Cardiac manifestation in primary systemic vasculitides is associated with poor outcomes, leading to the use of immunosuppressive therapy. In contrast, the spectrum and the outcome of cardiac involvement in the setting of mixed cryoglobulinemia vasculitis (CryoVas) have never been evaluated. To describe the clinical presentation and to evaluate clinical outcomes of cardiac manifestations during hepatitis C virus (HCV)–related mixed CryoVas, the clinical records of 165 consecutive patients with HCV-related mixed CryoVas followed from January 1, 1993, to January 1, 2010, were reviewed. Of the 165 patients with HCV-related mixed CryoVas, 7 (4%) had cardiac manifestations. Thoracic pain and congestive heart failure manifestations were the main clinical manifestations (n = 4 [57%] each). Cardiac imaging showed dilated cardiomyopathy in 5 patients and hypertrophic cardiomyopathy in 1. In multivariate analysis, patients with cardiac manifestations had more frequent B-cell lymphoma (odds ratio 18.1, 95% confidence interval 2.8 to 116.7, p = 0.0023) and gastrointestinal involvement (odds ratio 14.6, 95% confidence interval 2.0 to 104.9, p = 0.0078). All cardiac manifestations were reversible early after the initiation of corticosteroids and aggressive immunosuppressive therapy. However, after a median follow-up period of 19 months, 3 patients (43%) had died. Respective 6-month, 1-year, and 2-year survival rates in patients with and without cardiac involvement were 86% and 99%, 71% and 96%, and 48% and 90% (hazard ratio 5.01, p = 0.003). In conclusion, cardiac damage is a rare manifestation of HCV-related mixed cryoglobulinemia vasculitis. Cardiac involvement is associated with B-cell lymphoma and life-threatening manifestations. Despite favorable early outcomes, patients with cardiac damage had poorer survival than those without.
Systemic vasculitides are a group of disorders defined by inflammation of the blood vessel walls. Among the pathogenic mechanisms that have been implicated in the induction of vasculitis, circulating mixed cryoglobulinemia (MC) may be responsible for immune complex–mediated inflammation, leading to the occurrence of systemic manifestations. Shortly after the discovery of the hepatitis C virus (HCV) in 1989, there was evidence that >80% of MC cases were associated with HCV infection. In addition, roughly 5% of patients with HCV-related MC develop symptomatic MC-related small-vessel vasculitis and less frequently necrotizing medium-vessel vasculitis (polyarteritis nodosa [PAN] like). Cardiac involvement has been rarely described in the setting of HCV-related vasculitis. Increased levels of circulating N-terminal pro–brain natriuretic peptide were found in 30% of patients with HCV-related MC compared to 7% of controls, findings that could indicate the presence of a subclinical cardiac dysfunction in patients with HCV-related MC. However, the prevalence and the presentation of cardiac involvement related to HCV-related MC have not been evaluated to date. During primary systemic vasculitis, cardiac involvement has been mainly reported in Churg-Strauss syndrome (CSS), with a prevalence ranging from 13% to 75% of patients. In patients with PAN, cardiac involvement due to vasculitis of the coronary arteries or their branches with myocardial arteriolar infarcts was reported in 6% to 57% of patients when considering radiologic, electrocardiographic, or histopathologic studies. Congestive heart failure is the main clinical feature in PAN but usually less frequently than in CSS. In these patients, cardiac involvement has been identified as an independent factor associated with poor outcomes. The aims of this study were to describe the presentation and outcomes of patients with cardiac involvement and to compare them to patients with HCV-related vasculitis without cardiac involvement.
Methods
Data from 165 consecutive patients with HCV-related systemic vasculitis (76 mean, 89 women; median age 62 years, range 31 to 85) followed from January 1, 1993, to January 1, 2010, by the same physician (P.C.) in the Department of Internal Medicine at Groupe Hospitalier Pitié-Salpétrière (Paris, France) were retrospectively reviewed by the same physician (B.T.). For each patient, clinical and biologic data were recorded at the time of the initial evaluation, during follow-up, and at the end of follow-up. All patients were HCV ribonucleic acid positive at initial presentation of vasculitis.
