Clinical outcomes of intravenous iron therapy in patients with heart failure and iron deficiency: Meta-analysis and trial sequential analysis of randomized clinical trials.

BACKGROUND: Iron deficiency in patients with heart failure (HF) is underdiagnosed and undertreated. The role of intravenous (IV) iron is well-established to improve quality of life measures. Emerging evidence also supports its role in preventing cardiovascular events in patients with HF. METHODOLOGY: We conducted a literature search of multiple electronic databases. Randomized controlled trials that compared IV iron to usual care among patients with HF and reported cardiovascular (CV) outcomes were included. Primary outcome was the composite of first heart failure hospitalization (HFH) or CV death. Secondary outcomes included HFH (first or recurrent), CV death, all-cause mortality, hospitalization for any cause, gastrointestinal (GI) side effects, or any infection. We performed trial sequential and cumulative meta-analyses to evaluate the effect of IV iron on the primary endpoint, and on HFH. RESULTS: Nine trials enrolling 3337 patients were included. Adding IV iron to usual care significantly reduced the risk of first HFH or CV death [risk ratio (RR) 0.84; 95 % confidence interval (CI) 0.75-0.93; I2 = 0 %; number needed to treat (NNT) 18], which was primarily driven by a reduction in the risk of HFH of 25 %. IV iron also reduced the risk of the composite of hospitalization for any cause or death (RR 0.92; 95 % CI 0.85-0.99; I2 = 0 %; NNT 19). There was no significant difference in the risk of CV death, all-cause mortality, adverse GI events, or any infection among patients receiving IV iron compared to usual care. The observed benefits of IV iron were directionally consistent across trials and crossed both the statistical and trial sequential boundaries of benefit. CONCLUSION: In patients with HF and iron deficiency, the addition of IV iron to usual care reduces the risk of HFH without affecting the risk of CV or all-cause mortality.

Tricuspid Regurgitation: From Imaging to Clinical Trials to Resolving the Unmet Need for Treatment.

Tricuspid regurgitation (TR) is a highly prevalent and heterogeneous valvular disease, independently associated with excess mortality and high morbidity in all clinical contexts. TR is profoundly undertreated by surgery and is often discovered late in patients presenting with right-sided heart failure. To address the issue of undertreatment and poor clinical outcomes without intervention, numerous structural tricuspid interventional devices have been and are in development, a challenging process due to the unique anatomic and physiological characteristics of the tricuspid valve, and warranting well-designed clinical trials. The path from routine practice TR detection to appropriate TR evaluation, to conduction of clinical trials, to enriched therapeutic possibilities for improving TR access to treatment and outcomes in routine practice is complex. Therefore, this paper summarizes the key points and methods crucial to TR detection, quantitation, categorization, risk-scoring, intervention-monitoring, and outcomes evaluation, particularly of right-sided function, and to clinical trial development and conduct, for both interventional and surgical groups.

Part 1: The Clinical Applications of Left Ventricular Myocardial Strain.

There is an increasing prevalence of cardiovascular disease and heart failure. Indices of left ventricular (LV) systolic function such as LV ejection fraction used to identify those at risk of adverse cardiac events such as heart failure may not be truly representative of LV systolic function in certain cardiac diseases. Given that LV ejection fraction reduction may represent more advanced irreversible stages of disease, measures of myocardial strain have emerged as a feasible and robust instrument for the early identification of heart disease and subtle LV systolic dysfunction. The purpose of this review was to provide an overview of myocardial strain concepts and emerging clinical applications of global longitudinal strain in cardio-oncology.

The contribution of amyloid deposition in the aortic valve to calcification and aortic stenosis.

