Journal Scan: July 2020 to August 2020

Article 1

Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan, China: Prevalence, Risk Factors, and Outcome

Circulation. 2020, 14 Jul;142(2):114-128. doi:10.1161/CIRCULATIONAHA.120.046702. Epub 2020 May 18.

Li Zhang, Xiaokai Feng, Danqing Zhang, Chunguo Jiang, Heng Mei, Jing Wang, Cuihong Zhang, Hong Li, Xiaoling Xia, Shuangshuang Kong, Jia Liao, Huijun Jia, Xueqin Pang, Yue Song, Ying Tian, Bin Wang, Chun Wu, Hongliang Yuan, Yongxing Zhang, Yuman Li, Wei Sun, Yanting Zhang, Shuangshuang Zhu, Shuyuan Wang, Yuji Xie, Shuping Ge, Liming Zhang, Yu Hu, Mingxing Xie

Background: To investigate deep vein thrombosis (DVT) in hospitalized patients with coronavirus disease 2019 (COVID-19), we performed a single institutional study to evaluate its prevalence, risk factors, prognosis, and potential thromboprophylaxis strategies in a large referral and treatment center.

Methods: We studied a total of 143 patients with COVID-19 from January 29, 2020 to February 29, 2020. Demographic and clinical data, laboratory data, including ultrasound scans of the lower extremities, and outcome variables were obtained, and comparisons were made between groups with and without DVT.

Results: Of the 143 patients hospitalized with COVID-19 (age 63 ± 14 years, 74 [51.7%] men), 66 patients developed lower extremity DVT (46.1%: 23 [34.8%] with proximal DVT and 43 [65.2%] with distal DVT). Compared with patients who did not have DVT, patients with DVT were older and had a lower oxygenation index, a higher rate of cardiac injury, and worse prognosis, including an increased proportion of deaths (23 [34.8%] vs 9 [11.7%]; P = .001) and a decreased proportion of patients discharged (32 [48.5%] vs 60 [77.9%]; P < .001). Multivariant analysis showed an association only between CURB-65 (confusion status, urea, respiratory rate, and blood pressure) score 3 to 5 (odds ratio, 6.122; P = .031), Padua prediction score ≥4 (odds ratio, 4.016; P = .04), D-dimer >1.0 μg/mL (odds ratio, 5.818; P < .014), and DVT in this cohort, respectively. The combination of a CURB-65 score 3 to 5, a Padua prediction score ≥4, and D-dimer >1.0 μg/mL has a sensitivity of 88.52% and a specificity of 61.43% for screening for DVT. In the subgroup of patients with a Padua prediction score ≥4 and whose ultrasound scans were performed >72 hours after admission, DVT was present in 18 (34.0%) patients in the subgroup receiving venous thromboembolism prophylaxis vs 35 (66.0%) patients in the nonprophylaxis group (P = .010).

Conclusions: The prevalence of DVT is high and is associated with adverse outcomes in hospitalized patients with COVID-19. Prophylaxis for venous thromboembolism may be protective in patients with a Padua protection score ≥4 after admission. Our data seem to suggest that COVID-19 is probably an additional risk factor for DVT in hospitalized patients.

Comments: COVID-19 is now known to have a prominent component of vasculitis resulting in arterial and venous thrombotic events. Acute thrombotic occlusion has been demonstrated in the cerebral coronary, peripheral, and pulmonary arteries. This study proves that COVID-19 is also associated with DVT. It appears to an additional risk factor for DVT in hospitalized patients above and over that caused by prolonged immobilization due to severe illness. This study adds to the growing body of evidence that treatment of COVID-19 should include anticoagulation.

Article 2

Treatment with ACE Inhibitors or ARBs and Risk of Severe/Lethal COVID-19: A Meta-analysis

Heart. 2020, 1 Jul. doi:10.1136/heartjnl-2020-317336. Online ahead of print.

Maria Elena Flacco, Cecilia Acuti Martellucci, Francesca Bravi, Giustino Parruti, Rosaria Cappadona, Alfonso Mascitelli, Roberto Manfredini, Lorenzo G. Mantovani, Lamberto Manzoli

Objective: It has been hypothesized that the use of ACE inhibitors and angiotensin receptor blockers (ARBs) might either increase or reduce the risk of severe or lethal COVID-19. The findings from the available observational studies varied, and summary estimates are urgently needed to elucidate whether these drugs should be suspended during the pandemic, or patients and physicians should be definitely reassured. This meta-analysis of adjusted observational data aimed to summarize the existing evidence on the association between these medications and severe/lethal COVID-19.

Methods: We searched MedLine, Scopus, and preprint repositories up to June 8, 2020 to retrieve cohort or case–control studies comparing the risk of severe/fatal COVID-19 (either mechanical ventilation, intensive care unit admission, or death), among hypertensive subjects treated with: (1) ACE inhibitors, (2) ARBs, and (3) both, vs untreated subjects. Data were combined using a random-effect generic inverse variance approach.