Patients were considered to have HCV-related vasculitis if they had, in association with clinical manifestations of vasculitis (purpura or cutaneous ulcers, arthralgia, myalgia, peripheral neuropathy, renal involvement, cerebral vasculitis, gastrointestinal involvement, cardiac involvement), (1) histologically proved vasculitis (n = 103) (required for all patients without detectable MC) and/or (2) detectable MC with at least purpura as a clinical manifestation (n = 62). Patients without histologically proved vasculitis but with purpura and detectable MC were considered to have small-vessel vasculitis on the basis of previously defined clinical and biologic criteria. Cryoglobulin levels were measured and classified as previously described. Patients who were MC positive were defined as having MC in their serum that was >0.05 g/L on ≥2 occasions. The type of vasculitis for each patient was classified according to the Chapel Hill criteria. According to these criteria and to the American College of Rheumatology criteria, patients were classified as having MC-type small-vessel vasculitis and PAN-like medium-vessel vasculitis. Liver biopsy specimens were evaluated according to the previously validated METAVIR scoring system.
Cardiac involvement was defined as (1) cardiac manifestations present at the time of vasculitis and responding to vasculitis treatment, after exclusion of other causes of cardiac involvement, and (2) cardiac manifestations occurring during a relapse of vasculitis, diagnosed on the basis of extracardiac features of vasculitis and/or immunologic features, responding to vasculitis treatment, after exclusion of other causes of cardiac involvement. The following manifestations were considered to be cardiac manifestations: thoracic pain; heart failure; acute pulmonary edema; myocardial ischemia or infarction; abnormalities in serum troponin and brain natriuretic peptide levels; and abnormal findings on electrocardiographic, ultrasonography, scintigraphy, coronary angiography, and/or cardiac magnetic resonance imaging. Dilated cardiomyopathy was characterized by dilation and impaired contraction of 1 or both ventricles.
Clinical response of vasculitis to antiviral treatment was defined by analyzing the course of cardiac involvement (clinical, biologic, and radiologic improvement). Relapse was defined as the reappearance of clinical signs of vasculitis.
Data are presented as mean ± SD or as median (range), as appropriate for continuous variables, and as frequency (percentage) for qualitative variables. Fisher’s exact tests were used to compare qualitative variables, and nonparametric Mann-Whitney U tests were used to compare continuous variables. Multivariate analysis using logistic regression was used to determine the variables independently associated with cardiac involvement. Variables associated with cardiac involvement at the 0.20 level were considered in the multivariate analysis. Variable selections were performed using a backward procedure on the basis of a p value cutoff of 0.05. A p value <0.05 was considered significant. Statistical analyses were performed using GraphPad Prism version 4.0 and Instat version 3.0 for Windows (GraphPad Software, San Diego, California).
Results
The main characteristics of the 165 patients with HCV-related systemic vasculitis according to the presence of cardiac involvement are listed in Tables 1 and 2 . Cardiac involvement was present in 7 of 165 patients (4%), at the diagnosis of vasculitis in 3 patients (43%), and during clinical relapses of vasculitis in 4 patients (57%), including 2 patients without virologic relapse. No cardiac biopsy was available.
| Feature | All Patients (n = 165) | No Cardiac Involvement (n = 158) | Cardiac Involvement (n = 7) | p Value |
|---|---|---|---|---|
| Epidemiologic features | ||||
| Age (yrs) | 62 (31–85) | 62 (31–85) | 61 (40–76) | 0.93 |
| Women | 89 (54%) | 85 (54%) | 4 (57%) | 1.00 |
| Virologic features | ||||
| HCV genotype | 0.02 † | |||
| 1 | 92 (61%) | 89 (62%) | 3 (42%) | |
| 2 | 25 (17%) | 25 (17%) | 0 (0%) | |
| 3 | 14 (10%) | 12 (8%) | 2 (29%) | |
| 4 | 13 (9%) | 11 (8%) | 2 (29%) | |
| 5 | 7 (5%) | 7 (5%) | 0 (0%) | |
| Not available | 14 | 14 | 0 | |
| HCV ribonucleic acid level (log 10 IU) | 5.9 (3.3–7.9) | 5.8 (3.3–7.9) | 6.0 (5.0–7.0) | 0.69 |
| Median duration of infection (yrs) | 21 (3–48) | 21 (3–48) | 19 (16–28) | 0.57 |
| Liver METAVIR score ∗ | ||||
| Activity score | 1 (0–3) | 1 (0–3) | 1 (0–2) | 0.38 |
| Fibrosis score | 2 (0–4) | 2 (0–4) | 2 (0–4) | 0.70 |
| Fibrosis score ≥3 | 48/142 (34%) | 46/135 (34%) | 2 (29%) | 1.00 |
| Alanine aminotransferase (times upper limit of normal) | 1.5 (0.5–7) | 1.5 (0.5–7) | 1 (0.5–1.5) | 0.008 † |
∗ Liver biopsy specimens were evaluated according to the previously validated METAVIR scoring system.
