Significance of Pulmonary Hypertension in Cardiac Amyloidosis.

Pulmonary hypertension (PH) portends a poor prognosis in chronic heart failure and within distinct cardiomyopathies. There is a paucity of data on the impact of PH in patients with light-chain (AL) and transthyretin (ATTR) cardiac amyloidosis (CA). We sought to define the prevalence and significance of PH and PH subtypes in CA. We retrospectively identified patients with a diagnosis of CA who underwent right-sided cardiac catheterization (RHC) from January 2000 to December 2019. PH was defined as mean pulmonary artery pressure >20 mm Hg. PH was phenotyped as precapillary PH (PC-PH; pulmonary capillary wedge pressure [PCWP] <15, pulmonary vascular resistance [PVR] ≥3), isolated postcapillary PH (IpC-PH; PCWP >15, PVR <3), and combined postcapillary and precapillary PH (CpC-PH; PCWP >15 and PVR ≥3). Survival was assessed in those with CA and PH and for PH phenotypes. A total of 132 patients were included, 69 with AL CA and 63 with ATTR CA. A total of 75% (N = 99) had PH (76% of patients with AL and 73% of patients with ATTR, p = 0.615) and the predominant PH phenotype was IpC-PH. The degree of PH was comparable between ATTR CA and AL CA, and PH was observed in advanced stage disease (National Amyloid Center or Mayo stage II or greater). The overall survival for patients with CA and PH was similar to to those without PH. Higher mean pulmonary artery pressure independently predicted mortality in CA with PH (odds ratio 1.06, confidence interval 1.01 to 1.12, p = 0.03). In conclusion, PH was seen frequently in CA and tended to be IpC-PH; however, its presence did not significantly impact survival.

Sex, HIV Status, and Measures of Cardiac Stress and Fibrosis in Uganda.

Background Biomarkers of myocardial stress and fibrosis are elevated in people living with HIV and are associated with cardiac dysfunction. It is unknown whether sex influences these markers of heart failure risk in sub-Saharan Africa, where HIV burden is high and where the vast majority of women with HIV live. Methods and Results Echocardiograms and 6 plasma biomarkers (suppression of tumorigenicity-2, growth differentiation factor 15, galectin 3, soluble fms-like tyrosine kinase-1, NT-proBNP [N-terminal pro-B-type natriuretic peptide], and cystatin C) were obtained from 100 people living with HIV on antiretroviral therapy and 100 HIV-negative controls in Uganda. All participants were ≥45 years old with ≥1 major cardiovascular risk factor. Multivariable linear and logistic regression models were used to assess associations between biomarkers, echocardiographic variables, HIV status, and sex, and to assess whether sex modified these associations. Overall, mean age was 56 years and 62% were women. Suppression of tumorigenicity-2 was higher in men versus women (P<0.001), and growth differentiation factor 15 was higher in people living with HIV versus controls (P<0.001). Sex modified the HIV effect on cystatin C and NT-proBNP (both P for interaction <0.025). Women had more diastolic dysfunction than men (P=0.02), but there was no evidence of sex-modifying HIV effects on cardiac structure and function. Cardiac biomarkers were more strongly associated with left ventricular mass index in men compared with women. Conclusions There are prominent differences in biomarkers of cardiac fibrosis and stress by sex and HIV status in Uganda. The predictive value of cardiac biomarkers for heart failure in people living with HIV in sub-Saharan Africa should be examined, and novel risk markers for women should be further explored.

Association of Kidney Disease With Abnormal Cardiac Structure and Function Among Ugandans With HIV Infection.

BACKGROUND: People with HIV (PWH) are at an increased risk of both heart and kidney disease, but the relationship between kidney disease and cardiac structure and function in this population has not been well studied. In particular, whether the relationship between kidney disease and cardiac structure and function is stronger for PWH compared with uninfected controls is unknown. METHODS: One hundred PWH on antiretroviral therapy were compared with 100 age-matched and sex-matched controls without HIV in Uganda. Multivariable regression models were used to examine associations between creatinine-based and cystatin C-based estimated glomerular filtration rate (eGFR), albumin-creatinine ratio, and echocardiographic measures of cardiac structure and function. RESULTS: PWH had lower eGFRcr (ß -7.486, 95% confidence interval: -13.868 to -1.104, P = 0.022) and a higher rate of albumin-creatinine ratio ≥30 (odds ratio 2.146, 95% confidence interval: 1.027 to 4.484, P = 0.042) after adjustment for traditional risk factors. eGFR was inversely associated with both left ventricular mass index and diastolic dysfunction in adjusted models but not with systolic function. Albuminuria was associated with more diastolic dysfunction among PWH but not controls (P for interaction = 0.046). The association of HIV with a higher left ventricular mass index (P = 0.005) was not substantially affected by adjusting for eGFRcr. CONCLUSION: Among Ugandans, eGFR is associated with elevated LV mass and diastolic dysfunction. The association between albuminuria and diastolic dysfunction is particularly strong for PWH.

