Long-term cardiac surveillance and outcomes of COVID-19 patients.

Acute cardiac manifestions of COVID-19 have been well described, while chronic cardiac sequelae remain less clear. Various studies have shown conflicting data on the prevalence of new or worsening cardiovascular disease, myocarditis or cardiac dysrhythmias among patients recovered from COVID-19. Data are emerging that show that patients recovering from COVID-19 have an increased incidence of myocarditis and arrhythmias after recovery from COVID-19 compared with the control groups without COVID-19. The incidence of myocarditis after COVID-19 infection is low but is still significantly greater than the incidence of myocarditis from a COVID-19 vaccine. There have been several studies of athletes who underwent a variety of screening protocols prior to being cleared to return to exercise and competition. The data show possible, probable or definite myocarditis or cardiac injury among 0.4-3.0% of the athletes studied. Recent consensus statements suggest that athletes with full recovery and absence of cardiopulmonary symptoms may return to exercise and competition without cardiovascular testing. In conclusion, patients with COVID-19 may be expected to have an increased risk of cardiovascular disease, myocarditis or arrhythmias during the convalescent phase. Fortunately, the majority of patients, including athletes may return to their normal activity after recovery from COVID 19, in the absence of persisting cardiovascular symptoms.

Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study).

RATIONALE: Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure. OBJECTIVE: To compare the safety and efficacy of 2 doses of allogeneic bone marrow-derived human mesenchymal stem cells identically delivered in patients with ischemic cardiomyopathy. METHODS AND RESULTS: Thirty patients with ischemic cardiomyopathy received in a blinded manner either 20 million (n=15) or 100 million (n=15) allogeneic human mesenchymal stem cells via transendocardial injection (0.5 cc per injection × 10 injections per patient). Patients were followed for 12 months for safety and efficacy end points. There were no treatment-emergent serious adverse events at 30 days or treatment-related serious adverse events at 12 months. The Major Adverse Cardiac Event rate was 20.0% (95% confidence interval [CI], 6.9% to 50.0%) in 20 million and 13.3% (95% CI, 3.5% to 43.6%) in 100 million (P=0.58). Worsening heart failure rehospitalization was 20.0% (95% CI, 6.9% to 50.0%) in 20 million and 7.1% (95% CI, 1.0% to 40.9%) in 100 million (P=0.27). Whereas scar size reduced to a similar degree in both groups: 20 million by -6.4 g (interquartile range, -13.5 to -3.4 g; P=0.001) and 100 million by -6.1 g (interquartile range, -8.1 to -4.6 g; P=0.0002), the ejection fraction improved only with 100 million by 3.7 U (interquartile range, 1.1 to 6.1; P=0.04). New York Heart Association class improved at 12 months in 35.7% (95% CI, 12.7% to 64.9%) in 20 million and 42.9% (95% CI, 17.7% to 71.1%) in 100 million. Importantly, proBNP (pro-brain natriuretic peptide) increased at 12 months in 20 million by 0.32 log pg/mL (95% CI, 0.02 to 0.62; P=0.039), but not in 100 million (-0.07 log pg/mL; 95% CI, -0.36 to 0.23; P=0.65; between group P=0.07). CONCLUSIONS: Although both cell doses reduced scar size, only the 100 million dose increased ejection fraction. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action and enhance planning of pivotal Phase III trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02013674.

Randomized Comparison of Allogeneic Versus Autologous Mesenchymal Stem Cells for Nonischemic Dilated Cardiomyopathy: POSEIDON-DCM Trial.

