Donation after circulatory death: A transplant cardiologist's take on neuroprognostication.

Donation after circulatory death (DCD) is becoming increasingly utilized in heart transplantation and has the potential to further expand the donor pool. As transplant cardiologists gain more familiarity with DCD donor selection, there are many issues that lack consensus including how we incorporate the neurologic examination, how we measure functional warm ischemic time (fWIT), and what fWIT thresholds are acceptable. DCD donor selection calls for prognostication tools to help determine how quickly a donor may expire, and in current practice there is no standardization in how we make these predictions. Current scoring systems help to determine which donor may expire within a specified time window either require the temporary disconnection of ventilatory support or do not incorporate any neurologic examination or imaging. Moreover, the specified time windows differ from other DCD solid organ transplantation without standardization or strong scientific justification for these thresholds. In this perspective, we highlight the challenges faced by transplant cardiologists as they navigate the muddy waters of neuroprognostication in DCD cardiac donation. Given these difficulties, this is also a call to action for the creation of a more standardized approach to improve the DCD donor selection process for appropriate resource allocation and organ utilization.

Sex and gender differences in myocarditis and dilated cardiomyopathy: An update.

In the past decade there has been a growing interest in understanding sex and gender differences in myocarditis and dilated cardiomyopathy (DCM), and the purpose of this review is to provide an update on this topic including epidemiology, pathogenesis and clinical presentation, diagnosis and management. Recently, many clinical studies have been conducted examining sex differences in myocarditis. Studies consistently report that myocarditis occurs more often in men than women with a sex ratio ranging from 1:2-4 female to male. Studies reveal that DCM also has a sex ratio of around 1:3 women to men and this is also true for familial/genetic forms of DCM. Animal models have demonstrated that DCM develops after myocarditis in susceptible mouse strains and evidence exists for this progress clinically as well. A consistent finding is that myocarditis occurs primarily in men under 50 years of age, but in women after age 50 or post-menopause. In contrast, DCM typically occurs after age 50, although the age that post-myocarditis DCM occurs has not been investigated. In a small study, more men with myocarditis presented with symptoms of chest pain while women presented with dyspnea. Men with myocarditis have been found to have higher levels of heart failure biomarkers soluble ST2, creatine kinase, myoglobin and T helper 17-associated cytokines while women develop a better regulatory immune response. Studies of the pathogenesis of disease have found that Toll-like receptor (TLR)2 and TLR4 signaling pathways play a central role in increasing inflammation during myocarditis and in promoting remodeling and fibrosis that leads to DCM, and all of these pathways are elevated in males. Management of myocarditis follows heart failure guidelines and there are currently no disease-specific therapies. Research on standard heart failure medications reveal important sex differences. Overall, many advances in our understanding of the effect of biologic sex on myocarditis and DCM have occurred over the past decade, but many gaps in our understanding remain. A better understanding of sex and gender effects are needed to develop disease-targeted and individualized medicine approaches in the future.

Non-invasive detection of cardiac allograft rejection among heart transplant recipients using an electrocardiogram based deep learning model.

Aims: Current non-invasive screening methods for cardiac allograft rejection have shown limited discrimination and are yet to be broadly integrated into heart transplant care. Given electrocardiogram (ECG) changes have been reported with severe cardiac allograft rejection, this study aimed to develop a deep-learning model, a form of artificial intelligence, to detect allograft rejection using the 12-lead ECG (AI-ECG). Methods and results: Heart transplant recipients were identified across three Mayo Clinic sites between 1998 and 2021. Twelve-lead digital ECG data and endomyocardial biopsy results were extracted from medical records. Allograft rejection was defined as moderate or severe acute cellular rejection (ACR) based on International Society for Heart and Lung Transplantation guidelines. The extracted data (7590 unique ECG-biopsy pairs, belonging to 1427 patients) was partitioned into training (80%), validation (10%), and test sets (10%) such that each patient was included in only one partition. Model performance metrics were based on the test set (n = 140 patients; 758 ECG-biopsy pairs). The AI-ECG detected ACR with an area under the receiver operating curve (AUC) of 0.84 [95% confidence interval (CI): 0.78-0.90] and 95% (19/20; 95% CI: 75-100%) sensitivity. A prospective proof-of-concept screening study (n = 56; 97 ECG-biopsy pairs) showed the AI-ECG detected ACR with AUC = 0.78 (95% CI: 0.61-0.96) and 100% (2/2; 95% CI: 16-100%) sensitivity. Conclusion: An AI-ECG model is effective for detection of moderate-to-severe ACR in heart transplant recipients. Our findings could improve transplant care by providing a rapid, non-invasive, and potentially remote screening option for cardiac allograft function.

