after consultation with a neurologist (n = 14, 7%). Seventy-seven percent of patients were documented to have a "red flag" justifying the imaging study. Abnormal neuroimaging findings were found in 3.1% of patients with warning flags (5/161); carotid dissection (n = 3) and reversible cerebral vasoconstrictive syndrome (n = 2). An estimated 35% of patients were imaged against guidelines. Conclusions The prevalence of serious causes of headache in a community practice was low despite the presence of a documented red flag symptom. Inadequate understanding or application of red flags may be contributing to recommendations to image patients against current guidelines. Interventions to reduce unnecessary neuroimaging of patients with headache need to be designed and implemented.

Rationale and therapeutic opportunities for natriuretic peptide system augmentation in heart failure.

The natriuretic peptide system (NPS) is intimately involved in cardiorenal homeostasis in health, and dysregulation of the NPS plays an important role in the pathophysiology of heart failure (HF). Indeed, the diuretic, vasorelaxation, beneficial remodeling, and potent neurohumoral inhibition of the NPS support the therapeutic development of chronic augmentation of the NPS in symptomatic HF. Further, chronic augmentation of the protective NPS and in early stages of HF may ultimately prevent the progression of HF and reduced subsequent morbidity and mortality. In the current manuscript, we review the rationale for as well as previous and current efforts aimed at chronic therapeutic augmentation of the NPS in HF.

High-sensitivity troponin I and amino-terminal pro--B-type natriuretic peptide predict heart failure and mortality in the general population.

INTRODUCTION: High-sensitivity cardiac troponin assays have potent prognostic value in stable cardiovascular disease cohorts. Our objective was to assess the prognostic utility of a novel cardiac troponin I (cTnI) high-sensitivity assay, independently and in combination with amino-terminal pro-B-type natriuretic peptide (NT-proBNP), for the future development of heart failure and mortality in the general community. METHODS: A well-characterized community-based cohort of 2042 participants underwent clinical assessment and echocardiographic evaluation. Baseline measurements of cTnI with a high-sensitivity assay and NT-proBNP were obtained in 1843 individuals. Participants were followed for new-onset heart failure and mortality with median (25th, 75th percentile) follow-up of 10.7 (7.9, 11.6) and 12.1 (10.4, 13.0) years, respectively. RESULTS: When measured with a high-sensitivity assay, cTnI greater than the sex-specific 80th percentile was independently predictive of heart failure [hazard ratio 2.56 (95% confidence interval 1.88-3.50), P < 0.001] and mortality [1.91(1.49-2.46), P < 0.001] beyond conventional risk factors in this community-based cohort, with significant increases in the net reclassification improvement for heart failure. The prognostic utility of cTnI measured with a high-sensitivity assay goes beyond NT-proBNP, yet our data suggest that these 2 assays are complementary and most beneficial when evaluated together in identifying at-risk individuals in the community. CONCLUSIONS: Our findings lay the foundation for prospective studies aimed at identification of individuals at high risk by use of a multimarker approach, followed by aggressive prevention strategies to prevent subsequent heart failure.

MANP in Hypertension With Metabolic Syndrome: Proof-of-Concept Study of Natriuretic Peptide-Based Therapy for Cardiometabolic Disease.

Hypertension and metabolic syndrome frequently coexist to increase the risk for adverse cardiometabolic outcomes. To date, no drug has been proven to be effective in treating hypertension with metabolic syndrome. M-atrial natriuretic peptide is a novel atrial natriuretic peptide analog that activates the particulate guanylyl cyclase A receptor. This study conducted a double-blind, placebo-controlled trial in 22 patients and demonstrated that a single subcutaneous injection of M-atrial natriuretic peptide was safe, well-tolerated, and exerted pleiotropic properties including blood pressure-lowering, lipolytic, and insulin resistance-improving effects. (MANP in Hypertension and Metabolic Syndrome [MANP-HTN-MS]; NCT03781739).

Defining high-sensitivity cardiac troponin concentrations in the community.