BACKGROUND: Although human mesenchymal stem cells (hMSCs) have been tested in ischemic cardiomyopathy, few studies exist in chronic nonischemic dilated cardiomyopathy (NIDCM). OBJECTIVES: The authors conducted a randomized comparison of safety and efficacy of autologous (auto) versus allogeneic (allo) bone marrow-derived hMSCs in NIDCM. METHODS: Thirty-seven patients were randomized to either allo- or auto-hMSCs in a 1:1 ratio. Patients were recruited between December 2011 and July 2015 at the University of Miami Hospital. Patients received hMSCs (100 million) by transendocardial stem cell injection in 10 left ventricular sites. Treated patients were evaluated at baseline, 30 days, and 3-, 6-, and 12-months for safety (serious adverse events [SAE]), and efficacy endpoints: ejection fraction, Minnesota Living with Heart Failure Questionnaire, 6-min walk test, major adverse cardiac events, and immune biomarkers. RESULTS: There were no 30-day treatment-emergent SAEs. Twelve-month SAE incidence was 28.2% with allo-hMSCs versus 63.5% with auto-hMSCs (p = 0.1004 for the comparison). One allo-hMSC patient developed an elevated (>80) donor-specific calculated panel reactive antibody level. The ejection fraction increased in allo-hMSC patients by 8.0 percentage points (p = 0.004) compared with 5.4 with auto-hMSCs (p = 0.116; allo vs. auto p = 0.4887). The 6-min walk test increased with allo-hMSCs by 37.0 m (p = 0.04), but not auto-hMSCs at 7.3 m (p = 0.71; auto vs. allo p = 0.0168). MLHFQ score decreased in allo-hMSC (p = 0.0022) and auto-hMSC patients (p = 0.463; auto vs. allo p = 0.172). The major adverse cardiac event rate was lower, too, in the allo group (p = 0.0186 vs. auto). Tumor necrosis factor-α decreased (p = 0.0001 for each), to a greater extent with allo-hMSCs versus auto-hMSCs at 6 months (p = 0.05). CONCLUSIONS: These findings demonstrated safety and clinically meaningful efficacy of allo-hMSC versus auto-hMSC in NIDCM patients. Pivotal trials of allo-hMSCs are warranted based on these results. (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy [PoseidonDCM]; NCT01392625).

Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty.

Frailty is a syndrome associated with reduced physiological reserves that increases an individual's vulnerability for developing increased morbidity and/or mortality. While most clinical trials have focused on exercise, nutrition, pharmacologic agents, or a multifactorial approach for the prevention and attenuation of frailty, none have studied the use of cell-based therapies. We hypothesize that the application of allogeneic human mesenchymal stem cells (allo-hMSCs) as a therapeutic agent for individuals with frailty is safe and efficacious. The CRATUS trial comprises an initial non-blinded phase I study, followed by a blinded, randomized phase I/II study (with an optional follow-up phase) that will address the safety and pre-specified beneficial effects in patients with the aging frailty syndrome. In the initial phase I protocol, allo-hMSCs will be administered in escalating doses via peripheral intravenous infusion (n=15) to patients allocated to three treatment groups: Group 1 (n=5, 20 million allo-hMSCs), Group 2 (n=5, 100 million allo-hMSCs), and Group 3 (n=5, 200 million allo-hMSCs). Subsequently, in the randomized phase, allo-hMSCs or matched placebo will be administered to patients (n=30) randomly allocated in a 1:1:1 ratio to one of two doses of MSCs versus placebo: Group A (n=10, 100 million allo-hMSCs), Group B (n=10, 200 million allo-hMSCs), and Group C (n=10, placebo). Primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCs administered in frail older individuals. This study will determine the safety of intravenous infusion of stem cells and compare phenotypic outcomes in patients with aging frailty.

Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial.

IMPORTANCE: Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. OBJECTIVE: To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. DESIGN, SETTING, AND PATIENTS: A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. INTERVENTIONS: Injections in 10 LV sites with an infusion catheter. MAIN OUTCOMES AND MEASURES: Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. RESULTS: No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95% CI, -15.7% to 1.7%; within-group, P = .11) or placebo (-5.2%; 95% CI, -16.8% to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95% CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95% CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. CONCLUSIONS AND RELEVANCE: Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00768066.

Comparison of allogeneic vs autologous bone marrow­derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial.

CONTEXT: Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared. OBJECTIVE: To test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM. DESIGN, SETTING, AND PATIENTS: A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up. INTERVENTION: Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites. MAIN OUTCOME MEASURES: Thirty-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index. RESULTS: Within 30 days, 1 patient in each group (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEs observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = .10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P < .001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions. CONCLUSIONS: In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01087996.

Orthodeoxia platypnea syndrome in a patient with lipomatous hypertrophy of the interatrial septum due to long-term steroid use.

We describe an unusual case of orthodeoxia platypnea syndrome exacerbated by right ventricular inflow obstruction due to iatrogenic steroid-induced adipose deposition in cardiac tissues. A 68-year-old man on long-term prednisone therapy for eosinophilic pneumonia presented with progressive dyspnea worsened by bending forward. By using pulse oximetry, he was noted to have positional hypoxemia. Transthoracic echocardiogram demonstrated normal right-sided pressures but severe right to left shunting through a patent foramen ovale. Transesophageal echocardiogram showed a large patent foramen ovale, severe lipomatous hypertrophy of the interatrial septum, and massive adipose deposition in the pericardium causing compression of the right ventricular inflow tract. The patient underwent percutaneous closure of the patent foramen ovale, which resulted in the resolution of symptoms and hypoxemia. This case is unique because long-term steroid use resulted in reverse Lutembacher physiology and clinical orthodeoxia platypnea syndrome by inducing lipomatous hypertrophy of the interatrial septum and compression of the right atrium.

