key: cord-0961374-z79vxdh7
authors: Berg, David D.; Alviar, Carlos L; Bhatt, Ankeet S.; Baird-Zars, Vivian M.; Barnett, Christopher F.; Daniels, Lori B.; DeFilippis, Andrew P.; Fagundes, Antonio; Katrapati, Praneeth; Kenigsberg, Benjamin B.; Guo, Jianping; Keller, Norma; Lopes, Mathew S.; Mody, Anika; Papolos, Alexander I; Phreaner, Nicholas; Sedighi, Romteen; Sinha, Shashank S; Toomu, Sandeep; Varshney, Anubodh S.; Morrow, David A.; Bohula, Erin A.
title: Epidemiology of Acute Heart Failure in Critically Ill Patients with COVID-19: An Analysis from the Critical Care Cardiology Trials Network
date: 2022-01-17
journal: J Card Fail
DOI: 10.1016/j.cardfail.2021.12.020
sha: a3aa5afca6decae43eba1951656bdb7f18ebfc39
doc_id: 961374
cord_uid: z79vxdh7

BACKGROUND: Acute heart failure (HF) is an important complication of coronavirus disease 2019 (COVID-19) and has been hypothesized to relate to inflammatory activation. METHODS: We evaluated consecutive intensive care unit (ICU) admissions for COVID-19 across 6 centers in the Critical Care Cardiology Trials Network, identifying patients with vs. without acute HF. Acute HF was sub-classified as "de novo" vs. "acute-on-chronic" based on the absence or presence of prior HF. Clinical features, biomarker profiles, and outcomes were compared. RESULTS: Among 901 COVID-19 ICU admissions, 80 (8.9%) had acute HF, including 18 (2.0%) with classic cardiogenic shock (CS) and 37 (4.1%) with vasodilatory CS. The majority (n=45) were de novo HF presentations. Compared to patients without acute HF, those with acute HF had higher cardiac troponin (cTn) and natriuretic peptides, and similar inflammatory biomarkers; patients with de novo HF had the highest cTn. Notably, among critically ill patients with COVID-19, illness severity (median SOFA, 8 [IQR, 5-10] vs. 6 [4-9]; p=0.025) and mortality (43.8% vs. 32.4%; p=0.040) were modestly higher in patients with vs. without acute HF. CONCLUSIONS: Among critically ill COVID-19 patients, acute HF is distinguished more by biomarkers of myocardial injury and hemodynamic stress than by biomarkers of inflammation.

Conclusions: Among critically ill COVID-19 patients, acute HF is distinguished more by biomarkers of myocardial injury and hemodynamic stress than by biomarkers of inflammation. Keywords heart failure, biomarkers Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, acute heart failure (HF) has been recognized as an important complication of severe acute respiratory syndromecoronavirus 2 (SARS-CoV2) infection. [1, 2] Multiple mechanisms are potential drivers of acute HF in COVID-19 including myocarditis, systemic inflammation, catecholamine toxicity (i.e., takotsubo cardiomyopathy), and myocardial ischemia/infarction; however, cardiovascular histopathology and imaging studies have not identified one clear mechanistic culprit. [3] Furthermore, epidemiological data comparing patients who develop COVID-19-related HF syndromes to non-critically ill COVID-19 patients have made it difficult to discern whether their clinical characteristics are related specifically to the development of acute HF or more broadly to critical illness. Therefore, our objective was to describe the clinical features and hospital courses of critically ill COVID-19 patients with and without acute HF syndromes in a multiinstitutional cohort of intensive care unit (ICU) patients.

We analyzed consecutive ICU admissions with COVID-19 from 3/2020 to 12/2020 across six U.S. academic medical centers using data from the Critical Care Cardiology Trials Network (CCCTN). [4] Participating centers entered comprehensive clinical data for patients with a primary diagnosis of COVID-19 admitted to all ICUs at their institution into a central case report form. All patients admitted to the ICU with cardiogenic shock (CS; either classic or vasodilatory) or with acute HF without CS were classified as having an acute HF syndrome and compared to 3 patients without acute HF. CS was defined by sustained hemodynamic impairment (systolic blood pressure [SBP] <90 mmHg) and evidence of end-organ hypoperfusion due to a low cardiac output state. [5] The distinction between classic and vasodilatory CS was based on high vs. low systemic vascular resistance using either invasive hemodynamic or clinical assessment.

Classification of acute HF without CS was based on clinician assessment using local diagnostic standards and the entirety of the clinical record. Admissions for acute HF were further classified as "de novo" vs. "acute-on-chronic" presentations based on the absence or presence of a prior diagnosis of HF, respectively. The protocol and waiver of informed consent were approved by the Institutional Review Board at Mass General Brigham and at each center.

Baseline patient characteristics, presenting clinical features, and ICU resource utilization were summarized according to presenting HF categories. Categorical variables are presented as counts and percentages and continuous variables as medians with 25 th -75 th percentiles.

Differences between groups were evaluated using the Pearson χ 2 test for categorical and Wilcoxon rank sum test for continuous variables.

Among 901 COVID-19 ICU admissions, 80 (8.9%) had acute HF, including 18 (2.0%) with classic CS and 37 (4.1%) with vasodilatory CS. In our cohort, critically ill COVID-19 patients with acute HF had a median age of 64 (25 th -75 th percentile, 55-76) years and were predominantly male (70.0%). More than half were de novo presentations of HF (n=45).