BACKGROUND: High-sensitivity cardiac troponin (hs-cTn) assays are now available that can detect measurable troponin in significantly more individuals in the general population than conventional assays. The clinical use of these hs-cTn assays depends on the development of proper reference values. Therefore, our objective was to define hs-cTnI reference values and determinants in the general community, in a healthy reference cohort, and in subsets with diseases. MATERIALS AND METHODS: A well-characterized community-based cohort of 2042 study participants underwent clinical assessment and echocardiographic evaluation. Baseline hs-cTnI measurements were obtained in 1843 individuals. A healthy reference cohort (n = 565) without cardiac, renal, or echocardiographic abnormalities was identified. RESULTS: Measurable hs-cTnI was identified in 1716 (93%) of the community-based study cohort and 499 (88%) of the healthy reference cohort. Parameters that significantly contributed to higher hs-cTnI concentrations in the healthy reference cohort included age, male sex, systolic blood pressure, and left ventricular mass. Glomerular filtration rate and body mass index were not independently associated with hs-cTnI in the healthy reference cohort. Individuals with diastolic and systolic dysfunction, hypertension, and coronary artery disease (but not impaired renal function) had significantly higher hs-cTnI values than the healthy reference cohort. CONCLUSIONS: We assessed an hs-cTnI assay with the aid of echocardiographic imaging in a large, well-characterized community-based cohort. hs-cTnI is remarkably sensitive in the general population, and there are important sex and age differences among healthy reference individuals. These results have important implications for defining hs-cTnI reference values and identifying disease.

Differential expression of the pro-natriuretic peptide convertases corin and furin in experimental heart failure and atrial fibrosis.

In heart failure (HF), the cardiac hormone natriuretic peptides (NPs) atrial (ANP), B-type (BNP), and C-type (CNP) play a key role to protect cardiac remodeling. The proprotein convertases corin and furin process their respective pro-NPs into active NPs. Here we define in a canine model of HF furin and corin gene and protein expression in normal and failing left atrium (LA) or ventricle (LV) testing the hypothesis that the NP proproteins convertases production is altered in experimental HF. Experimental canine HF was produced by rapid right ventricular pacing for 10 days. NPs, furin, and corin mRNA expression were determined by quantitative RT-PCR. Protein concentration or expression was determined by immunostaining, radioimmunoassay, or Western blot. Furin and corin proteins were present in normal canine LA and LV myocardium and vasculature and in smooth muscle cells. In normal canines, expression of NPs was dominant in the atrium compared with the ventricle. In experimental early stage HF characterized with marked atrial fibrosis, ANP, BNP, and CNP mRNA, and protein concentrations were higher in HF LA but not HF LV compared with normals. In LA, corin mRNA and protein expressions in HF were lower, whereas furin mRNA and protein expressions were higher than normals. NPs and furin expressions were augmented in the atrium in experimental early stage HF and, conversely, corin mRNA and protein expressions were decreased with atrial remodeling. Selective changes of these NP convertases may have significance in the regulation of pro-NP processing and atrial remodeling in early stage HF.

Rationale and design of a randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy of B-type natriuretic peptide for the preservation of left ventricular function after anterior myocardial infarction.

BACKGROUND: B-type natriuretic peptide (BNP) is a hormone with pleiotropic cardioprotective properties. Previously in our non-placebo-controlled non-blinded pilot study (BELIEVE) in human ST-segment-elevation anterior acute myocardial infarction (AMI), a 72-hour intravenous (IV) infusion of recombinant human BNP (nesiritide) at a dose of 0.006 µg kg(-1) min(-1) suppressed plasma aldosterone, reduced cardiac dilatation, and improved left ventricular (LV) ejection fraction (LVEF) at 1 month compared with baseline. METHODS AND DESIGN: The BELIEVE II study is a phase II, randomized, double-blind, placebo-controlled, single-center clinical trial to assess the efficacy of 72-hour IV infusion of nesiritide therapy (0.006 µg kg(-1) min(-1)) in humans with first-time ST-segment-elevation anterior AMI and successful reperfusion, in preventing adverse LV remodeling and preserving LV function. A total of 60 patients will be randomized to placebo or nesiritide therapy. The primary efficacy end point is LV end-systolic and end-diastolic dimensions determined by multiple gated acquisition scan between placebo and nesiritide groups at 30 days; secondary end points include 30-day LVEF, diastolic function, infarct size, LV mass, and combined total mortality and heart failure hospitalization. CONCLUSIONS: This will be the first randomized, double-blind, placebo-controlled clinical trial to assess the clinical efficacy of nesiritide in human ST-segment-elevation anterior AMI.

Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction: a kidney-heart connection.

Impaired renal function with loss of nephron number in chronic renal disease (CKD) is associated with increased cardiovascular morbidity and mortality. However, the structural and functional cardiac response to early and mild reduction in renal mass is poorly defined. We hypothesized that mild renal impairment produced by unilateral nephrectomy (UNX) would result in early cardiac fibrosis and impaired diastolic function, which would progress to a more global left ventricular (LV) dysfunction. Cardiorenal function and structure were assessed in rats at 4 and 16 wk following UNX or sham operation (Sham); (n = 10 per group). At 4 wk, blood pressure (BP), aldosterone, glomerular filtration rate (GFR), proteinuria, and plasma B-type natriuretic peptide (BNP) were not altered by UNX, representing a model of mild early CKD. However, UNX was associated with significantly greater LV myocardial fibrosis compared with Sham. Importantly, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining revealed increased apoptosis in the LV myocardium. Further, diastolic dysfunction, assessed by strain echocardiography, but with preserved LVEF, was observed. Changes in genes related to the TGF-ß and apoptosis pathways in the LV myocardium were also observed. At 16 wk post-UNX, we observed persistent LV fibrosis and impairment in LV diastolic function. In addition, LV mass significantly increased, as did LVEDd, while there was a reduction in LVEF. Aldosterone, BNP, and proteinuria were increased, while GFR was decreased. The myocardial, structural, and functional alterations were associated with persistent changes in the TGF-ß pathway and even more widespread changes in the LV apoptotic pathway. These studies demonstrate that mild renal insufficiency in the rat results in early cardiac fibrosis and impaired diastolic function, which progresses to more global LV remodeling and dysfunction. Thus, these studies importantly advance the concept of a kidney-heart connection in the control of myocardial structure and function.

M-atrial natriuretic peptide: a novel antihypertensive protein therapy.

The natriuretic peptides, specifically atrial natriuretic peptide (ANP), are increasingly recognized to play a fundamental role in blood pressure (BP) regulation. This role in BP regulation reflects the pluripotent cardiorenal actions of ANP, which include diuresis, enhancement of renal blood flow and glomerular filtration rate, systemic vasodilatation, suppression of aldosterone, and inhibition of the sympathetic nervous system. These actions of ANP, in addition to recent human studies demonstrating an association of higher plasma ANP with lower risk of hypertension, support the development of an ANP-based therapy for hypertension. M-ANP is a novel ANP-based peptide that is resistant to proteolytic degradation and possesses greater BP-lowering, renal function-enhancing, and aldosterone-suppressing properties than native ANP. In an animal model of hypertension, M-ANP lowers BP via multiple mechanisms, including vasodilatation, diuresis, and inhibition of aldosterone. Importantly, M-ANP enhances both glomerular filtration rate and renal blood flow despite reductions in BP. The pluripotent BP-lowering actions and concomitant enhancement of renal function associated with M-ANP are highly attractive characteristics for an antihypertensive agent and underscore the therapeutic potential of M-ANP. M-ANP currently is heading into clinical testing, which may advance this novel strategy for human hypertension.

Urinary C-type natriuretic peptide excretion: a potential novel biomarker for renal fibrosis during aging.

Renal aging is characterized by structural changes in the kidney including fibrosis, which contributes to the increased risk of kidney and cardiac failure in the elderly. Studies involving healthy kidney donors demonstrated subclinical age-related nephropathy on renal biopsy that was not detected by standard diagnostic tests. Thus there is a high-priority need for novel noninvasive biomarkers to detect the presence of preclinical age-associated renal structural and functional changes. C-type natriuretic peptide (CNP) possesses renoprotective properties and is present in the kidney; however, its modulation during aging remains undefined. We assessed circulating and urinary CNP in a Fischer rat model of experimental aging and also determined renal structural and functional adaptations to the aging process. Histological and electron microscopic analysis demonstrated significant renal fibrosis, glomerular basement membrane thickening, and mesangial matrix expansion with aging. While plasma CNP levels progressively declined with aging, urinary CNP excretion increased, along with the ratio of urinary to plasma CNP, which preceded significant elevations in proteinuria and blood pressure. Also, CNP immunoreactivity was increased in the distal and proximal tubules in both the aging rat and aging human kidneys. Our findings provide evidence that urinary CNP and its ratio to plasma CNP may represent a novel biomarker for early age-mediated renal structural alterations, particularly fibrosis. Thus urinary CNP could potentially aid in identifying subjects with preclinical structural changes before the onset of symptoms and disease, allowing for the initiation of strategies designed to prevent the progression of chronic kidney disease particularly in the aging population.