Association of Pulmonary Hypertension and Monoclonal Gammopathy of Undetermined Significance.

Objective: To determine the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with PH as well as precapillary PH. Methods: Olmsted County residents with PH, diagnosed between 1/1/1995 and 9/30/2017, were identified, and age and sex were matched to a normal control group. The PH group and normal control group were then cross-referenced with the Mayo Clinic MGUS database. Charts were reviewed to verify MGUS and PH. Heart catheterization data were then analyzed in these patients for reference to the gold standard for diagnosis. Results: There were 3419 patients diagnosed with PH by echocardiography between 1995 and 2017 in Olmsted County that met the criteria of our study. When the PH group (N = 3313) was matched to a normal control group (3313), a diagnosis of MGUS was significantly associated with PH 10.2% (OR = l.84 [95% CI 1.5-2.2], p < 0.001), compared with controls 5.8% based on echo diagnosis. Using heart catheterization data (484 patients), a diagnosis of MGUS was associated with PH 13.0% (OR = 3.94 [95% CI 2.28-6.82], p < 0.001). For pulmonary artery hypertension (N = 222), a diagnosis of MGUS was associated with PH at similar 12.2% (OR = 4.50 [95%CI 1.86-10.90], p < 0.001. Conclusions: There is a higher prevalence of MGUS in patients with PH and precapillary PH compared with normal controls. This association cannot be explained fully by other underlying diagnoses associated with PH. Assessing for this in patients with PH of unclear etiology may be reasonable in the workup of patients found to have PH.

Heart transplantation in Val142Ile mutation in the modern era: A single center experience.

Little is known about the post heart transplantation management of extra cardiac manifestations in patients with hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) in the new era of disease modifying treatment for ATTR amyloidosis. This is a retrospective study of all patients with hATTR-CM associated with the Val142Ile variant who underwent heart transplantation (HT) from January 2014 to February 2022. All 10 patients with the Val142Ile mutation were successfully transplanted, with a 1 year survival post heart transplantation (HT) of 90%, comparable to an age, sex, and race matched cohort of patients transplanted for non-amyloid indications. However, 4 (40%) of these patients developed progressive extracardiac manifestations requiring initiation of TTR silencer therapy with the small interfering RNA (siRNA) drug patisiran, which was well tolerated with no significant side effects in this population. We recommend formal neurologic evaluation and assessment of extracardiac manifestations annually as part of routine post-transplant care, and disease modifying therapy, aimed at TTR stabilization or silencing, should be initiated in the context of previously untreated extracardiac manifestations or evidence of subclinical neuropathy to prevent progression.

Ventricular arrhythmia burden and implantable cardioverter-defibrillator outcomes in transthyretin cardiac amyloidosis.