Calcific aortic valve disease (CAVD) and stenosis have a complex pathogenesis, and no therapies are available that can halt or slow their progression. Several studies have shown the presence of apolipoprotein-related amyloid deposits in close proximity to calcified areas in diseased aortic valves. In this Perspective, we explore a possible relationship between amyloid deposits, calcification and the development of aortic valve stenosis. These amyloid deposits might contribute to the amplification of the inflammatory cycle in the aortic valve, including extracellular matrix remodelling and myofibroblast and osteoblast-like cell proliferation. Further investigation in this area is needed to characterize the amyloid deposits associated with CAVD, which could allow the use of antisense oligonucleotides and/or isotype gene therapies for the prevention and/or treatment of CAVD.

American Society of Echocardiography Algorithm for Degenerative Mitral Regurgitation: Comparison With CMR.

OBJECTIVES: The purpose of this study was to compare the American Society of Echocardiography (ASE) algorithm for assessing mitral regurgitation (MR) to cardiac magnetic resonance (CMR) and left ventricular (LV) remodeling following mitral intervention. BACKGROUND: The ASE recommends integrating multiple echocardiographic parameters for assessing MR. The ASE guidelines include an algorithm that weighs the parameters and highlights those considered indicative of definitely mild or definitely severe MR. METHODS: We prospectively enrolled 152 (age 62 ± 13 years; 59% male) patients with degenerative MR who underwent ASE algorithm-guided echocardiographic and CMR grading of MR severity. Using the ASE algorithm, patients were graded as definitely mild, grade I, grade II, grade III, grade IV, or definitely severe MR. CMR MR volume was graded as mild (<30 mL), grade II moderate (30-44 mL), grade III moderate (45-59 mL), or severe (≥60 mL). A subgroup of 63 patients underwent successful mitral intervention, of whom 48 had postintervention CMR. RESULTS: Only 52% of patients with definitely severe MR by the ASE algorithm had severe MR by CMR, and 10% had mild MR by CMR. There was an increase in post mitral intervention LV reverse remodeling with worsening MR severity using CMR (P < 0.0001) but not the ASE algorithm (P = 0.07). Severe MR by CMR was an independent predictor of post mitral intervention LV reverse remodeling and definitely severe MR by the ASE algorithm was not. CONCLUSIONS: In patients with degenerative MR, agreement between CMR and the ASE algorithm was suboptimal. Severe MR by CMR was an independent predictor of post mitral intervention LV reverse remodeling, whereas definitely severe MR by the ASE algorithm was not. These findings suggest an important role for CMR in surgical decision making in degenerative MR. (Comparison Study of Echocardiography and Cardiovascular Magnetic Resonance Imaging in the Assessment of Mitral and Aortic Regurgitation; NCT04038879).

Functional Effects of Cardiomyocyte Injury in COVID-19.

COVID-19 affects multiple organs. Clinical data from the Mount Sinai Health System show that substantial numbers of COVID-19 patients without prior heart disease develop cardiac dysfunction. How COVID-19 patients develop cardiac disease is not known. We integrated cell biological and physiological analyses of human cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of interleukins (ILs) with clinical findings related to laboratory values in COVID-19 patients to identify plausible mechanisms of cardiac disease in COVID-19 patients. We infected hiPSC-derived cardiomyocytes from healthy human subjects with SARS-CoV-2 in the absence and presence of IL-6 and IL-1ß. Infection resulted in increased numbers of multinucleated cells. Interleukin treatment and infection resulted in disorganization of myofibrils, extracellular release of troponin I, and reduced and erratic beating. Infection resulted in decreased expression of mRNA encoding key proteins of the cardiomyocyte contractile apparatus. Although interleukins did not increase the extent of infection, they increased the contractile dysfunction associated with viral infection of cardiomyocytes, resulting in cessation of beating. Clinical data from hospitalized patients from the Mount Sinai Health System show that a significant portion of COVID-19 patients without history of heart disease have elevated troponin and interleukin levels. A substantial subset of these patients showed reduced left ventricular function by echocardiography. Our laboratory observations, combined with the clinical data, indicate that direct effects on cardiomyocytes by interleukins and SARS-CoV-2 infection might underlie heart disease in COVID-19 patients. IMPORTANCE SARS-CoV-2 infects multiple organs, including the heart. Analyses of hospitalized patients show that a substantial number without prior indication of heart disease or comorbidities show significant injury to heart tissue, assessed by increased levels of troponin in blood. We studied the cell biological and physiological effects of virus infection of healthy human iPSC-derived cardiomyocytes in culture. Virus infection with interleukins disorganizes myofibrils, increases cell size and the numbers of multinucleated cells, and suppresses the expression of proteins of the contractile apparatus. Viral infection of cardiomyocytes in culture triggers release of troponin similar to elevation in levels of COVID-19 patients with heart disease. Viral infection in the presence of interleukins slows down and desynchronizes the beating of cardiomyocytes in culture. The cell-level physiological changes are similar to decreases in left ventricular ejection seen in imaging of patients' hearts. These observations suggest that direct injury to heart tissue by virus can be one underlying cause of heart disease in COVID-19.