Results: Ten studies, enrolling 9890 hypertensive subjects were included in the analyses. Compared with untreated subjects, those using either ACE inhibitors or ARBs showed a similar risk of severe or lethal COVID-19 (summary OR: 0.90; 95% CI 0.65-1.26 for ACE inhibitors; 0.92; 95% CI 0.75-1.12 for ARBs). The results did not change when both drugs were considered together, when death was the outcome and excluding the studies with significant, divergent results.

Conclusion: The present meta-analysis strongly supports the recommendation of several scientific societies to continue ARBs or ACE inhibitors for all patients, unless otherwise advised by their physicians who should thus be reassured.

Comments: The much publicized suggestion based on the hypothesis that over expression of ACE-2 receptors might be responsible for the higher mortality of COVID-19 seen in hypertensives has resulted in a great deal of anxiety among patients with hypertension, heart failure, kidney disease, and post-myocardial infarction as well as among treating physicians. Later, several studies failed to find a correlation between usage of ACEI or ARBs and mortality in patients who develop COVID-19. This meta-analysis involving just under 10 000 patients should finally put these fears to rest. The conclusion is clear that patients on these drugs should continue them unless stopped for some other valid reason.

Article 3

Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection

J Am Coll Cardiol. 2020, 4 Aug;76(5):533-546. doi:10.1016/j.jacc.2020.06.007. Epub 2020 Jun 8.

Anuradha Lala, Kipp W. Johnson, James L. Januzzi, Adam J. Russak, Ishan Paranjpe, Felix Richter, Shan Zhao, Sulaiman Somani, Tielman Van Vleck, Akhil Vaid, Fayzan Chaudhry, Jessica K. De Freitas, Zahi A. Fayad, Sean P. Pinney, Matthew Levin, Alexander Charney, Emilia Bagiella, Jagat Narula, Benjamin S. Glicksberg, Girish Nadkarni, Donna M Mancini, Valentin Fuster, Mount Sinai COVID Informatics Center

Background: The degree of myocardial injury, as reflected by troponin elevation, and associated outcomes among US hospitalized patients with coronavirus disease 2019 (COVID-19) are unknown.

Objectives: The purpose of this study was to describe the degree of myocardial injury and associated outcomes in a large-hospitalized cohort with laboratory-confirmed COVID-19.

Methods: Patients with COVID-19 admitted to one of five Mount Sinai Health System hospitals in New York City between February 27, 2020 and April 12, 2020, with troponin-I (normal value < 0.03 ng/mL) measured within 24 hours of admission were included (n = 2736). Demographics, medical histories, admission laboratory results, and outcomes were captured from the hospitals’ electronic health records.

Results: The median age was 66.4 years, with 59.6% men. Cardiovascular disease (CVD), including coronary artery disease, atrial fibrillation, and heart failure, was more prevalent in patients with higher troponin concentrations, as were hypertension and diabetes. A total of 506 (18.5%) patients died during hospitalization. In all, 985 (36%) patients had elevated troponin concentrations. After adjusting for disease severity and relevant clinical factors, even small amounts of myocardial injury (eg, troponin I > 0.03-0.09 ng/mL; n = 455; 16.6%) were significantly associated with death (adjusted hazard ratio: 1.75; 95% CI: 1.37-2.24; P < .001) while greater amounts (eg, troponin I > 0.09 ng/dL; n = 530; 19.4%) were significantly associated with higher risk (adjusted HR: 3.03; 95% CI: 2.42-3.80; P < .001).

Conclusions: Myocardial injury is prevalent among patients hospitalized with COVID-19; however, troponin concentrations were generally present at low levels. Patients with CVD are more likely to have myocardial injury than patients without CVD. Troponin elevation among patients hospitalized with COVID-19 is associated with higher risk of mortality.

Comments: Myocardial injury is known to occur in COVID-19. Several mechanisms have been postulated and all appear to be in play in different patients (right ventricular injury due to severe respiratory disease, acute coronary thrombosis, myocarditis, arrhythmias). This study shows that while myocardial injury is quite common in patients with COVID-19, in most cases the injury is mild as demonstrated by low troponin elevations. However, patients with pre-existing CVD are more likely to have significant myocardial injury. In all cases, troponin elevation is a marker of higher mortality risk.

Article 4

Transethnic Genome-wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

Circulation. 2020, 28 Jul;142(4):324-338. doi:10.1161/CIRCULATIONAHA.120.045956. Epub 2020 May 20.