BACKGROUND: As targeted treatments for amyloid transthyretin cardiomyopathy (ATTR-CM) are becoming available, we aim to characterize the rates of ventricular arrhythmias (VAs), implantable cardioverter-defibrillator (ICD) utilization, and their impact on survival. METHODS: This is a retrospective cohort study of 130 patients with ATTR-CM diagnosed at Emory University's Cardiac Amyloidosis Center between April 2012 and September 2020. VAs were defined as nonsustained or sustained ventricular tachycardia and ventricular fibrillation. RESULTS: Of 130 patients, 42 had wild-type disease (wtATTR) and 88 had hereditary variants (hATTR), most commonly Val122Ile (89%). At ATTR-CM diagnosis, 80 (62%) patients had EF ≤ 40% consistent with systolic heart failure. Of the 69 (53%) patients with documented VAs significantly higher rates occurred among those with EF ≤ 40% compared with EF > 40% (67% vs. 28%, p = .001). Thirty-two patients (25 hATTR, 7 wtATTR) had primary prevention ICDs implanted. Eight (25%) of these patients received appropriate ICD therapy while two (6%) experienced inappropriate therapy. Comparing patients with EF ≤ 35% with and without ICDs did not reveal any survival difference (3.3 ± 0.5 vs. 2.8 ± 0.4 years, p = .699). CONCLUSIONS: High rates of VAs and appropriate ICD therapy were found among a unique cohort of largely hereditary ATTR-CM patients with a high rate of systolic heart failure.

The vasculature in HFpEF vs HFrEF: differences in contractile protein expression produce distinct phenotypes.

Both heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction are associated with abnormalities of the vasculature, including a resting vasoconstriction and a decrease in sensitivity to nitric oxide (NO) mediated vasodilation. Vascular tone is controlled by the expression and activation of both smooth muscle (SM) and nonmuscle (NM) myosin, and NO mediated vasodilation is regulated by the expression of the leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase (MLCP). This study was designed to determine the expression of these contractile proteins in humans with HFrEF and HFpEF vs normal controls. We isolated tertiary mesenteric vessels from remnant biospecimens of patients undergoing partial or total colectomy at Mayo Clinic Rochester from August 2017 to December 2018, and examined the expression of MYPT1 and the LZ + MYPT1 isoform with immunoblots, while 2D SDS-PAGE was used to resolve the phosphorylated and nonphosphorylated regulatory light chains of NM and SM myosin. Our data show that NM myosin expression, as a percentage of total myosin, was 12 ± 3% (controls, n = 6), 7 ± 5% (HFpEF, n = 4) and 37 ± 18% (HFrEF, n = 5, p < 0.05). Total MYPT1 expression was significantly reduced (p < 0.05) in both HFpEF (70 ± 11%) and HFrEF (48 ± 6%); and in HFrEF, LZ + MYPT1 was also depressed (62 ± 19%, <0.05). These results demonstrate that HFrEF and HFpEF are distinct vascular entities, and the changes in protein expression contribute to the vascular abnormalities associated with these diseases. Further in HFpEF, the decrease in MYPT1 would explain why pharmacologic therapies that are designed to activate the NO/cGMP/PKG signaling pathway do not produce a clinical benefit.

Circulating Neprilysin in Patients With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: In heart failure with reduced ejection fraction (HFrEF), elevated soluble neprilysin (sNEP) levels are associated with an increased risk of cardiovascular death, and its inhibition with sacubitril/valsartan has improved survival. OBJECTIVES: This study sought to determine the relevance of sNEP as a biomarker in heart failure with preserved ejection fraction (HFpEF) and to compare circulating sNEP levels in patients with HFpEF with normal controls. METHODS: A case-control study was performed in 242 symptomatic patients with HFpEF previously enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) and Nitrates's Effect on Activity Tolerance in Heart Failure With Preserved Ejection (NEAT-HFpEF) clinical trials and 891 asymptomatic subjects without HF or diastolic dysfunction (confirmed by NT-proBNP levels <200 pg/ml and echocardiography) who were enrolled in the Prevalence of Asymptomatic Left Ventricular Dysfunction study. sNEP was measured using a sandwich enzyme-linked immunosorbent assay (ELISA) in all subjects. RESULTS: Overall, sNEP levels were lower in HFpEF compared with controls (3.5 ng/ml; confidence interval [CI]: 2.5 to 4.8 vs. 8.5 ng/ml; CI: 7.2 to 10.0; p < 0.001). After adjusting for age, gender, body mass index (BMI), and smoking history, mean sNEP levels were also lower in HFpEF compared with controls (4.0 ng/ml [CI: 2.7 to 5.4] vs. 8.2 ng/ml [CI: 6.8 to 9.7]; p = 0.002). The cohorts were propensity matched based on age, BMI, diabetes, hypertension, smoking history, and renal function, and sNEP levels remained lower in HFpEF compared with controls (median 2.4 ng/ml [interquartile range: 0.6 to 27.7] vs. 4.9 ng/ml [interquartile range: 1.2 to 42.2]; p = 0.02). CONCLUSIONS: Patients with HFpEF on average have significantly lower circulating sNEP levels compared with controls. These findings challenge our current understanding of the complex biology of circulating sNEP in HFpEF.