Association of the V122I Hereditary Transthyretin Amyloidosis Genetic Variant With Heart Failure Among Individuals of African or Hispanic/Latino Ancestry.

Importance: Hereditary transthyretin (TTR) amyloid cardiomyopathy (hATTR-CM) due to the TTR V122I variant is an autosomal-dominant disorder that causes heart failure in elderly individuals of African ancestry. The clinical associations of carrying the variant, its effect in other African ancestry populations including Hispanic/Latino individuals, and the rates of achieving a clinical diagnosis in carriers are unknown. Objective: To assess the association between the TTR V122I variant and heart failure and identify rates of hATTR-CM diagnosis among carriers with heart failure. Design, Setting, and Participants: Cross-sectional analysis of carriers and noncarriers of TTR V122I of African ancestry aged 50 years or older enrolled in the Penn Medicine Biobank between 2008 and 2017 using electronic health record data from 1996 to 2017. Case-control study in participants of African and Hispanic/Latino ancestry with and without heart failure in the Mount Sinai BioMe Biobank enrolled between 2007 and 2015 using electronic health record data from 2007 to 2018. Exposures: TTR V122I carrier status. Main Outcomes and Measures: The primary outcome was prevalent heart failure. The rate of diagnosis with hATTR-CM among TTR V122I carriers with heart failure was measured. Results: The cross-sectional cohort included 3724 individuals of African ancestry with a median age of 64 years (interquartile range, 57-71); 1755 (47%) were male, 2896 (78%) had a diagnosis of hypertension, and 753 (20%) had a history of myocardial infarction or coronary revascularization. There were 116 TTR V122I carriers (3.1%); 1121 participants (30%) had heart failure. The case-control study consisted of 2307 individuals of African ancestry and 3663 Hispanic/Latino individuals; the median age was 73 years (interquartile range, 68-80), 2271 (38%) were male, 4709 (79%) had a diagnosis of hypertension, and 1008 (17%) had a history of myocardial infarction or coronary revascularization. There were 1376 cases of heart failure. TTR V122I was associated with higher rates of heart failure (cross-sectional cohort: n = 51/116 TTR V122I carriers [44%], n = 1070/3608 noncarriers [30%], adjusted odds ratio, 1.7 [95% CI, 1.2-2.4], P = .006; case-control study: n = 36/1376 heart failure cases [2.6%], n = 82/4594 controls [1.8%], adjusted odds ratio, 1.8 [95% CI, 1.2-2.7], P = .008). Ten of 92 TTR V122I carriers with heart failure (11%) were diagnosed as having hATTR-CM; the median time from onset of symptoms to clinical diagnosis was 3 years. Conclusions and Relevance: Among individuals of African or Hispanic/Latino ancestry enrolled in 2 academic medical center-based biobanks, the TTR V122I genetic variant was significantly associated with heart failure.

Advanced Imaging in Cardiac Sarcoidosis.

