Cardiovascular toxicity in TGCT survivors encompasses a spectrum of clinical manifestations of cardiac and vascular damage, ranging from asymptomatic ECG changes, cardiac conduction system abnormalities, and alterations in cardiac function or structure, to life-threatening cardiovascular events (CVE) such as myocardial infarction, heart failure, thromboembolism, and cerebrovascular accidents. However, subclinical electrophysiological, structural, and functional cardiovascular abnormalities may not necessarily progress to clinical CVE (15, 16).

Although cardiac toxicity associated with cisplatin is relatively rare, some reports have described cardiac events suggestive of vasospasm, ischemia, hypertension, decreased diastolic and/or systolic function, myocarditis, pericarditis, myocardial infarction, stroke, and heart failure (15, 17, 26, 27). In addition, cisplatin has occasionally been reported to cause cardiac arrhythmias, including supraventricular tachycardia, atrial fibrillation, ventricular arrhythmias, sinus bradycardia, left bundle branch block, atrioventricular block, and, infrequently, complete atrioventricular block (28). Cisplatin is also associated with an increased risk of thromboembolic events, such as arterial thrombosis, deep venous thrombosis, and pulmonary embolism (16, 29).

Over the years, multiple studies have demonstrated increased risk of CVD among survivors treated for testicular cancer, particularly those who received cisplatin-based chemotherapy (16–24). In contrast, the risk of CVD and CVD-related mortality in patients with clinical stage I disease treated with orchiectomy alone appears to be comparable to that of the general population (25). Studies reporting the risk of CVD in TGCT survivors are summarized in Table 1 .

The risk of cisplatin-induced CVD appears to be highest within the first year after treatment but may persist or increase again after several years, suggesting a biphasic pattern of cardiovascular risk (16, 19, 21). Late cisplatin-related cardiovascular toxicity can occur more than ten years post-treatment, leading to atherogenesis, thrombosis, and premature vascular aging (30–32).

It remains unclear whether cardiovascular events in TGCT survivors are solely attributable to cisplatin, other anticancer agents or the underlying malignancy itself (11). Current evidence suggests that testicular cancer, compared to other malignancies such as pancreatic, gastric, or lung cancer, carries a relatively low intrinsic risk of cancer-associated thrombosis. Rather, the increased cardiovascular risk appears to result from cancer treatments, treatment-induced metabolic changes, and both preexisting and therapy-related cardiovascular risk factors (13). Importantly, thrombotic risk is also influenced by disease stage and patients with advanced TGCT, where orchiectomy alone is insufficient, exhibit a higher incidence of thrombotic and cardiovascular events (12–14). This helps explain the apparent discrepancy: while orchiectomy in early-stage TGCT does not increase CVD risk, the need for systemic treatment in advanced-stage disease introduces additional cardiovascular burden.

A Dutch study (17) reported major CVE in 5 (6%) of 87 TGCT survivors (aged 30–42 years; 9–16 years post-chemotherapy). Two experienced myocardial infarctions (one of which was fatal), and three developed angina pectoris with confirmed myocardial ischemia. Compared to the general Dutch male population, the observed-to-expected ratio for coronary artery disease was 7.1 (95% CI, 1.9–18.3). In addition, one patient aged 41 experienced a cerebrovascular accident 11 years after chemotherapy. Huddart et al. (18) observed 68 CVE (including 18 deaths) among 992 TGCT patients after a median follow-up of 10.2 years. Compared to the orchiectomy-only group, the risk of developing CVD was more than two-fold higher following chemotherapy (relative risk [RR] 2.59; 95% CI, 1.15–5.84; p = 0.022), radiotherapy (RR 2.40; 95% CI, 1.04–5.45; p = 0.036), and chemotherapy + radiotherapy (RR 2.78; 95% CI, 1.09–7.07; p = 0.032).

A large retrospective study from the Netherlands (19) reported 694 cases of CVD among 2,512 TGCT survivors after a median follow-up of 18.4 years (range 5–38.4). The most prevalent diagnoses were coronary artery disease - including 141 cases of myocardial infarction (20.3%) and 150 cases of angina pectoris (21.6%) - followed by peripheral vascular disease (79; 11.4%), heart failure (66; 9.5%), and cerebrovascular accidents (55; 7.9%). Compared to age-matched data from the general Dutch male population, the standardized incidence ratio (SIR) for coronary artery disease was 1.17 (95% CI, 1.04–1.31). The risk of myocardial infarction was significantly higher in nonseminoma survivors under 45 years and those aged 45–54 years (SIR 2.06 and 1.86, respectively), compared to the age-matched general population. An almost two-fold increased risk was also observed across all age groups within 5 to 9 years after treatment (SIR 1.91). However, the risk in this study declined in survivors aged > 54 years and in those followed for 10 years or more. In a subsequent study (20), a higher risk of coronary artery disease was observed in patients who received subdiaphragmatic radiotherapy combined with chemotherapy compared to those treated with chemotherapy alone (SIR 2.3; 95% CI, 1.6–3.1 vs. SIR 1.4; 95% CI, 1.0–1.8).