Najim Lahrouchi, Rafik Tadros, Lia Crotti, Yuka Mizusawa, Pieter G. Postema, Leander Beekman, Roddy Walsh, Kanae Hasegawa, Julien Barc, Marko Ernsting, Kari L. Turkowski, Andrea Mazzanti, Britt M. Beckmann, Keiko Shimamoto, Ulla-Britt Diamant, Yanushi D. Wijeyeratne, Yu Kucho, Tomas Robyns, Taisuke Ishikawa, Elena Arbelo, Michael Christiansen, Annika Winbo, Reza Jabbari, Steven A. Lubitz, Johannes Steinfurt, Boris Rudic, Bart Loeys, M. Ben Shoemaker, Peter E. Weeke, Ryan Pfeiffer, Brianna Davies, Antoine Andorin, Nynke Hofman, Federica Dagradi, Matteo Pedrazzini, David J. Tester, J. Martijn Bos, Georgia Sarquella-Brugada, Óscar Campuzano, Pyotr G. Platonov, Birgit Stallmeyer, Sven Zumhagen, Eline A. Nannenberg, Jan H. Veldink, Leonard H. van den Berg, Ammar Al-Chalabi, Christopher E. Shaw, Pamela J. Shaw, Karen E Morrison, Peter M. Andersen, Martina Müller-Nurasyid, Daniele Cusi, Cristina Barlassina, Pilar Galan, Mark Lathrop, Markus Munter, Thomas Werge, Marta Ribasés, Tin Aung, Chiea C. Khor, Mineo Ozaki, Peter Lichtner, Thomas Meitinger, J. Peter van Tintelen, Yvonne Hoedemaekers, Isabelle Denjoy, Antoine Leenhardt, Carlo Napolitano, Wataru Shimizu, Jean-Jacques Schott, Jean-Baptiste Gourraud, Takeru Makiyama, Seiko Ohno, Hideki Itoh, Andrew D. Krahn, Charles Antzelevitch, Dan M. Roden, Johan Saenen, Martin Borggrefe, Katja E. Odening, Patrick T. Ellinor, Jacob Tfelt-Hansen, Jonathan R. Skinner, Maarten P. van den Berg, Morten Salling Olesen, Josep Brugada, Ramón Brugada, Naomasa Makita, Jeroen Breckpot, Masao Yoshinaga, Elijah R. Behr, Annika Rydberg, Takeshi Aiba, Stefan Kääb, Silvia G. Priori, Pascale Guicheney, Hanno L. Tan, Christopher Newton-Cheh, Michael J. Ackerman, Peter J. Schwartz, Eric Schulze-Bahr, Vincent Probst, Minoru Horie, Arthur A. Wilde, Michael W.T. Tanck, Connie R. Bezzina

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.

Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.

Results: Genome-wide association analysis identified three loci associated with LQTS at genome-wide statistical significance (P < 5 × 10⁻⁸) near NOS1AP, KCNQ1, and KLF12, and one missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold (P < 10⁻⁶). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg = 0.40; P = 3.2 × 10⁻³). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P < 10⁻¹³), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P < .005).

Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Comments: It is good to remember that other diseases have not taken a vacation during the pandemic. This elegant study demonstrates that the classical genotypes for LQTS are responsible for only a part of the cases. Several common genetic variants have been found to result in susceptibility to LQTS with a polygenic inheritance pattern. Thus, the study proves that an entire subset of patients with LQTS susceptibility inherit the condition through multiple genes acting together. While these patients may not satisfy high risk criteria, they may develop symptomatic arrhythmias when receiving QT prolonging drugs. Therefore, once again, we have data demonstrating the need for vigilance when prescribing drugs that are known to prolong QT.

Article 5

Effect of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF

J Am Coll Cardiol. 2020, 4 Aug 4;76(5):503-514. doi:10.1016/j.jacc.2020.05.072.

Jonathan W. Cunningham, Brian L. Claggett, Eileen O’Meara, Margaret F. Prescott, Marc A. Pfeffer, Sanjiv J. Shah, Margaret M. Redfield, Faiez Zannad, Lu-May Chiang, Adel R Rizkala, Victor C. Shi, Martin P. Lefkowitz, Jean Rouleau, John J.V. McMurray, Scott D. Solomon, Michael R. Zile

Background: Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone.

Objectives: This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death).

Methods: N-terminal propeptide of collagens I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1135) and 16 (n = 1113) and 48 weeks (n = 1016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint.

Results: At baseline, all five biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6-10%; P < .001), soluble ST2 by 4% (95% CI: 1-7%; P = .002), and N-terminal propeptide of collagen III by 3% (95% CI: 0-6%; P = .04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1-8%; P = .02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates.

Conclusions: Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711.)

Comments: The current therapy of HF with preserved ejection fraction is mainly symptomatic and does not prevent disease progression or decrease long-term mortality. Sacubitril/valsartan has shown excellent effects in HF with reduced fraction. This study shows that the drug seems to have favorable effects on the pathophysiology of HF with preserved ejection fraction as well. While data from trials for mortality reduction are still awaited, this study is encouraging and raises hopes that ARNI may finally be the therapy that works in this debilitating condition.