Sarcoidosis is a chronic disease of unknown etiology characterized by the presence of noncaseating granulomas. Cardiac involvement in sarcoidosis may lead to adverse outcomes such as advanced heart block, arrhythmias, cardiomyopathy, or death. Cardiac sarcoidosis can occur in patients with established sarcoidosis, or it can be the sole manifestation of the disease. Traditional diagnostic techniques, including echocardiography, have poor sensitivity for diagnosing cardiac sarcoidosis. The accumulating evidence supports the essential role of advanced cardiac imaging modalities such as MRI and PET in diagnosis, risk stratification, and management of patients with cardiac sarcoidosis. The current review highlights important theoretic and practical aspects of using cardiac imaging tools in the evaluation of patients with suspected or established cardiac sarcoidosis.

Association Between Layer-Specific Longitudinal Strain and Risk Factors of Heart Failure and Dyspnea: A Population-Based Study.

BACKGROUND: Global longitudinal strain (GLS), derived from speckle-tracking echocardiography (STE), is a widely used and reproducible left ventricular deformation parameter; assessment of multilayer strain components has also become possible. However, its association with comorbidities/symptoms in low-risk populations without cardiac disease remains understudied. We report reference ranges for longitudinal deformation and their association with cardiovascular risk factors and dyspnea in a large population-based cohort. METHODS: We studied 1,243 subjects without cardiac disease (47 ± 14 years, 47.4% men; 13.8% with dyspnea) enrolled at the fourth visit of the STANISLAS Cohort (Lorraine, France). Clinical evaluation included a comprehensive dyspnea questionnaire. Multilayer GLS (full-wall, subendocardial, and subepicardial) and strain rate (systolic, early, and late diastolic) were evaluated by GLS STE acquisition and measurement protocols as per recommendations by the European Association of Cardiovascular Imaging, American Society of Echocardiography, and Industry Task Force. RESULTS: Full-wall GLS was 23.4% ± 2.7% (mean ± SD) with a subendocardial/subepicardial ratio of 1.2 ± 0.1. Age, gender, smoking status, and body mass index were significantly associated with strain variables, whereas diabetes, dyslipidemia, and hypertension/systolic blood pressure were not. Specifically, there were reductions in diastolic strain rate with aging but no differences in GLS. After propensity score matching, subjects with dyspnea had lower global endocardial strain (-23.48 ± 2.70 vs -23.02 ± 2.81; P = .043) and lower global subendocardial/subepicardial strain ratio (P = .034), whereas transmural strain and classical echocardiographic measurements were unrelated to dyspnea. CONCLUSIONS: Higher body mass index was found to be significantly associated with impaired strain variables in a low-risk population without cardiac disease. In addition, lower global endocardial strain and lower global subendocardial/subepicardial strain ratio were significantly associated with dyspnea contrary to other echocardiographic variables.

Is Cardiac Diastolic Dysfunction a Part of Post-Menopausal Syndrome?

Post-menopausal women exhibit an exponential increase in the incidence of heart failure with preserved ejection fraction compared with men of the same age, which indicates a potential role of hormonal changes in subclinical and clinical diastolic dysfunction. This paper reviews the preclinical evidence that demonstrates the involvement of estrogen in many regulatory molecular pathways of cardiac diastolic function and the clinical data that investigates the effect of estrogen on diastolic function in post-menopausal women. Published reports show that estrogen deficiency influences both early diastolic relaxation via calcium homeostasis and the late diastolic compliance associated with cardiac hypertrophy and fibrosis. Because of the high risk of diastolic dysfunction and heart failure with preserved ejection fraction in post-menopausal women and the positive effects of estrogen on preserving cardiac function, further clinical studies are needed to clarify the role of endogenous estrogen or hormone replacement in mitigating the onset and progression of heart failure with preserved ejection fraction in women.

Impact of gender on in-hospital outcomes in patients with Takotsubo syndrome: A nationwide analysis from 2006 to 2014.