HIV and pericardial fat are associated with abnormal cardiac structure and function among Ugandans.

OBJECTIVES: To examine the relationship between pericardial fat (PCF) and cardiac structure and function among HIV-infected patients in the sub-Saharan African country of Uganda. People living with HIV (PLHIV) have altered fat distribution and an elevated risk for heart failure. Whether altered quantity and radiodensity of fat surrounding the heart relates to cardiac dysfunction in this population is unknown. METHODS: One hundred HIV-positive Ugandans on antiretroviral therapy were compared with 100 age and sex-matched HIV-negative Ugandans; all were >45 years old with >1 cardiovascular disease risk factor. Subjects underwent ECG-gated non-contrast cardiac CT and transthoracic echocardiography with speckle tracking strain imaging. Multivariable linear and logistic regression models were used to explore the association of PCF with echocardiographic outcomes. RESULTS: Median age was 55% and 62% were female. Compared with uninfected controls, PLHIV had lower body mass index (27 vs 30, p=0.02) and less diabetes (26% vs 45%, p=0.005). Median left ventricular (LV) ejection fraction was 67%. In models adjusted for traditional risk factors, HIV was associated with 10.3 g/m2 higher LV mass index (LVMI) (95% CI 3.22 to 17.4; p=0.005), 0.87% worse LV global longitudinal strain (GLS) (95% CI -1.66 to -0.07; p=0.03) and higher odds of diastolic dysfunction (OR 1.96; 95% CI 0.95 to 4.06; p=0.07). In adjusted models, PCF volume was significantly associated with increased LVMI and worse LV GLS, while PCF radiodensity was associated with worse LV GLS (all p<0.05). CONCLUSIONS: In Uganda, HIV infection, PCF volume and density are associated with abnormal cardiac structure and function.

A case of prosthetic aortic valve dehiscence due to infective endocarditis without paravalvular regurgitation.

Aortic prosthetic valve endocarditis is often a challenging disease process that carries high morbidity and mortality. Echocardiography is widely used to identify infected valves and associated complications. One major complication of an infection involving the aortic annulus is dehiscence of the prosthetic valve from the aortic root and is usually associated with paravalvular regurgitation. Here, we present a rare case of complete prosthetic valve dehiscence without paravalvular regurgitation on transthoracic and transesophageal echocardiography.

Left atrial strain: measurement and clinical application.

PURPOSE OF REVIEW: To summarize recent literature on the use of left atrial strain in the diagnosis and management of patients with heart failure. RECENT FINDINGS: Left atrial dysfunction is a hallmark of diastolic dysfunction and heart failure, in particular, heart failure with preserved ejection fraction (HFpEF). Recently, myocardial deformation analysis via strain and strain rate measurements have been applied to the left atrium. These measurements have been shown to aid in the diagnosis of heart failure and be accurate predictors of cardiac pressures, diastolic dysfunction, exercise performance, and clinical outcomes such as cardiac hospitalizations and mortality. However, limitations related to the technical aspect of accurately imaging and tracking the thin-walled left atrium and the current lack of consensus on 'normal' reference values remain. SUMMARY: Left atrial strain represents a novel, noninvasive technique to aid in the diagnosis, prognosis, and management of patients with heart failure. Although it is not yet a part of routine clinical practice, the measurement has significant promise within this population pending further validation.

Myocarditis and cardiomyopathy.

PURPOSE OF REVIEW: The aim of this study is to summarize the literature describing the pathogenesis, diagnosis and management of cardiomyopathy related to myocarditis. RECENT FINDINGS: Myocarditis has a variety of causes and a heterogeneous clinical presentation with potentially life-threatening complications. About one-third of patients will develop a dilated cardiomyopathy and the pathogenesis is a multiphase, mutlicompartment process that involves immune activation, including innate immune system triggered proinflammatory cytokines and autoantibodies. In recent years, diagnosis has been aided by advancements in cardiac MRI, and in particular T1 and T2 mapping sequences. In certain clinical situations, endomyocardial biopsy (EMB) should be performed, with consideration of left ventricular sampling, for an accurate diagnosis that may aid treatment and prognostication. SUMMARY: Although overall myocarditis accounts for a minority of cardiomyopathy and heart failure presentations, the clinical presentation is variable and the pathophysiology of myocardial damage is unique. Cardiac MRI has significantly improved diagnostic abilities, but endomyocardial biopsy remains the gold standard. However, current treatment strategies are still focused on routine heart failure pharmacotherapies and supportive care or cardiac transplantation/mechanical support for those with end-stage heart failure.