Comprehensive evaluation of Kawasaki disease with electrocardiogram-gated cardiac multidetector computed tomography.

We present a case of a young woman with Kawasaki disease who was comprehensively evaluated by electrocardiograph-gated cardiac multidetector computed tomography (MDCT). MDCT disclosed 3-vessel giant coronary arterial aneurysms and associated focal apical septal myocardial pathology. This was characterized by an early enhancement defect, myocardial thinning, and hypokinesia. These findings are likely due to focal ischemic insult resulting from distal embolization of thrombus material from the giant proximal right coronary arterial aneurysms. This case illustrates the full capabilities of MDCT in the comprehensive evaluation of Kawasaki disease.

Comparison of epicardial and pericardial fat thickness assessed by echocardiography in African American and non-Hispanic White men: a pilot study.

OBJECTIVES: Compared to non-Hispanic Whites, African American men have less intra-abdominal visceral adipose tissue (VAT) relative to total fat mass despite having a higher risk of obesity-related diseases. This study explores whether this racial pattern of VAT distribution extends to the intrathoracic VAT. METHODS: We used two-dimensional transthoracic echocardiography to measure pericardial and maximum and minimum epicardial fat thickness anterior to the right ventricle in 50 African American and 106 non-Hispanic White men, aged 40-75 years, consecutively referred for echocardiography for standard clinical indications. Age, coronary risk factors, height, and weight were recorded, and body mass index (BMI) was calculated. The two groups were compared with respect to pericardial and maximum, minimum, and average epicardial fat thicknesses. RESULTS: Among non-Hispanic Whites, pericardial and minimum epicardial fat measured at the mid-rightventricular wall were higher by 37% and 69%, respectively, than among African Americans (5.2+/-3.1 mm vs 3.8+/-3.1 mm, P<.011; 2.2+/-1.6 mm vs 1.3+/-1.2 mm, P<.001). Maximum epicardial fat along the distal right ventricular wall was 19% greater in non-Hispanic Whites, but this difference was not statistically significant (4.3+/-2.6 mm vs 3.6+/-2.0 mm, P=.133). The average epicardial fat measured at two sites was 26% greater in non-Hispanic Whites (2.9+/-2.0 mm vs 2.3+/-1.3 mm, P=.019). CONCLUSIONS: Among men referred for echocardiography, non-Hispanic Whites have more epicardial and pericardial fat than do African Americans. Echocardiography may be a useful research tool for investigating VAT distribution and its relationship to cardiovascular risk.

Effects of age and pulmonary arterial hypertension on the different phases of right atrial function.

To evaluate the effects of age and pulmonary hypertension on phasic right atrial function we measured right atrial volumes at 3 different points in the cardiac cycle in 57 healthy subjects and 33 patients with pulmonary arterial hypertension. Right atrial reservoir function was assessed by systolic filling volume and passive and active emptying by passive and active emptying volume and fraction of total emptying. We compared these phases of right atrial function in 30 healthy subjects <60 and 27 > or = 60 years old, and in a separate analysis, in 33 patients with pulmonary arterial hypertension and 33 matched controls. Healthy subjects > or =60 years had lower passive emptying fraction (46.0 +/- 23.3% vs 59.9 +/- 15.4%, P = 0.011) and larger active emptying volume (7.0 +/- 3.5 vs 4.9 +/- 2.5 ml/m2, P = 0.013 ) and fraction (54.0 +/- 23.3% vs 40.1 +/- 15.4%, P = 0.011) compared to those <60. Patients with pulmonary arterial hypertension had larger right atrial volumes, systolic filling volume (18.3 +/- 6.9 vs 12.3 +/- 4.9 ml/m2, P < or = 0.001) and active emptying volume and fraction (11.2 +/- 6.9 vs 5.4 +/- 3.0 ml/m2, P < or = 0.001; 60.7 +/- 29.9 vs 44.9 +/- 19.0%, P = 0.017 ) and smaller passive emptying fraction (39.3 +/- 29.9% vs 55.1 +/- 19.0%, P = 0.017) compared to controls. Aging and pulmonary arterial hypertension are associated with a decrease in passive right atrial emptying and an increase in right atrial active emptying.

Effects of weight loss after gastric bypass on right and left ventricular function assessed by tissue Doppler imaging.

