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Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a morbid condition, though recent advances in diagnosis and therapy stand to change its natural history. Patients’ TTR genotype may guide family screening as more treatments and preventive strategies become available. An efficient, intuitive means of determining pretest genetic risk may better inform patients/clinicians when pursuing genetic testing. Methods: This is a cohort study of 767 consecutive patients diagnosed with ATTR-CM who underwent genetic testing. Classification and regression trees (CART) analysis created a decision tree assessing likelihood of carrying a pathologic TTR gene variant. Age, sex, and race were used as independent variables. Logistic regression was also performed to model probability of pathologic TTR genotype. The primary outcome was the decision tree’s accuracy in 2 separate institutions’ ATTR-CM registry. Results: In our study cohort, 208 patients (27.1%) had ATTRv. Race has served most efficiently as the root node followed by age and sex in a CART algorithm, and showed 88.2% accuracy (75.3% sensitivity, 93.9% specificity) in the validation cohort. The odds of having a TTR gene variant were greater in Black patients compared with non-Black patients (OR, 34.6 [95% CI, 20.5–58.3]; P Conclusions: This CART algorithm incorporating age, sex, and race was able to determine which patients with ATTR-CM have pathogenic TTR mutations with high specificity. Non-Black patients diagnosed at age 69 years or older with ATTR-CM have a low likelihood to have ATTRv.

Heart failure affects over 2.6 million women and 3.4 million men in the United States with known sex differences in epidemiology, management, response to treatment, and outcomes across a wide spectrum of cardiomyopathies that include peripartum cardiomyopathy, hypertrophic cardiomyopathy, stress cardiomyopathy, cardiac amyloidosis, and sarcoidosis. Some of these sex-specific considerations are driven by the cellular effects of sex hormones on the renin-angiotensin-aldosterone system, endothelial response to injury, vascular aging, and left ventricular remodeling. Other sex differences are perpetuated by implicit bias leading to undertreatment and underrepresentation in clinical trials. The goal of this narrative review is to comprehensively examine the existing literature over the last decade regarding sex differences in various heart failure syndromes from pathophysiological insights to clinical practice.

Background The coronavirus disease 2019 pandemic has contributed to growing demand for mental health services, but patients face significant barriers to accessing care. Direct-to-consumer(DTC) telemedicine has been proposed as one way to increase access, yet little is known about its pre-pandemic use for mental healthcare. Objective To characterize patients, providers, and their use of a large nationwide DTC telemedicine platform for mental healthcare. Design Retrospective cross-sectional study. Setting Mental health encounters conducted on the American Well DTC telemedicine platform from 2016 to 2018. Participants Patients and physicians. Main Measures Patient measures included demographics, insurance report, and number of visits. Provider characteristics included specialty, region, and number of encounters. Encounter measures included wait time, visit length and timing, out-of-pocket payment, coupon use, prescription outcome, referral receipt, where care otherwise would have been sought, and patient satisfaction. Factors associated with five-star physician ratings and prescription receipt were assessed using logistic regression. Key Results We analyzed 19,270 mental health encounters between 6708 patients and 1045 providers. Visits were most frequently for anxiety (39.1%) or depression (32.5%), with high satisfaction (4.9/5) across conditions. Patients had a median 2.0 visits for psychiatry (IQR 1.0–3.0) and therapy (IQR 1.0–5.0), compared to 1.0 visit (IQR 1.0–1.0) for urgent care. High satisfaction was positively correlated with prescription receipt (OR 1.89, 95% CI 1.54–2.32) and after-hours timing (aOR 1.18, 95% CI 1.02–1.36). Prescription rates ranged from 79.6% for depression to 32.2% for substance use disorders. Prescription receipt was associated with increased visit frequency (aOR 1.95, 95% CI 1.57–2.42 for ≥ 3 visits). Conclusions As the burden of psychiatric disease grows, DTC telemedicine offers one solution for extending access to mental healthcare. While most encounters were one-off, evidence of some continuity in psychiatry and therapy visits—as well as overall high patient satisfaction—suggests potential for broader DTC telemental health use. Supplementary Information The online version contains supplementary material available at 10.1007/s11606-021-07326-y.