Corin is present in the normal human heart, kidney, and blood, with pro-B-type natriuretic peptide processing in the circulation.

BACKGROUND: B-type natriuretic peptide (BNP), which is activated in heart failure (HF), is processed to an active form by corin. The corin gene is expressed in the human heart and kidney, but corin protein expression in the heart, kidney, and circulation, along with whether proBNP is processed by circulating corin, remains unknown. METHODS: We examined corin protein expression by immunostaining and Western blot in human heart and kidney, and we assessed the circulating corin concentration by ELISA. We examined histidine-tagged (His-tag) proBNP(1-108) processing in serum and plasma by immunoprecipitation and Western blot and sequenced the processed form. RESULTS: Normal human heart and kidney displayed the presence of corin, especially in cells around the vasculature. Both corin and proBNP(1-108) were present in the plasma of healthy human subjects, with circulating corin significantly higher in men than women (P < 0.0001) and a positive correlation of corin to age (P = 0.0497, r = 0.27). In fresh normal plasma and serum, His-tag proBNP(1-108) was processed to a lower molecular weight form confirmed to be BNP. Processed BNP was higher in men than women (P = 0.041) and was positively correlated to plasma corin concentrations (P = 0.041, r = 0.65). CONCLUSIONS: Our results support the concept that proBNP(1-108) may be processed outside of the heart in the circulation where the proprotein convertase is present. Moreover, sex may impact this process, since corin concentrations are higher in men. These findings may have important physiologic and pathophysiologic implications for the proBNP/corin system in the human.

STOP-HF Trial: Higher Endogenous BNP and Cardiovascular Protection in Subjects at Risk for Heart Failure.

B-type natriuretic peptide (BNP) possesses blood-pressure-lowering, antifibrotic, and aldosterone-suppressing properties. In Stage A and B heart failure, the carriers of the minor C allele of the BNP genetic variant rs198389 have higher circulating levels of BNP and are at decreased risk of hypertension, new-onset left ventricular systolic dysfunction, and hospitalization for major adverse cardiovascular events. Future studies are warranted to investigate the role of BNP genetic testing and BNP-based therapy in the prevention of heart failure.

Effects of phosphodiesterase V inhibition alone and in combination with BNP on cardiovascular and renal response to volume load in human preclinical diastolic dysfunction.

Preclinical diastolic dysfunction (PDD) results in impaired cardiorenal response to volume load (VL) which may contribute to the progression to clinical heart failure with preserved ejection fraction (HFpEF). The objective was to evaluate if phosphodiesterase V inhibition (PDEVI) alone or combination PDEVI plus B-type natriuretic peptide (BNP) administration will correct the impaired cardiorenal response to VL in PDD. A randomized double-blinded placebo-controlled cross-over study was conducted in 20 subjects with PDD, defined as left ventricular ejection fraction (LVEF) >50% with moderate or severe diastolic dysfunction by Doppler echocardiography and without HF diagnosis or symptoms. Effects of PDEVI with oral tadalafil alone and tadalafil plus subcutaneous (SC) BNP, administered prior to acute volume loading, were assessed. Tadalafil alone did not result in improvement in cardiac response to VL, as measured by LVEF, LV end diastolic volume, left atrial volume (LAV), or right ventricular systolic pressure (RVSP). Tadalafil plus SC BNP resulted in improved cardiac response to VL, with increased LVEF (4.1 vs. 1.8%, p = 0.08) and heart rate (4.3 vs. 1.6 bpm, p = 0.08), and reductions in both LAV (-4.3 ± 10.4 vs. 2.8 ± 6.6 ml, p = 0.03) and RVSP (-4.0 ± 3.0 vs. 2.1 ± 6.0 mmHg, p < 0.01) versus tadalafil alone. Plasma and urinary cyclic guanosine monophosphate (cGMP) excretion levels were higher (11.3 ± 12.3 vs. 1.7 ± 3.8 pmol/ml, 1851.0 ± 1386.4 vs. 173.4 ± 517.9 pmol/min, p < 0.01) with tadalafil plus SC BNP versus tadalafil alone. There was no improvement in renal response as measured by GFR, renal plasma flow, sodium excretion, and urine flow with tadalafil plus SC BNP compared to tadalafil alone. In subjects with PDD, tadalafil alone resulted in no improvement in cardiac adaptation, while tadalafil and SC BNP resulted in enhanced cardiac adaptation to VL. TRIAL REGISTRATION: ClinicalTrials.gov NCT01544998.