Left ventricular global longitudinal strain in patients with heart failure with preserved ejection fraction: outcomes following an acute heart failure hospitalization.

AIMS: While abnormal resting LV GLS has been described in patients with chronic heart failure with preserved ejection fraction (HFpEF), its prognostic significance when measured during an acute heart failure hospitalization remains unclear. We assessed the association between left ventricular global longitudinal strain (LV GLS) and outcomes in patients hospitalized with acute HFpEF. METHODS AND RESULTS: We studied patients discharged alive for acute HFpEF from Duke University Medical Center between 2007 and 2010. Among patients with measurable LV GLS, we performed 2D, speckle-tracking analysis and Cox proportional hazards models assessed the association between continuous LV GLS and outcomes. Baseline characteristics were stratified by normal (≤-16%) or abnormal (>-16%) LV GLS for comparison. Among 463 patients, the median LV GLS was -12.8% (Interquartile range, -15.8 to -10.8%) and was abnormal in 352 (76%). Overall patients in the cohort were generally elderly, female and had hypertension. After multivariable adjustment, worse outcomes were noted between LV GLS and mortality (HR 1.19 per 1% increase; 95% CI 1.00-1.42; P = 0.046) and a composite endpoint of mortality or rehospitalization at 30 days (HR 1.08 per 1% increase; 95% CI 0.99-1.18; P = 0.08). There was no association between LV GLS and mortality or a composite of mortality or rehospitalization at 1 year. CONCLUSIONS: A high prevalence of patients hospitalized with acute HFpEF have abnormal LV GLS suggesting unrecognized myocardial systolic dysfunction. Furthermore, worse LV GLS is associated with worse clinical outcomes at 30 days but not by1 year.

Heart fat in HIV: marker or mediator of risk?

PURPOSE OF REVIEW: The review aims to summarize the literature describing the clinical impact of cardiac fat depots in patients with HIV infection. RECENT FINDINGS: People living with HIV (PLHIV) have accelerated rates of cardiovascular disease, and are prone to the development of ectopic fat deposition. Specifically, PLHIV have higher volumes of epicardial and intracardiac fat quantified by noninvasive imaging. Higher volumes of epicardial fat may be related to antiretroviral therapy duration and chronic inflammation, independently of other measures of body adiposity such as BMI. They have been associated with increased coronary artery calcium, myocardial perfusion defects, death, and myocardial infarction. The association with risk may be partly mediated through direct actions of cytokines and adipokines produced by the adipose tissue. Furthermore, HIV-infected patients have increased myocardial fat deposition that is also associated with antiretroviral therapy duration, and may be responsible for myocardial systolic and diastolic dysfunction. SUMMARY: PLHIV have increased fat deposition surrounding and inside the heart that may serve as an important imaging marker of risk but may also directly mediate coronary artery disease and cardiac dysfunction. Although robust data of targeted therapies is lacking, some pharmacotherapies may be able to reduce cardiac fat volumes. In the meantime, as the evidence grows, physicians may consider intensifying preventive strategies and monitoring in patients with abnormal heart fat on noninvasive imaging.

End-of-life Heart Failure Care in the United States.

Heart failure (HF) is increasingly common in the United States and is associated with a high degree of morbidity and mortality. As patients approach the end of life there is a significant increase in health care resource use. Patients with end-stage HF have a unique set of needs at the end of life, including symptoms such as dyspnea, uremia, and depression, as well as potentially deactivating implantable defibrillators and mechanical circulatory support devices. Improved palliative care services for patients with HF may improve quality of life and decrease health care resource use near the end of life.

Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact.

Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future.

Amiodarone-Induced Liver Injury and Cirrhosis.

We present a case report of an 80-year-old woman with volume overload thought initially to be secondary to heart failure, but determined to be amiodarone-induced acute and chronic liver injury leading to submassive necrosis and bridging fibrosis consistent with early cirrhosis. Her histopathology was uniquely absent of steatosis and phospholipidosis, which are commonly seen in AIC.

Torsemide versus furosemide in heart failure patients: insights from Duke University Hospital.

Furosemide has historically been the primary loop diuretic in heart failure patients despite data suggesting potential advantages with torsemide. We used the Duke Echocardiography Lab Database to investigate patients admitted with heart failure to Duke Hospital from 2000 to 2010 who were discharged on either torsemide or furosemide. We described baseline characteristics based on discharge diuretic and assessed the relationship with all-cause mortality through 5 years. Of 4580 patients, 86% (n = 3955) received furosemide and 14% (n = 625) received torsemide. Patients receiving torsemide were more likely to be female and had more comorbidities compared with furosemide-treated patients. Survival was worse in torsemide-treated patients [5-year Kaplan-Meier estimated survival of 41.4% (95% CI: 36.7-46.0) vs. 51.5% (95% CI: 49.8-53.1)]. After risk adjustment, torsemide use was no longer associated with increased mortality (hazard ratio 1.16; 95% CI: 0.98-1.38; P = 0.0864). Prospective trials are needed to investigate the effect of torsemide versus furosemide because of the potential for residual confounding.