IntroductionChemotherapy-induced cardiomyopathy has been increasingly recognised as patients are living longer with more effective treatments for their malignancies. Anthracyclines are known to cause left ventricular (LV) dysfunction. While heart failure medications are frequently used, some patients may need consideration for device-based therapies such as cardiac resynchronisation therapy (CRT). However, the role of CRT in anthracycline-induced cardiomyopathy (AIC) is not well understood.MethodsWe performed a retrospective review of all patients undergoing CRT implantation at our centre from 2003 to 2019 with a diagnosis of AIC. The LV remodelling and survival outcomes of this population were obtained and then compared with consecutive patients with other aetiologies of non-ischaemic cardiomyopathy (NICM).ResultsA total of 34 patients underwent CRT implantation with a diagnosis of AIC with a mean age of 60.5±12.7 years, left ventricular ejection fraction (LVEF) of 21.7%±7.4%, and 11.3±7.5 years and 10.2±7.4 years from cancer diagnosis and last anthracycline exposure, respectively. At 9.6±8.1 months after CRT implantation, there was an increase of LVEF from 21.8%±7.6% to 30.4%±13.0% (pConclusionsPatients with AIC undergo LV remodelling with CRT at rates similar to other aetiologies of NICM. Furthermore, AIC post-CRT responders have a favourable long-term mortality compared with non-responders.

Despite the rapid expansion of noninvasive (nonbiopsy) diagnosis, contemporary patients with cardiac amyloidosis too often present with advanced features of disease, such as diminished quality of life, elevated natriuretic peptides, and advanced heart failure. Therapeutics for transthyretin cardiomyopathy (ATTR-CM) are most effective when administered before significant symptoms of cardiac dysfunction manifest, making early identification of affected individuals of paramount importance. Community engagement and ensuring that a broad range of clinicians have working knowledge of how to screen for ATTR-CM in everyday practice will be an important step in moving disease identification further upstream. However, reliance on the appropriate and timely diagnosis by individual clinicians may continue to underperform. This review highlights how targeted screening of special populations may facilitate earlier diagnosis. Systems of care that operationalize screening of high-risk subpopulations and prospective validation of novel approaches to ATTR-CM identification are needed.

Given the limited population level, adoption of optimal therapy that has been shown in recent clinical trials and heart failure registries, efforts to rapidly and safely improve adoption of guideline-directed medical therapy for heart failure should be prioritized. Opportunities to leverage remote monitoring technology, the electronic health record (EHR), and multidisciplinary teams to improve heart failure care merit review.Dedicated multidisciplinary teams employing algorithmic medication titration schema have shown better efficacy than clinician alerts or quality initiatives that focus on education and audit-feedback processes alone. Technology that enables invasive pressure monitoring and wearable devices that transmit physiologic data have the potential to predict decompensation and allow for early intervention by alerting clinicians to signs of congestion/clinical worsening but further real-world data is needed to prove efficacy and develop effective treatment protocols.The combination of technology, multidisciplinary teams, and identification of populations for intervention using the EHR will be central to impactful innovation in heart failure population health and prevention of avoidable morbidity. Novel approaches to study implementation efforts including cluster randomized trials are needed.

Background: Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized disease, in which atrial fibrillation (AF) has been shown to be prevalent. Cardiac scintigraphy with technetium-99m-pyrophosphate (99mTc-PyP) labeled bone-seeking tracers is used to noninvasively make the diagnosis of ATTR-CA, based on ventricular myocardial uptake. Assessment of atrial wall uptake (AU) on 99mTc-PyP is currently not used in the clinical setting Methods: We analyzed a cohort of patients referred for 99mTc-PyP scan at a tertiary center to explore AU and associations between any and incident AF, ATTR-CA, and all-cause mortality. Results: Among 580 patients included, 296 patients (51%) had a diagnosis of AF; 164 patients (28%) had scans consistent with ATTR-CA while 117 patients (20%) had AU. Of 117 patients with AU, 107 (91%) had any AF. In contrast, of 463 patients without AU 191(41%) had any AF. Of those with AU, 59/117(50%) patients had a 99mTc-PyP diagnosis of ATTR-CA while 58/117(50%) patients did not have such a diagnosis ( P =1.00). Patients with AU had significantly more any AF (hazard ratio [HR], 1.03 [95% CI, 1.02–1.04]; P P P P P Conclusions: In a consecutive cohort of patients undergoing 99mTc-PyP scans, 20% had AU, which was statistically associated with any AF, independently of ATTR-CA diagnosis and sex. AU was associated with significantly lower freedom from incident AF at 1-year. Overlooking AU on 99mTc-PyP scans could potentially miss an earlier disease manifestation, or an additional risk factor for any/incident AF.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. Given the expansion of noninvasive diagnosis withThis single-center retrospective cohort study included 351 consecutive patients who underwent a standardized imaging protocol withWe included 318 patients in the analysis (n = 86 patients +ATTR-CM; n = 232 patients -ATTR-CM). The median follow-up time was 20.1 months. During the study period, 67% of +ATTR-CM patients received tafamidis (median treatment duration, 17 months). The median H/CL ratio was 1.58 (interquartile range, 1.40-1.75). An H/CL ratio of more than 1.6 or less than 1.6 did not seem to have an impact on survival probability in +ATTR-CM patients (P = .30; hazard ratio, 0.65; 95% confidence interval, 0.31-1.41). Cardiac biomarkers were poorly correlated with H/CL (troponin T, RAt a large referral center, the intensity of