HFpEF, a Disease of the Vasculature: A Closer Look at the Other Half.

Patients with heart failure are commonly divided into those with reduced ejection fraction (EF<40%) and those with preserved ejection fraction (HFpEF; EF>50%). For heart failure with reduced EF, a number of therapies have been found to improve patient morbidity and mortality, and treatment is guideline based. However for patients with HFpEF, no treatment has been found to have clinical benefit. To objectively assess treatments for HFpEF, a comprehensive PubMed literature search was performed using the terms HFpEF, heart failure, smooth muscle, myosin, myosin phosphatase, and PKG (up to December 31, 2017), with an unbiased focus on pathophysiology, cell signaling, and therapy. This review provides evidence that could explain the lack of clinical benefit in treating patients with HFpEF with sildenafil and long-acting nitrates. Furthermore, the review highlights the vascular abnormalities present in patients with HFpEF, and these abnormalities of the vasculature could potentially contribute to the pathophysiology of HFpEF. Thus, focusing on HFpEF as a vascular disease could result in the development of novel and effective treatment paradigms.

Regulation of Pulmonary Vascular Smooth Muscle Contractility in Pulmonary Arterial Hypertension: Implications for Therapy.

There are two primary components that produce pulmonary arterial hypertension (PAH); aberrant structural changes (smooth muscle cell proliferation, smooth muscle cell hypertrophy, and the deposition of matrix proteins within the media of pulmonary arterial vessels), and excess vasoconstriction. However, in PAH, the target and aim of all current therapeutic agents is to reduce the contractility of the pulmonary vasculature; prostaglandins, phosphodiesterase inhibitors, guanylate cyclase stimulators, endothelin antagonists, NO inhalation and Rho kinase inhibitors all influence signaling pathways in the pulmonary vascular smooth muscle to decrease vasoconstriction, and hence, pulmonary vascular resistance (PVR). This review will therefore primarily focus on discussing the signaling pathways regulating contractility in pulmonary vascular smooth muscle, the mechanism for current treatments, as well as highlighting potential targets for the development of novel therapies.

Speaker Introductions at Internal Medicine Grand Rounds: Forms of Address Reveal Gender Bias.

BACKGROUND: Gender bias has been identified as one of the drivers of gender disparity in academic medicine. Bias may be reinforced by gender subordinating language or differential use of formality in forms of address. Professional titles may influence the perceived expertise and authority of the referenced individual. The objective of this study is to examine how professional titles were used in the same and mixed-gender speaker introductions at Internal Medicine Grand Rounds (IMGR). METHODS: A retrospective observational study of video-archived speaker introductions at consecutive IMGR was conducted at two different locations (Arizona, Minnesota) of an academic medical center. Introducers and speakers at IMGR were physician and scientist peers holding MD, PhD, or MD/PhD degrees. The primary outcome was whether or not a speaker's professional title was used during the first form of address during speaker introductions at IMGR. As secondary outcomes, we evaluated whether or not the speakers professional title was used in any form of address during the introduction. RESULTS: Three hundred twenty-one forms of address were analyzed. Female introducers were more likely to use professional titles when introducing any speaker during the first form of address compared with male introducers (96.2% [102/106] vs. 65.6% [141/215]; p < 0.001). Female dyads utilized formal titles during the first form of address 97.8% (45/46) compared with male dyads who utilized a formal title 72.4% (110/152) of the time (p = 0.007). In mixed-gender dyads, where the introducer was female and speaker male, formal titles were used 95.0% (57/60) of the time. Male introducers of female speakers utilized professional titles 49.2% (31/63) of the time (p < 0.001). CONCLUSION: In this study, women introduced by men at IMGR were less likely to be addressed by professional title than were men introduced by men. Differential formality in speaker introductions may amplify isolation, marginalization, and professional discomfiture expressed by women faculty in academic medicine.