A reappraisal of loop diuretic choice in heart failure patients.

The health and economic burden of heart failure is significant and continues to grow each year. Loop diuretics are an integral part of symptom management in heart failure. Furosemide is used disproportionately compared with other loop diuretics, and there is currently no guidance for physicians regarding which agent to choose. However, there exist pharmacologic differences as well as other mechanistic differences that appear to favor torsemide use over furosemide. Compared with furosemide, torsemide improves surrogate markers of heart failure severity such as left ventricular function, plasma brain natriuretic peptide levels, and New York Heart Association functional class and may also reduce hospitalizations, readmissions, and mortality. Data suggest that these benefits could be mediated through torsemide's ability to positively affect the renin-angiotensin-aldosterone system. Specifically, torsemide has been shown to inhibit aldosterone secretion, synthesis, and receptor binding in vitro, as well as decrease transcardiac extraction of aldosterone, myocardial collagen production, and cardiac fibrosis in patients with heart failure. We identified pertinent literature using keyword MEDLINE searches and cross-referencing prior bibliographies. We summarize the available data suggesting potential benefits with torsemide over furosemide, and call attention to the need for a reappraisal of diuretic use in heart failure patients and also for a well-powered, randomized control trial assessing torsemide versus furosemide use.

Chemoattractant stimulation of TORC2 is regulated by receptor/G protein-targeted inhibitory mechanisms that function upstream and independently of an essential GEF/Ras activation pathway in Dictyostelium.

Global stimulation of Dictyostelium with different chemoattractants elicits multiple transient signaling responses, including synthesis of cAMP and cGMP, actin polymerization, activation of kinases ERK2, TORC2, and phosphatidylinositide 3-kinase, and Ras-GTP accumulation. Mechanisms that down-regulate these responses are poorly understood. Here we examine transient activation of TORC2 in response to chemically distinct chemoattractants, cAMP and folate, and suggest that TORC2 is regulated by adaptive, desensitizing responses to stimulatory ligands that are independent of downstream, feedback, or feedforward circuits. Cells with acquired insensitivity to either folate or cAMP remain fully responsive to TORC2 activation if stimulated with the other ligand. Thus TORC2 responses to cAMP or folate are not cross-inhibitory. Using a series of signaling mutants, we show that folate and cAMP activate TORC2 through an identical GEF/Ras pathway but separate receptors and G protein couplings. Because the common GEF/Ras pathway also remains fully responsive to one chemoattractant after desensitization to the other, GEF/Ras must act downstream and independent of adaptation to persistent ligand stimulation. When initial chemoattractant concentrations are immediately diluted, cells rapidly regain full responsiveness. We suggest that ligand adaptation functions in upstream inhibitory pathways that involve chemoattractant-specific receptor/G protein complexes and regulate multiple response pathways.

Chemotactic activation of Dictyostelium AGC-family kinases AKT and PKBR1 requires separate but coordinated functions of PDK1 and TORC2.

Protein kinases AKT and PKBR1 of Dictyostelium belong to the AGC protein kinase superfamily. AKT and PKBR1 are phosphorylated at similar sites by phosphoinositide-dependent kinase 1 (PDK1) and TORC2 kinases; however, they have different subcellular localizing domains. AKT has a phosphoinositide 3-kinase (PI3K)/phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)]-regulated PH (pleckstrin homology) domain whereas PKBR1 is myristoylated and persistently membrane localized. Using strains defective for PI3K/PtdIns(3,4,5)P(3)-, PDK1- and TORC2-signaling or strains that express phospho-site mutants of AKT and PKBR1, we dissect the different roles of PI3K/PtdIns(3,4,5)P(3), PDK1 and TORC2. We show that activation of AKT and PKBR1 requires PDK1-site phosphorylation, but that phosphorylation by TORC2 is insufficient for AKT or PKBR1 activation. However, PDK1-site phosphorylation is dependent on phosphorylation by TORC2, which suggests that there is regulatory coordination among PDK1, TORC2 and their phospho-site targets. This defines a separate input for signaling in control of chemotaxis and dependency on PDK1 function. We also demonstrate that PDK1 in Dictyostelium functions independently of PI3K/PtdIns(3,4,5)P(3). Finally, we show that AKT and PKBR1 exhibit substrate selectivity and identify two novel lipid-interacting proteins preferentially phosphorylated by AKT. Despite certain similarities, AKT and PKBR1 have distinct regulatory paths that impact activation and effector targeting, with PDK1 serving a central role.