Non-alcoholic fatty liver disease (NAFLD) affects over 30% of adults in the United States. Bone morphogenetic protein (BMP) signaling is known to contribute to hepatic fibrosis, but the role of BMP signaling in the development of NAFLD is unclear. In this study, treatment with either of two BMP inhibitors reduced hepatic triglyceride content in diabetic (db/db) mice. BMP inhibitor-induced decrease in hepatic triglyceride levels was associated with decreased mRNA encoding Dgat2, an enzyme integral to triglyceride synthesis. Treatment of hepatoma cells with BMP2 induced DGAT2 expression and activity via intracellular SMAD signaling. In humans we identified a rare missense single nucleotide polymorphism in the BMP type 1 receptor ALK6 (rs34970181;R371Q) associated with a 2.1-fold increase in the prevalence of NAFLD. In vitro analyses revealed R371Q:ALK6 is a previously unknown constitutively active receptor. These data show that BMP signaling is an important determinant of NAFLD in a murine model and is associated with NAFLD in humans.

Introduction Functional status assessment in the HF population has typically relied on self-reported questionnaires like Kansas City Cardiomyopathy Questionnaire (KCCQ). Since 2011, Cleveland Clinic physical therapists have administered an objective, validated measure of physical function—the Activity Measure for Post-Acute Care (PAC) ”6-Clicks”. 6-Clicks assesses ability to turn in bed, sit, transfer from bed to chair, stand, walk, eat, dress, bathe, perform personal care and use the bathroom. Scores range from 6 to 24, with higher scores representing greater functional independence. We characterized the association between 6-clicks score and PAC disposition (home, home care, or SNF) in patients admitted for HF whose relative functional status was moderate (score >12) or better. Establishing if an objective functional status assessment is associated with PAC disposition in HF patients has not been previously described. Understanding factors driving facility use post-discharge may have implications for length of stay, patient satisfaction, health system costs, external quality measures, and efforts to decrease facility usage in the COVID era. Methods/Results In 2019, 772 patients with CHF-DRGs were admitted to the Cleveland Clinic hospitals across Ohio. Patients with 6-clicks Conclusion Lower 6-clicks functional status scores were associated with discharge to SNF in HF patients. Living alone had a trend toward association with facility use but did not meet statistical significance. Given significant overlap in functional status across disposition destinations, however, other factors beyond functional status including family support factor into discharge disposition.

Purpose PIONEER-HF established the safety of the angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril-valsartan (S/V), in patients hospitalized with acute decompensated heart failure after achieving hemodynamic stability. We have previously shown that transitioning patients in ADHF with low cardiac output directly from intravenous (IV) vasoactive (i.e. vasodilators or inotropes) drugs to ARNI can be done safely with tolerance to one-month follow-up. Here we further characterize the acute hemodynamic impact of ARNI therapy after patients have been optimized on IV vasoactive therapy. Methods A single-center, retrospective analysis of all patients with HFrEF (EF Conclusions ICU patients can be successfully bridged from vasoactive IV therapy to oral ARNI with sustained improvement in cardiac index garnered from vasoactive agents. We also observed improvement in PAPI along with maintenance of LV/RV unloading with ARNI. These encouraging findings merit prospective validation of ARNI compared to more commonly used oral vasodilators in ICU care.

Purpose PIONEER-HF established the safety of the angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril-valsartan (S/V), in patients hospitalized with acute decompensated heart failure after achieving hemodynamic stability. We have previously shown that transitioning patients in cardiogenic shock directly from intravenous (IV) vasoactive (i.e. vasodilators or inotropes) drugs to S/V can be done safely with tolerance to one-month follow-up. Here we further characterize the hemodynamic impact of S/V after patients have been optimized on vasoactive therapy. Methods A single-center, retrospective analysis of all patients with HFrEF (EF Results Twenty-two patients with HFreF and cardiac index below 2.2 L/min/m2 were admitted to the CICU and newly initiated on S/V. Table 1a contains baseline characteristics and vasoactive therapy given. All patients were weaned off vasoactive medications prior to transfer out of CICU. Patients maintained their significant hemodynamic improvement on transition from IV to oral vasoactive therapy. There was an increase in Pulmonary Artery Pulsatility index (PAPi) with S/V therapy (Table 1b). Patients who did not tolerate ARNI initiation had lower filling pressures and systolic blood pressure compared to patients who tolerated ARNI initiation. Seventeen patients were discharged home on S/V, and 94% remained on S/V one-month in follow-up. Conclusion ICU patients can be successfully bridged from vasoactive IV therapy to oral S/V with sustained hemodynamic improvement garnered from vasoactive agents. We also observed improvement in PAPi with S/V compared to both admission and vasoactive therapy. These encouraging findings merit further prospective study.