Most data on the incidence of cardiovascular late effects in testicular cancer survivors have been derived from epidemiological studies with follow-up periods of up to 20 years post-treatment. Consequently, limited information is available on the health status of TGCT survivors beyond 20 years after the completion of cancer treatment (15, 26, 31).

A Norwegian study (N = 990) with a median follow-up of 19 years (range, 13-28) (21) demonstrated increased risks of atherosclerotic disease in all treatment groups compared to the surgery only: radiotherapy (hazard ratio [HR] 2.3; 95% CI, 1.03–5.3), BEP (bleomycin, etoposide, and cisplatin) chemotherapy (HR 4.7; 95% CI, 1.8–12.2), and radiotherapy + chemotherapy (HR 4.7; 95% CI, 1.6–14.1). Furthermore, BEP chemotherapy was associated with a 3.1-fold increased risk of myocardial infarction (95% CI, 1.2–7.7) compared to age-matched healthy male controls, with an even higher risk observed in the radiotherapy + chemotherapy group (HR 4.8; 95% CI, 1.6–13.9). Notably, the risk of incident stroke was significantly elevated in survivors treated with radiotherapy alone (HR 4.0; 95% CI, 1.4–11.7), while no significant increase was observed in the other treatment groups compared to healthy controls.

A population-based study (22) evaluated short- and long-term CVD mortality in nonseminoma patients treated with chemotherapy (n = 6,909) or surgery alone (n = 8,097). CVD mortality was significantly increased in the chemotherapy group (standardized mortality ratio [SMR] 1.36; 95% CI, 1.03–1.78), but not in the surgery-only group (SMR 0.81; 95% CI, 0.60–1.07). The excess CVD mortality following chemotherapy was primarily confined to the first year after diagnosis (SMR 5.31; absolute excess risk [AER] 13.90 per 10,000 person-years), and was mainly attributable to cerebrovascular disease (SMR 21.72; AER 7.43) and heart disease (SMR 3.45; AER 6.64).

Consistent with previous findings, Lauritsen et al. (16) reported that among 1,819 patients treated with BEP chemotherapy, there were significantly increased risks for myocardial infarction (HR 6.3; 95% CI, 2.9–13.9), cerebrovascular accident (HR 6.0; 95% CI, 2.6–14.1), and venous thromboembolism (HR 24.7; 95% CI, 14.0–43.6) during the first year after treatment initiation. One year after completing BEP treatment, the risk of CVD returned to levels comparable to the general population. However, after 10 years, an increased risk re-emerged for myocardial infarction (HR 1.4; 95% CI, 1.0–2.0) and cardiovascular-related mortality (HR 1.6; 95% CI, 1.0–2.5).

In a recent study (24) with a median follow-up of 16.1 years (range, 0–38.5), 272 out of 4,748 TGCT patients developed CVD. Among them, 64% experienced a myocardial infarction, and 28% had coronary artery disease without infarction. Subsequently, 16% of these patients developed heart failure. In 6% of cases CVE were fatal (n = 16). Compared to orchiectomy alone, cisplatin-based chemotherapy was associated with an increased risk of CVD (HR 1.9; 95% CI, 1.1–3.1). Additionally, survivors who developed CVD after treatment reported significantly lower quality of life across multiple domains, including physical and social functioning, role limitations due to physical health, less energy and vitality, and had lower general health score compared to survivors without CVD (all p ≤ 0.01).

In summary, evidence from multiple studies demonstrates a consistently increased risk of CVD among testicular cancer survivors, particularly following cisplatin-based chemotherapy and radiotherapy. Combined modality treatment appears to be associated with a higher cardiovascular risk than chemotherapy alone. The most commonly reported clinical manifestations include myocardial infarction, angina pectoris, cerebrovascular accident, venous thromboembolism, and heart failure. The risk is highest in the first year after treatment but can persist or recur even after a decade. Furthermore, TGCT survivors who develop CVD report significantly lower quality of life.

The mechanisms by which cisplatin may cause arrhythmias and heart failure are not yet completely understood. However, the mechanisms of acute and late vascular toxicity have been more clearly explained. Cisplatin-based regimens used in the treatment of TGCT primarily drive vascular toxicity by endothelial dysfunction and prothrombotic state (30, 31). Platinum-therapy related damage of vasculature may be mediated also through inflammatory response to cytokine release, oxidative stress and electrolyte dysbalance (35).

Pathogenesis of cisplatin-induced cardiac toxicity is complex and not yet fully understood. However, findings from preclinical studies suggest multiple mechanisms including oxidative stress, mitochondrial damage, inflammatory process, apoptosis, and alterations in cardiac proteins and hemodynamics.

Cisplatin-induced cardiac damage is thought to be primarily exacerbated by oxidative stress. Cisplatin causes excessive production of ROS in cardiac tissue, overwhelming the antioxidant defense systems such as glutathione and superoxide dismutase. This oxidative stress can lead to mitochondrial DNA damage, mitochondrial membrane depolarization, and ultrastructural abnormalities in the mitochondria (28, 44). Cisplatin may accumulate in the mitochondrial matrix, disrupting mitochondrial respiration and depleting intracellular energy levels. Moreover, it may activate signaling pathways such as MAPKs and PI3K/Akt, which are involved in apoptosis in cardiac cells (49).