As compared to critically ill COVID-19 patients without acute HF, those with acute HF were more likely to have prior HF (43.8% vs. 8.8%; p<0.001), coronary artery disease (26.3% vs 9.5%; p<0.001), atrial fibrillation (27.5% vs. 8.8%; p<0.001), and chronic kidney disease (32.5% 4 vs 14.6%; p<0.001; Table 1 ). These comorbidities were more common in acute-on-chronic HF than in de novo HF ( Table 2) .

Presentations with acute HF were most commonly due to left ventricular (LV)predominant failure. Among acute HF patients with available presenting LVEF data (n=67), 65.6% had LV systolic dysfunction (LVEF <50%), which was more common in patients with de novo (74.3%) vs. acute-on-chronic HF (56.3%; p=0.03; Figure 1 ). Sixteen percent of patients with acute HF had concurrent acute coronary syndromes (ACS; vs. 123 (22-257) mg/L (p=0.14); median interleukin-6 (IL-6) 72 (54-304) vs. 91 (30-297) pg/ml (p=0.98); and median ferritin 1,480 (575-3,522) vs. 1,375 (652-2,798) mg/L (p=0.60; Table 1 ).

However, patients with de novo HF tended to be more inflamed than those with acute-onchronic HF ( 

Prior HF is an important prognostic indicator in COVID-19. [6, 7] Our analysis extends this observation by demonstrating that pre-existing HF is also an important risk factor for the 6 development of severe acute HF syndromes among critically ill patients with COVID-19. At the same time, more than half of ICU admissions for acute HF occurred in patients without a prior diagnosis of HF, highlighting the clinically important risk of de novo myocardial dysfunction and HF in this population. In a single-center analysis of hospitalized (critically ill and non-critically ill) COVID-19 patients, 37 were identified as having de novo HF, eight of whom had no prior cardiovascular disease or known risk factors. [8] The point prevalence of de novo HF in our cohort was >8-fold higher than that observed in that study (5.0% vs. 0.6%), likely related to the higher overall risk of our exclusively ICU-based population. Nevertheless, we also observed that many de novo HF patients had no known prior cardiovascular disease or risk factors.

Collectively, these findings underscore the importance of recognizing this subset of patients and investigating their mechanisms of myocardial injury to potentially tailor acute and chronic therapies and future preventive interventions.

The biomarker profiles observed in our study also offer potentially important and clinically relevant insights. Both cTn and natriuretic peptide concentrations were strongly associated with acute HF presentation in critically ill COVID-19 patients; however, cTn was particularly elevated in de novo compared with acute-on-chronic HF, suggesting more acute myocardial injury in this group. Notably, although COVID-19 ICU patients with acute HF had elevated inflammatory markers, the degree of inflammation was comparable to those without acute HF, suggesting that the hyperinflammatory phenotype may not distinguish presentation with acute HF. Whether these biomarker patterns reflect the underlying mechanisms driving acute HF syndromes in critically ill patients with COVID-19 warrants further investigation (e.g., correlation with cardiac MRI, endomyocardial biopsy). 7 Finally, although mortality was high in critically ill COVID-19 patients both with and without acute HF, those with acute HF had a higher risk of cardiac arrest and of dying from a cardiovascular cause, which may have implications for optimal triage of these patients (e.g., to cardiac ICUs). It is important to note that mortality estimates from our study period may be higher than contemporary estimates due to subsequent adoption of effective therapies (e.g., corticosteroids).

In conclusion, acute HF is an important complication in critically ill patients with COVID- Values indicate the "worst" levels (i.e., peak or nadir, as appropriate) of the biomarker during ICU admission. 3 Includes intra-aortic balloon pump counter-pulsation, Impella percutaneous ventricular assist systems (2.5, CP, 5.0, 5.5, RP), TandemHeart percutaneous ventricular assist systems, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) 4 Among those surviving to ICU discharge 5 Modes of death are not mutually exclusive categories , meters-squared; mg, milligrams; ml, milliliter; mmHg, millimeters of mercury; ng, nanograms; NSTEMI, non-ST-segment elevation myocardial infarction; NT-proBNP, N-terminal pro-Btype natriuretic peptide; PaO 2 , partial pressure of oxygen in arterial blood; PCI, percutaneous coronary intervention; PEA, pulseless electrical activity; pg, picograms; PPV, positive pressure ventilation; rpm, respirations per minute; SOFA, Sequential Organ Failure Assessment; STEMI, ST-segment elevation myocardial infarction; ULN, upper limit of normal; VF, ventricular fibrillation; VT, ventricular tachycardia. 1 Values indicate the "worst" levels (i.e, peak or nadir, as appropriate) of the biomarker during ICU admission. 2 Includes intra-aortic balloon pump counter-pulsation, Impella percutaneous ventricular assist systems (2.5, CP, 5.0, 5.5, RP), TandemHeart percutaneous ventricular assist systems, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) 3 Among those surviving to ICU discharge 4 Modes of death are not mutually exclusive categories 

Heart failure in COVID-19 patients: prevalence, incidence and prognostic implications

Coronavirus Disease-2019 and Heart Failure: A Scientific Statement From the Heart Failure Society of America

COVID-19 for the Cardiologist: Basic Virology, Epidemiology, Cardiac Manifestations, and Potential Therapeutic Strategies

Care Patterns, and Outcomes of Patients Admitted to Cardiac Intensive Care Units: The Critical Care Cardiology Trials Network Prospective North American Multicenter Registry of Cardiac Critical Illness

Epidemiology of Shock in Contemporary Cardiac Intensive Care Units

Impact of heart failure on the clinical course and outcomes of patients hospitalized for COVID-19. Results of the Cardio-COVID-Italy multicentre study

Prognostic Impact of Prior Heart Failure in Patients Hospitalized With COVID-19

New Heart Failure Diagnoses Among Patients Hospitalized for COVID-19