The benefits of angiotensin receptor-neprilysin inhibitor (ARNI) in patients with heart failure with reduced ejection fraction (HFrEF) are well established [(1)][1]. The majority of patients with HFrEF are receiving suboptimal guideline-directed medical therapy (GDMT). Data from the CHAMP-HF (Change

Introduction Sacubitril/valsartan (S/V) is superior to enalapril in reducing mortality and morbidity in patients with chronic stable heart failure with reduced ejection fraction (HFrEF). The goal of this investigation was to determine if S/V could be used safely as an oral vasodilator when weaning intravenous vasoactive therapies. Methods Invasive hemodynamic data was prospectively collected from ten consecutive patients with Stage D HFrEF admitted to the heart failure intensive care unit (HF-ICU) for treatment of acute decompensated heart failure. All patients were admitted for pulmonary artery catheter hemodynamic guided therapy and were initiated on S/V. Results Ten patients were included in the cohort and were on either intravenous inotropes n=3 or sodium nitroprusside (SNP) n=7. Mean dose of SNP was 151 mcg/min, mean dose for dobutamine was 5 mcg/kg/min and milrinone dose was 0.5 mcg/kg/min. Mean age was 50 years old, with 4 females and 6 males. Three patients with ischemic cardiomyopathy, 7 non-ischemic cardiomyopathy. All patients were successfully weaned from inotropes or SNP and tolerated S/V initiation. Average mean arterial pressure of the cohort decreased from 88.3 to 80.6 mmHg (9% reduction), right atrial pressure decreased from 15.6 to 5 mmHg (70% reduction), mean pulmonary artery pressure decreased from 43.6 to 27.3 mmHg (37% reduction), pulmonary capillary wedge pressure decreased from 28.4 to 14.7 mmHg (48% reduction), mean cardiac index increased from 1.7 to 2.56 l/min/m2 (51% increase) and mixed venous saturation increased from 52.6 to 67.2% (22% increase). The detailed hemodynamic results for each patient are summarized in Table 1. S/V was well tolerated and hemodynamics were stable after weaning IV therapy. Conclusion Patients with cardiogenic shock tolerated initiation of S/V and subsequent successful weaning of intravenous vasodilator or inotropic therapy. These preliminary novel hemodynamic observations suggest S/V may be initiated safely in ICU patients and facilitate weaning from intravenous therapies.

Introduction A recent randomized clinical study established the safety of the angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril-valsartan (S/V), in patients hospitalized with acute decompensated heart failure after achieving hemodynamic stability. Transitioning patients in cardiogenic shock managed with pulmonary artery catheters directly from intravenous vasoactive (i.e. vasodilators or inotropes) drugs to S/V represents a potentially novel use for ARNIs. The tolerability and hemodynamic characteristics of S/V in patients with cardiogenic shock has not been previously established. Methods A single-center, retrospective analysis of all patients with heart failure and a reduced ejection fraction (HFrEF) (EF Results Twenty-two patients in the CICUs with HFrEF were started on S/V. The baseline characteristics, pertinent lab values, and hemodynamic profile (CI, SVR), are presented (Image 1). Ninety-five percent (n=21) of patients were on either of sodium nitroprusside, milrinone, dobutamine, or a combination these agents, at the time of initiation. Seventy-seven percent (n=17/22) patients were discharged on S/V with improved hemodynamics (Image 1,2). Hypotension was the most common reason for discontinuation (n=4) however one patient had both acute kidney injury and hypotension (n=1); no patients had hyperkalemia or death (n=0) (Image 2). Two of five intolerant patients were initiated on moderate (49-51) dose S/V. Conclusions The novel use S/V as oral vasodilator therapy in patients with cardiogenic shock shows favorable hemodynamic impact and tolerability. Long term tolerability and outcomes are required.