| Feature | All Patients (n = 165) | No Cardiac Involvement (n = 158) | Cardiac Involvement (n = 7) | p Value |
|---|---|---|---|---|
| Median duration between diagnosis of vasculitis and treatment (mo) | 12 (1–192) | 12 (1–192) | 1 (1–6) | 0.0002 ∗ |
| Clinical features | ||||
| Deterioration of the general health status | 36 (22%) | 31 (20%) | 5 (71%) | 0.006 ∗ |
| Purpura | 117 (71%) | 111 (70%) | 6 (86%) | 0.67 |
| Arthralgia | 87 (53%) | 85 (54%) | 2 (29%) | 0.26 |
| Myalgia | 23 (14%) | 21 (13%) | 2 (29%) | 0.25 |
| Peripheral neuropathy | 122 (74%) | 119 (75%) | 3 (43%) | 0.08 |
| Renal involvement | 56 (34%) | 50 (32%) | 6 (86%) | 0.007 ∗ |
| Central nervous system involvement | 15 (9%) | 14 (9%) | 1 (14%) | 0.49 |
| Gastrointestinal involvement | 12 (7%) | 9 (6%) | 3 (43%) | 0.009 ∗ |
| B-cell lymphoma | 26 (16%) | 21 (13%) | 5 (71%) | 0.001 ∗ |
| Biologic features | ||||
| Median C-reactive protein (mg/L) | 2 (0–158) | 2 (0–158) | 11 (1–89) | 0.10 |
| Median C4 (mg/L) | 0.06 (0.01–0.41) | 0.06 (0.01–0.41) | 0.02 (0.01–0.04) | 0.0005 ∗ |
| Rheumatoid factor positivity | 109/141 (77%) | 102/134 (76%) | 7 (100%) | 0.35 |
| Characteristics of MC | ||||
| Detectable MC | 149 (90%) | 142 (90%) | 7 (100%) | 1.00 |
| Median MC level (g/L) | 0.76 (0.05–7.00) | 0.70 (0.05–7.00) | 1.25 (0.61–3.44) | 0.08 |
| Type II MC | 123 | 116 | 7 | |
| Type III MC | 26 | 26 | 0 | |
| Histologic features | 0.61 | |||
| MC vasculitis | 135 (82%) | 130 (82%) | 5 (71%) | |
| PAN-like vasculitis | 30 (18%) | 28 (18%) | 2 (29%) |
The comparison of patients with and without cardiac involvement is listed in Tables 1 and 2 . Cardiac involvement was significantly associated with higher rates of deterioration of the general health status, renal and gastrointestinal involvement, and B-cell non-Hodgkin lymphoma (B-NHL). Median serum C4 complement fraction level was significantly higher in patients with than those without cardiac involvement, while median MC levels tended to be higher in patients with cardiac involvement. In multivariate analysis, the presence of B-NHL (odds ratio 18.1, 95% confidence interval 2.8 to 116.7, p = 0.0023) and gastrointestinal involvement (odds ratio 14.6, 95% confidence interval 2.0 to 104.9, p = 0.0078) were independently associated with cardiac involvement.
The individual characteristics of the 7 patients with cardiac involvement are listed in Tables 3 and 4 . None of the patients had histories of cardiomyopathy. Thoracic pain was present in 4 patients (57%), and congestive heart failure manifestations were noted in 4 patients (57%), including acute pulmonary edema in 4 and massive lower limb edema in 2 patients. Electrocardiography showed negative or flattened T waves in 6 patients (involving the inferior territory in 3, the lateral territory in 2, leads V 1 to V 6 in 2, the apical territory in 1, and the septal territory in 1), associated with ST-segment depression in 1 (involving the inferior and septal territories). Cardiac ultrasound revealed abnormalities in all cases: dilated cardiomyopathy in 5 patients (71%), global hypokinesia with left ventricular ejection fractions <40% in 4 (57%), pericardial effusion in 2 (29%) and acute hypertrophic cardiomyopathy with a left ventricular mass index of 123 g/m 2 in 1 patient. Cardiac magnetic resonance imaging was performed in 5 patients, showing dilated left ventricles in 4 patients ( Figure 1 ), hypokinetic left ventricles in 3, hypertrophic cardiomyopathy in 1 ( Figure 1 ), and late gadolinium enhancement in 3 patients (including diffuse nodular enhancement in 2 and subendocardial enhancement in 1) ( Figure 1 ). Four patients underwent coronary angiography, which revealed no coronary stenosis, but the presence of microaneurysms on right and left coronary arteries was noted in 1 patient ( Figure 2 ). Myocardial scintigraphy, performed in 2 patients, showed abnormal myocardial defects in both patients.