BACKGROUND: Takotsubo syndrome (TTS) is characterized by acute, transient systolic dysfunction of the left ventricle not attributed to coronary artery disease (CAD). HYPOTHESIS: There are differences in hospital outcomes in patients admitted with TTS based on their gender. METHODS: The National Inpatient Sample database was searched for patients admitted with a principal diagnosis of TTS from 2006 to 2014 using the ICD9-CM code 429.83. Using Pearson's χ2 and Student's t test analyses, the P-value was calculated for differences among baseline characteristics of patients. Multivariate regression models were then created to adjust for potential confounders. RESULTS: A total of 39 662 admissions with TTS were identified, 91.7% female and 8.3% male with mean age of 66.5 and 61.6 years, respectively. The incidence of TTS increased progressively from 2006 to 2014. Female patients were more likely to have hypertension, hypothyroidism, or depression. Males were more likely to use tobacco, or have known CAD. Males had almost 4-fold higher probability of in-hospital mortality compared to females (3.7% vs 1.1%; P<0.001). Certain complications including cardiogenic shock, ventricular fibrillation/tachycardia, and acute kidney injury were more common in males. CONCLUSIONS: There are distinct gender differences in clinical characteristics of patients admitted with TTS. Although TTS is more common in females, it is associated with higher morbidity and mortality in males.

The Burden of Modifiable Risk Factors in Newly Defined Categories of Blood Pressure.

BACKGROUND: The 2017 American College of Cardiology/American Heart Association Guideline introduced new categories of high blood pressure. The vast majority of individuals in these newly defined categories are recommended for nonpharmacological intervention rather than antihypertensive therapy. This study sought to determine the burden of potentially modifiable risk factors of hypertension among untreated adults in the newly defined categories of blood pressure. METHODS: We analyzed data from the 1999-2014 National Health and Nutrition Examination Survey (N = 37,448). Potentially modifiable risk factors included abdominal obesity, high non-high-density lipoprotein (HDL) cholesterol, secondhand smoking, binge drinking, suboptimal physical activity, and low-fiber diet. RESULTS: Although the prevalence of certain modifiable risk factors decreased during the study period, the prevalence of low fiber intake, suboptimal physical activity, abdominal obesity, and binge drinking remained high during the last combined survey cycle (2011-2014). Modifiable risk factors generally demonstrated dose-response relationships with high blood pressure categories. The most common type of risk factor clustering included low fiber intake, suboptimal physical activity, high non-HDL cholesterol, and abdominal obesity, with its prevalence increasing gradually from 9.5% (95% confidence interval, 8.8%-10.3%) in the normal blood pressure group to 16.5% (95% confidence interval, 14.8%-18.3%) in the stage 2 hypertension group (Ptrend < .001). The prevalence of 4 or more modifiable risk factors per participant increased stepwise, ranging from 28.5% in the normal blood pressure group to 48.0% in the stage 2 hypertension group (Ptrend < .001). CONCLUSIONS: The burden of potentially modifiable risk factors for hypertension shows progressive increase along the blood pressure categories and represents an important target for nonpharmacologic intervention.

Misconceptions and Facts About Mitral Regurgitation.

Mitral regurgitation is a common heart valve disease. It is defined to be primary when it results from the pathology of the mitral valve apparatus itself and secondary when it is caused by distortion of the architecture or function of the left ventricle. Although the diagnosis and management of mitral regurgitation rely heavily on echocardiography, one should bear in mind the caveats and shortcomings of such an approach. Clinical decision making commonly focuses on the indications for surgery, but it is complex and mandates precise assessment of the mitral pathology, symptom status of the patient, and ventricular performance (right and left) among other descriptors. It is important for healthcare providers at all levels to be familiar with the clinical picture, diagnosis, disease course, and management of mitral regurgitation.

Discordance between echocardiography and MRI in the assessment of mitral regurgitation severity: a prospective multicenter trial.