Artificial Intelligence-Augmented Electrocardiogram Detection of Left Ventricular Systolic Dysfunction in the General Population.

OBJECTIVE: To validate an artificial intelligence-augmented electrocardiogram (AI-ECG) algorithm for the detection of preclinical left ventricular systolic dysfunction (LVSD) in a large community-based cohort. METHODS: We identified a randomly selected community-based cohort of 2041 subjects age 45 years or older in Olmsted County, Minnesota. All participants underwent a study echocardiogram and ECG. We first assessed the performance of the AI-ECG to identify LVSD (ejection fraction ≤40%). After excluding participants with clinical heart failure, we further assessed the AI-ECG to detect preclinical LVSD among all patients (n=1996) and in a high-risk subgroup (n=1348). Next we modelled an imputed screening program for preclinical LVSD detection where a positive AI-ECG triggered an echocardiogram. Finally, we assessed the ability of the AI-ECG to predict future LVSD. Participants were enrolled between January 1, 1997, and September 30, 2000; and LVSD surveillance was performed for 10 years after enrollment. RESULTS: For detection of LVSD in the total population (prevalence, 2.0%), the area under the receiver operating curve for AI-ECG was 0.97 (sensitivity, 90%; specificity, 92%); in the high-risk subgroup (prevalence 2.7%), the area under the curve was 0.97 (sensitivity, 92%; specificity, 93%). In an imputed screening program, identification of one preclinical LSVD case would require 88.3 AI-ECGs and 8.7 echocardiograms in the total population and 65.7 AI-ECGs and 5.5 echocardiograms in the high-risk subgroup. The unadjusted hazard ratio for a positive AI-ECG for incident LVSD over 10 years was 2.31 (95% CI, 1.32 to 4.05; P=.004). CONCLUSION: Artificial intelligence-augmented ECG can identify preclinical LVSD in the community and warrants further study as a screening tool for preclinical LVSD.

Prevalence of Transthyretin Amyloid Cardiomyopathy in Heart Failure With Preserved Ejection Fraction.