Exuberant mitral annular calcification.

Mitral annular calcification (MAC) is a chronic, progressive process characterized by calcium deposition on the mitral valve annulus. There is no current grading system to relay the severity of MAC. The primary purpose of this study was to investigate the extreme end of the severity spectrum in order to describe "exuberant mitral annular calcification", and a retrospective chart review of all patients with exuberant mitral annulus calcification evaluated at Mayo Clinic Rochester between January 1996 and December 2014 was performed. This is the first study to define criteria of "exuberant mitral annular calcification", emphasizing the importance of identifying the extreme degree of mitral annular calcification.

Pulmonary Hypertension in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: A subset of patients with hereditary hemorrhagic telangiectasia (HHT) develops pulmonary hypertension (PH) by mechanisms including pulmonary arterial hypertension, high flow, and elevated pulmonary arterial wedge pressure (PAWP). We aimed to describe echocardiographic and hemodynamic characteristics of patients with coexisting HHT and PH. METHODS: We conducted a single-center cohort study of patients with confirmed HHT who underwent right-sided heart catheterization (RHC) and transthoracic two-dimensional echocardiography for suspected PH between June 1, 2003 and September 1, 2013 at Mayo Clinic Rochester, Minnesota. RESULTS: Of 38 patients with confirmed HHT who underwent RHC and echocardiography, 28 (74%) had a mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg. Of those 28, 12 (43%) had pulmonary arterial hypertension. Two patients had normal PAWP and pulmonary vascular resistance (PVR), with PH secondary to either an atrial septal defect or high cardiac flow. Fourteen patients (50%) had elevated PAWP (≥ 15 mm Hg), nine with evidence of high flow. RHC in all 28 patients demonstrated a MPAP of 41 ± 11 mm Hg, PAWP of 17 ± 10 mm Hg, and PVR of 4.5 ± 4.2 Wood units. Echocardiography demonstrated moderate/severe right ventricular dysfunction in nine patients (32%). The presence of PH trended toward worse survival (P = .06). CONCLUSIONS: PH in patients with HHT occurs by different mechanisms, and there is a trend toward worse survival in patients who develop PH despite the mechanism. The equal predilection toward all subtypes of PH illustrates the necessity of RHC to clarify the hemodynamics.

Ultrasound-guided fine-needle aspiration biopsy of thyroid nodules in patients taking novel oral anticoagulants.

BACKGROUND: Ultrasound-guided fine-needle aspiration biopsy (USGFNAB) is the most accurate form of evaluation for thyroid nodules. Many patients with thyroid nodules who present for USGFNAB are on anticoagulant agents, including the novel oral anticoagulants (NOACs), for stroke prevention in atrial fibrillation or venous thrombosis prophylaxis. SUMMARY: There has been at least one retrospective study describing neck USGFNAB bleeding risks in patients on antithrombotic and/or anticoagulant agents. This study concluded that there was no major bleeding risk or increase in hematoma formation in patients on antithrombotic or anticoagulant agents while undergoing USGFNAB, and there was no need to discontinue these agents prior to the procedure. With the emergence of NOACs, further recommendations should be made for patients on these agents who will be undergoing USGFNAB for thyroid nodules. Currently, there are no published studies regarding patients on NOACs who undergo USGFNAB. CONCLUSIONS: It has previously been established that patients on historical anticoagulant agents do not need to discontinue therapy prior to minor procedures such as needle aspirations or dental procedures. Therefore, in patients currently taking dabigatran, rivaroxaban, or apixaban, it is concluded that it is reasonable and safe to continue the novel oral anticoagulant agents prior to USGFNAB of thyroid nodules without major risk of bleeding. This conclusion is based not only on the fact that minor procedures are considered safe in patients on NOACs, but also because patients on historical anticoagulant agents do not need to discontinue therapy prior to minor procedures.