BACKGROUND: The decision to undergo mitral valve surgery is often made on the basis of echocardiographic criteria and clinical assessment. Recent changes in treatment guidelines recommending surgery in asymptomatic patients make the accurate assessment of mitral regurgitation (MR) severity even more important. OBJECTIVES: The purpose of this study was to compare echocardiography and magnetic resonance imaging (MRI) in the assessment of MR severity using the degree of left ventricular (LV) remodeling after surgery as the reference standard. METHODS: In this prospective multicenter trial, MR severity was assessed in 103 patients using both echocardiography and MRI. Thirty-eight patients subsequently had isolated mitral valve surgery, and 26 of these had an additional MRI performed 5 to 7 months after surgery. The pre-surgical estimate of regurgitant severity was correlated with the postoperative decrease in LV end-diastolic volume. RESULTS: Agreement between MRI and echocardiographic estimates of MR severity was modest in the overall cohort (r = 0.6; p < 0.0001), and there was a poorer correlation in the subset of patients sent for surgery (r = 0.4; p = 0.01). There was a strong correlation between post-surgical LV remodeling and MR severity as assessed by MRI (r = 0.85; p < 0.0001), and no correlation between post-surgical LV remodeling and MR severity as assessed by echocardiography (r = 0.32; p = 0.1). CONCLUSIONS: The data suggest that MRI is more accurate than echocardiography in assessing the severity of MR. MRI should be considered in those patients when MR severity as assessed by echocardiography is influencing important clinical decisions, such as the decision to undergo MR surgery.

A structured, parsimonious approach to establish the cause of moderate-to-large pericardial effusion.

The workup of moderate-to-large pericardial effusion should focus on its hemodynamic impact and potential cause. A structured approach to diagnostic evaluation of pericardial effusion is needed. We retrospectively studied a contemporary cohort of 103 patients with moderate-to-large pericardial effusion hospitalized at St. Luke's Roosevelt Hospital Center from July 2009 till August 2013. Diagnosis of pericardial effusion was independently ascertained by chart review. We applied a stepwise parsimonious approach to establish the cause of pericardial effusion. In the studied cohort, the mean age was 61 years, 50% were men, and 65 patients (63%) underwent pericardial effusion drainage. Using the structured approach, the cause of the effusion was ascertained in 70 patients (68%) by noninvasive targeted testing. Malignant effusion was confirmed in 19 patients (19%). All patients with malignant effusion had either history of malignancy or suggestive noninvasive findings. In conclusion, a structured approach can help to ascertain the diagnosis in patients with moderate-to-large pericardial effusion and guide the need for pericardial drainage or sampling.

Paradoxical hypertension with cardiac tamponade.

Subacute (medical) tamponade develops over a period of days or even weeks. Previous studies have shown that subacute tamponade is uncommonly associated with hypotension. On the contrary, many of those patients are indeed hypertensive at initial presentation. We sought to determine the prevalence and predictors of hypertensive cardiac tamponade and hemodynamic response to pericardial effusion drainage. We conducted a retrospective study of patients who underwent pericardial effusion drainage for subacute pericardial tamponade. Diagnosis of pericardial tamponade was established by the treating physician based on clinical data and supportive echocardiographic findings. Patients were defined as hypertensive if initial systolic blood pressure (BP) was ≥140 mm Hg. Thirty patients with subacute tamponade who underwent pericardial effusion drainage were included in the analysis. Eight patients (27%) were hypertensive with a mean systolic BP of 167 compared to 116 mm Hg in 22 nonhypertensive patients. Hypertensive patients with tamponade were more likely to have advanced renal disease (63% vs 14%, p <0.05) and pre-existing hypertension (88% vs 46, p <0.05) and less likely to have systemic malignancy (0 vs 41%, p <0.05). Systolic BP decreased significantly in patients with hypertensive tamponade after pericardial effusion drainage. Those results are consistent with previous studies with an estimated prevalence of hypertensive tamponade from 27% to 43%. In conclusion, a hypertensive response was observed in approximately 1/3 of patients with subacute pericardial tamponade. Relief of cardiac tamponade commonly resulted in a decrease in BP.