| Patient | Age at Diagnosis of Vasculitis (yrs) | Age at Diagnosis of Cardiac Involvement (yrs) | Gender | Medical History | Vasculitis Involvement | Lymphoma Characteristics | Biologic Features | Histologic Features | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cardiovascular Risk Factors | Cardiovascular Drugs | Purpura | Peripheral Neuropathy | Renal | Central Nervous System | Gastrointestinal | Age at Diagnosis (yrs) | Type | MC Type | MC Level (g/L) | C4 Level (mg/L) | Rheumatoid Factor | |||||
| 1 | 40 | 40 | M | 0 | 0 | + | 0 | + | 0 | + | 40 | SLVL | II | 1.20 | 0.01 | + | MC |
| 2 | 46 | 47 | M | Tobacco | 0 | + | + | 0 | 0 | 0 | 46 | MZL | II | 1.30 | 0.03 | + | PAN |
| 3 | 54 | 56 | F | HT | 0 | + | + | + | + | 0 | 54 | SLVL | II | 3.44 | 0.01 | + | MC |
| 4 | 61 | 61 | F | 0 | 0 | + | 0 | + | 0 | + | — | — | II | 0.61 | 0.04 | + | PAN |
| 5 | 62 | 63 | F | 0 | ACE inhibitor | 0 | + | + | 0 | 0 | — | — | II | 1.05 | 0.02 | + | MC |
| 6 | 75 | 75 | F | 0 | 0 | + | 0 | + | 0 | + | 75 | MZL | II | 1.98 | 0.01 | + | MC |
| 7 | 75 | 76 | M | HT | ACE inhibitor | + | 0 | + | 0 | 0 | 76 | MZL | II | 0.25 | 0.02 | + | MC |
| Patient | Cardiac Involvement | Troponin Level (μg/L) | BNP Level (ng/L) | Hb Level (g/L) | ECG | Ultrasonography | CMR | Coronary angiography | Treatment | US LVEF | CMR LVEF | Outcome | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| T-Wave Abnormalities | ST-Segment Abnormalities | DC | Hypokinesia | Pericardial Effusion | Coronary Stenosis | Coronary Artery Microaneurysms | 0 Months | 6 Months | 12 Months | 0 Months | 6 Months | 12 Months | ||||||||
| 1 | Myocardial ischemia | 0.93 | — | 105 | + | 0 | 0 | 0 | 0 | — | 0 | 0 | IFN, CTC, CYC | 55 | 60 | — | — | — | — | Death (7 mo) |
| 2 | Myocardial ischemia, DC | 2.10 | 1,320 | 105 | + | 0 | + | + | 0 | DC, diffuse nodular LGE | 0 | + | CTC, RTX, CYC, plasmapheresis, peg-IFN/RBV | 39 | 51 | 60 | 28 | 49 | 66 | Death (24 mo) ∗ |
| 3 | HC | <0.05 | 1,692 | 87 | 0 | 0 | + | 0 | + | HC, no LGE | — | — | CTC, RTX, CYC, fludarabine | 60 | 70 | — | 56 | 68 | — | Remission |
| 4 | Myocardial ischemia, DC | 0.50 | 1,945 | 93 | + | 0 | + | + | 0 | DC, no LGE | — | — | Peg-IFN/RBV, CTC, RTX | 35 | 40 | 45 | 45 | — | — | Remission |
| 5 | Myocardial ischemia, DC | 0.07 | 4,278 | 113 | + | 0 | + | + | + | DC, sub-endocardial LGE | 0 | 0 | Peg-IFN/RBV, CTC, RTX | 29 | 45 | 55 | 20 | 53 | — | Remission |
| 6 | Myocardial ischemia, DC | 0.36 | 932 | 101 | + | 0 | + | 0 | 0 | DC, diffuse nodular LGE | — | — | Peg-IFN/RBV, CTC, RTX | 55 | — | — | 61 | — | — | Death (5 mo) |
| 7 | Myocardial ischemia, DC | 0.40 | — | 97 | + | + | + | + | 0 | — | 0 | 0 | CTC, RTX, plasmapheresis | 40 | 55 | — | — | — | — | Remission |
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