Importance: Heart failure (HF) with preserved ejection fraction (HFpEF) is common, is frequently associated with ventricular wall thickening, and has no effective therapy. Transthyretin amyloid cardiomyopathy (ATTR-CM) can cause the HFpEF clinical phenotype, has highly effective therapy, and is believed to be underrecognized. Objective: To examine the prevalence of ATTR-CM without and with systematic screening in patients with HFpEF and ventricular wall thickening. Design, Setting, and Participants: This population-based cohort study assessed ATTR-CM prevalence in 1235 consecutive patients in southeastern Minnesota with HFpEF both without (prospectively identified cohort study) and with (consenting subset of cohort study, n = 286) systematic screening. Key entry criteria included validated HF diagnosis, age of 60 years or older, ejection fraction of 40% or greater, and ventricular wall thickness of 12 mm or greater. In this community cohort of 1235 patients, 884 had no known ATTR-CM, contraindication to technetium Tc 99m pyrophosphate scanning, or other barriers to participation in the screening study. Of these 884 patients, 295 consented and 286 underwent scanning between October 5, 2017, and March 9, 2020 (community screening cohort). Exposures: Medical record review or technetium Tc 99m pyrophosphate scintigraphy and reflex testing for ATTR-CM diagnosis. Main Outcomes and Measures: The ATTR-CM prevalence by strategy (clinical diagnosis or systematic screening), age, and sex. Results: A total of 1235 patients participated in the study, including a community cohort (median age, 80 years; interquartile range, 72-87 years; 630 [51%] male) and a community screening cohort (n = 286; median age, 78 years; interquartile range, 71-84 years; 149 [52%] male). In the 1235 patients in the community cohort without screening group, 16 patients (1.3%; 95% CI, 0.7%-2.1%) had clinically recognized ATTR-CM. The prevalence was 2.5% (95% CI, 1.4%-4.0%) in men and 0% (95% CI, 0.0%-0.6%) in women. In the 286 patients in the community screening cohort, 18 patients (6.3%; 95% CI, 3.8%-9.8%) had ATTR-CM. Prevalence increased with age from 0% in patients 60 to 69 years of age to 21% in patients 90 years and older (P < .001). Adjusting for age, ATTR-CM prevalence differed by sex, with 15 of 149 men (10.1%; 95% CI, 5.7%-16.1%) and 3 of 137 women (2.2%; 95% CI, 0.4%-6.3%) having ATTR-CM (P = .002). Conclusions and Relevance: In this cohort study based in a community-based setting, ATTR-CM was present in a substantial number of cases of HFpEF with ventricular wall thickening, particularly in older men. These results suggest that systematic evaluation can increase the diagnosis of ATTR-CM, thereby providing therapeutically relevant phenotyping of HFpEF.

CD-NP: an innovative designer natriuretic peptide activator of particulate guanylyl cyclase receptors for cardiorenal disease.

The natriuretic peptide (NP) family consists of structurally similar, although physiologically distinct, peptides that play an important role in cardiorenal homeostasis. CD-NP is a novel chimeric natriuretic peptide developed by the Mayo Clinic, in which the 15-amino acid COOH-terminus of dendroaspis NP is fused to C-type NP. CD-NP is a dual activator of NP receptors A and B, and therefore, possesses the strong antiproliferative and antifibrotic properties of C-type NP with the potent natriuretic, diuretic, and aldosterone-inhibiting properties of dendroaspis NP. CD-NP has favorable cardiorenal properties when compared to recombinant B-type NP (nesiritide), including preservation of glomerular filtration rate with minimal blood pressure-lowering effects. Thus, CD-NP has emerged as an appealing novel therapeutic strategy for heart failure. The endogenous NP system, the development rationale for CD-NP, as well as in vitro, animal, and human studies and future directions will be reviewed.

Synchronous neurology-primary care collaboration in a medical home.

BACKGROUND: Synchronous collaboration as defined by a simultaneous encounter between primary care providers (PCPs), patients, and neurologists may improve access to neurologic expertise, care value, and satisfaction of PCPs and patients. We examined a series of synchronous collaborations and report outcomes, PCP satisfaction, downstream utilization, and illustrative case examples. METHODS: Within an outpatient collaborative primary care-neurology care model, we implemented synchronous video consultations from a central hub to satellite clinics while increasing availability of synchronous telephone and face-to-face collaboration. PCP experience was assessed by a postcollaboration survey. Individual cases were summarized. Clinical and utilization outcomes were assessed by a neurologist immediately after and by follow-up chart review. RESULTS: A total of 58 total synchronous collaborations were performed: 30 by telephone (52%), 18 face to face (31%), and 10 by video (17%) over 27 clinic half-days. The most frequent outcomes as assessed by the neurologist were reassurance of the PCP (23/58; 40%) and patient (22/59; 38%), and the neurologist changed the treatment plan (23/58; 40%). A subsequent face-to-face consultation was completed in 15% (6/58) of patients initially assessed by telephone or video. Test utilization was avoided in 40% (23/58). Unintended utilization occurred 9% (5/58). Most PCPs were very satisfied with the ease of access, quality of care, and reported high likelihood of subsequent use. PCPs perceived similar or less time spent during synchronous vs asynchronous collaboration and neurologist usually altered the testing (87.8%) and treatment plan (95.2%). CONCLUSIONS: Synchronous collaboration between neurologists and PCPs may improve timely access to neurologic expertise, downstream utilization, and PCP satisfaction.