To evaluate the effects of substantial weight loss on tissue Doppler imaging parameters of right ventricular (RV) and left ventricular (LV) systolic and diastolic function, we performed standard echocardiography and tissue Doppler imaging in 17 patients with severe obesity before and after gastric bypass. Patients lost 39 +/- 10 kg over 7.6 +/- 3.6 months. Adjusted LV mass decreased (134 +/- 41 to 119 +/- 31 kg/m, p = 0.031). After weight loss, the ratios of early-to-late diastolic mitral and tricuspid inflow velocities increased (1.3 +/- 0.2 to 1.6 +/- 0.5, p = 0.02; 1.0 +/- 0.1 to 1.6 +/- 0.3, p = 0.003). Early diastolic tissue Doppler velocities increased at both the lateral and septal mitral annulus (7.6 +/- 1.5 to 9.3 +/- 2.5 cm/s, p = 0.009; and 6.6 +/- 1.4 to 7.7 +/- 1.7 cm/s; p = 0.028, respectively) and for their 2-site average (7.2 +/- 1.0 to 8.5 +/- 1.7 cm/s, p = 0.007). Early diastolic tricuspid annular velocity increased (7.2 +/- 2.8 to 10.6 +/- 2.3 cm/s, p <0.001) as did the ratio of early-to-late tricuspid annular diastolic velocity (0.9 +/- 0.4 to 1.1 +/- 0.2, p = 0.038). Tricuspid annular systolic velocity increased (8.6 +/- 2.5 to 10.3 +/- 2.7 cm/s, p = 0.037). In patients with severe obesity, significant weight loss results in an increase in tricuspid annular systolic and early diastolic velocities and mitral annular early diastolic velocities.

Tissue Doppler imaging of the right and left ventricle in severe obesity (body mass index >35 kg/m2).

We investigated right and left heart function in 51 patients with a body mass index of >35 kg/m(2) who underwent evaluation for gastric bypass surgery using standard Doppler echocardiography and color tissue Doppler imaging. Left atrial diameter (3.7 +/- 0.5 vs 3.3 +/- 0.4 cm, p <0.001), left ventricular end-diastolic diameter (5.0 +/- 0.6 vs 4.5 +/- 0.4 cm, p <0.001), and left ventricular mass index (119 +/- 49 vs 76 +/- 26 g/m, p <0.001) were increased in patients with severe obesity. Early diastolic mitral annular velocity (7.5 +/- 2.1 vs 9.6 +/- 3.0 cm/s, p <0.001), early diastolic/late diastolic mitral annular velocity ratio (1.38 +/- 0.6 vs 1.94 +/- 1.3, p = 0.007), early diastolic tricuspid annular velocity (7.8 +/- 2.6 vs 9.5 +/- 2.4 cm/s, p = 0.002), early diastolic/late diastolic tricuspid annular velocity ratio (0.9 +/- 0.36 vs 1.1 +/- 0.4, p = 0.048), and mitral annular systolic velocity (5.7 +/- 1.3 vs 6.5 +/- 1.5 cm/s, p = 0.012) were significantly lower in obese patients. Early diastolic mitral inflow/mitral annular velocity ratio was increased in the obese (13.5 +/- 4.7 vs 9.1 +/- 3.6, p <0.001). Tricuspid annular systolic velocities did not differ.

Rapid resolution of left ventricular thrombus in antiphospholipid syndrome.

A 43-year-old male with recurrent cerebral infarctions and high titers of antiphospholipid antibodies was found to have a thrombus in his left ventricular outflow tract by transthoracic echocardiography. This thrombus disappeared after less than 24 hours of intravenous heparin therapy due to resolution or asymptomatic embolism. Left ventricular thrombi in patients with antiphospholipid syndrome and rapid disappearance of left ventricular thrombi with heparin therapy are infrequently reported occurrences.

Noncompaction of the ventricular myocardium: the use of contrast-enhanced echocardiography in diagnosis.

We describe a case of noncompaction of the ventricular myocardium diagnosed in the preoperative evaluation of a patient undergoing renal transplantation. Ventricular noncompaction is characterized by numerous prominent trabecular recesses with intratrabecular blood from the ventricular cavity. Color Doppler was suggestive of intramyocardial flow. With contrast-enhanced echocardiography the endocardial borders were clearly demarcated, allowing for visualization of trabecular recesses and intratrabecular flow. Contrast-enhanced echocardiography facilitates the diagnosis of noncompaction of the ventricular myocardium, circumventing the need for invasive diagnostic testing.