Cardiovascular disease is the leading cause of morbidity and mortality in the world. Atherosclerotic plaques, consisting of lipid-laden macrophages and calcification, develop in the coronary arteries, aortic valve, aorta, and peripheral conduit arteries and are the hallmark of cardiovascular disease. In humans, imaging with computed tomography allows for the quantification of vascular calcification; the presence of vascular calcification is a strong predictor of future cardiovascular events. Development of novel therapies in cardiovascular disease relies critically on improving our understanding of the underlying molecular mechanisms of atherosclerosis. Advancing our knowledge of atherosclerotic mechanisms relies on murine and cell-based models. Here, a method for imaging aortic calcification and macrophage infiltration using two spectrally distinct near-infrared fluorescent imaging probes is detailed. Near-infrared fluorescent imaging allows for the ex vivo quantification of calcification and macrophage accumulation in the entire aorta and can be used to further our understanding of the mechanistic relationship between inflammation and calcification in atherosclerosis. Additionally, a method for isolating and culturing animal aortic vascular smooth muscle cells and a protocol for inducing calcification in cultured smooth muscle cells from either murine aortas or from human coronary arteries is described. This in vitro method of modeling vascular calcification can be used to identify and characterize the signaling pathways likely important for the development of vascular disease, in the hopes of discovering novel targets for therapy.

PLoS one 10(1), e0117098 (2015). doi:10.1371/journal.pone.0117098, Published by PLoS, Lawrence, Kan.

Background: Matrix Gla protein (MGP) is an extracellular matrix protein that inhibits bone morphogenetic protein (BMP) signaling in vitro. MGP deficiency induces vascular calcification associated with osteogenic transdifferentiation of endothelial cells (via endothelial-mesenchymal transition, EndMT) and vascular smooth muscle cells (VSMCs). We previously reported that treatment with two pharmacologic inhibitors of BMP signaling reduced aortic calcification in MGP-/- mice. We hypothesized that BMP signaling is essential for EndMT and VSMC osteogenic transdifferentiation induced by MGP deficiency. Methods and Results: Aortic levels of mRNAs encoding markers of osteogenesis (Runx2 and osteopontin) and EndMT (nanog, Sox2, and Oct3/4) were greater in MGP-/- than in wild-type mice (P Conclusions: Inhibition of BMP signaling suppresses osteogenic and EndMT gene programs in MGP-/- mice and reduces calcification of siMGP-treated VSMCs. However, MGP deficiency induces VSMC de-differentiation via a BMP-independent mechanism. These findings suggest that the processes underlying vascular calcification in MGP deficiency are mediated by both BMP signaling-dependent and -independent mechanisms.

Transfusion of stored RBCs is associated with increased morbidity and mortality in trauma patients. Plasma hemoglobin scavenges nitric oxide, which can cause vasoconstriction, induce inflammation, and activate platelets. We hypothesized that transfusion of RBCs stored for prolonged periods would induce adverse effects (pulmonary vasoconstriction, tissue injury, inflammation, and platelet activation) in lambs subjected to severe hemorrhagic shock and that concurrent inhalation of nitric oxide would prevent these adverse effects.Animal study.Research laboratory at the Massachusetts General Hospital, Boston, MA.Seventeen awake Polypay-breed lambs.Lambs were subjected to 2 hours of hemorrhagic shock by acutely withdrawing 50% of their blood volume. Lambs were resuscitated with autologous RBCs stored for 2 hours or less (fresh) or 39 ± 2 (mean ± SD) days (stored). Stored RBCs were administered with or without breathing nitric oxide (80 ppm) during resuscitation and for 21 hours thereafter.We measured hemodynamic and oxygenation variables, markers of tissue injury and inflammation, plasma hemoglobin concentrations, and platelet activation. Peak pulmonary arterial pressure was higher after resuscitation with stored than with fresh RBCs (24 ± 4 vs 14 ± 2 mm Hg, p0.001) and correlated with peak plasma hemoglobin concentrations (R = 0.56, p = 0.003). At 21 hours after resuscitation, pulmonary myeloperoxidase activity was higher in lambs resuscitated with stored than with fresh RBCs (11 ± 2 vs 4 ± 1 U/g, p = 0.007). Furthermore, transfusion of stored RBCs increased plasma markers of tissue injury and sensitized platelets to adenosine diphosphate activation. Breathing nitric oxide prevented the pulmonary hypertension and attenuated the pulmonary myeloperoxidase activity, as well as tissue injury and sensitization of platelets to adenosine diphosphate.Our data suggest that resuscitation of lambs from hemorrhagic shock with autologous stored RBCs induces pulmonary hypertension and inflammation, which can be ameliorated by breathing nitric oxide.

PLoS one 8(10), e76947 (2013). doi:10.1371/journal.pone.0076947, Published by PLoS [u.a.], Lawrence, Kan.