Cisplatin- related cardiac damage may be mediated through an inflammatory process, Accumulating evidence indicates that cisplatin increases secretion of several pro-inflammatory cytokines and chemokines (such as interleukin-1 and -6, tumor necrosis factor alpha (TNF-α) The translocation of the transcription factor nuclear factor kappa B (NF-κB) from the cytosol to the nucleus promotes the production pro-inflammatory TNF-α in cardiomyocytes (28, 50, 51).

In addition to oxidative stress and inflammation, apoptosis plays a crucial role in cisplatin-induced cardiac toxicity. It has been demonstrated in both in vivo and in vitro models. Cisplatin induces the release of pro-apoptotic factors such as cytochrome c, endonuclease G, and apoptosis-inducing factor (AIF) from the mitochondria into the cytosol. Cytochrome c activates caspase-9, which in turn triggers a cascade of downstream caspase activation, leading to apoptosis in a caspase-dependent manner. Conversely, endonuclease G and AIF translocate to and accumulate in the nucleus after their mitochondrial release, inducing apoptosis via a caspase-independent pathway (51). Furthermore, cisplatin induces alterations in renal tubular cells functions, which leads to impaired magnesium reabsorption. Hypomagnesemia is associated with an increased incidence or aggravation of hypertension, heart failure, serious cardiac arrhythmias, including torsades de points (52).

Myocardial toxicity is primarily mediated by oxidative stress, inflammation, and apoptosis, resulting in mitochondrial dysfunction and cardiac cell injury. Together, these processes can contribute to the increased cardiovascular risk seen in long-term survivors of testicular cancer treated with cisplatin. Mechanisms of cisplatin-induced cardiovascular toxicity, along with the most common clinical manifestations, are illustrated in Figure 1 .

Smoking is a well-known risk factor for CVD and many types of cancer, and remains the leading preventable cause of disease, death, and disability in the United States (62). According to data from the 1992–2023 National Health Interview Survey, 11.4% of cancer survivors aged 18 and older reported current cigarette smoking (63). In TGCT patients, two studies have demonstrated that smoking is associated with worse outcomes and survival in both stage I and metastatic disease (64, 65). The reported prevalence of smoking among TGCT survivors varies in the literature, ranging from 8.4% to 40% (18, 21, 26, 56, 58, 61). In most studies, no significant differences in smoking status were observed between TGCT survivors and the general population, or between different treatment groups (17, 18, 26, 58).

Although the definition of arterial hypertension varied across studies, its high prevalence among TGCT survivors appears indisputable. Over 25 years ago, Meinardi et al. (17) reported a hypertension prevalence of 39% in survivors treated with cisplatin-based chemotherapy, significantly higher than in those with stage I disease treated with orchiectomy alone (13%). A large study (56) evaluating blood pressure in 1,289 TGCT survivors treated with different modalities found a higher prevalence of hypertension in patients who received chemotherapy or radiotherapy compared to those who underwent surgery alone, after a median follow-up of 11.2 years (range, 5–22). Moreover, hypertension rates increased with cumulative cisplatin dose: 39% in the surgery group, 50% in those receiving ≤ 850 mg of cisplatin, and 53% in those receiving > 850 mg (p < 0.001). Compared to healthy controls, TGCT survivors who received more than 850 mg of cisplatin had over twice the risk of hypertension (age-adjusted OR 2.3; 95% CI, 1.5–3.7). Notably, the prevalence of hypertension was also high among patients treated with radiotherapy, reaching 54%. The increased odds of hypertension with higher cumulative doses of cisplatin have been confirmed by other studies (16, 57). Furthermore, Beitzen-Heineke et al. (15) demonstrated that a cumulative cisplatin dose ≥ 200 mg/m² was associated with attenuated biventricular systolic function and myocardial tissue alterations in asymptomatic long-term TGCT survivors. Lauritsen et al. (16) reported a persistently elevated risk of hypertension in patients treated with BEP and those receiving more than one line of therapy (HR 1.4, 95% CI, 1.3–1.6; and HR 1.7, 95% CI, 1.3–2.3, respectively), from treatment initiation through the end of follow-up, compared with the general population. In contrast, radiotherapy was not associated with a significantly increased risk of hypertension. Another study (21) found no significant differences in systolic or diastolic blood pressure between treatment groups. However, the use of antihypertensive medication was highest among patients treated with chemotherapy alone (OR 3.1; 95% CI, 1.9–5.2) and with combined chemotherapy and radiotherapy (OR 3.7; 95% CI, 1.6–8.9). In contrast, the radiotherapy-only group did not differ significantly from the surgery group (OR 1.5; 95% CI, 0.9–2.5). Additionally, all cytotoxic treatment groups showed significantly higher prevalences of antihypertensive medication use compared to the general population.

Dyslipidemia is defined as abnormalities in serum lipid levels, including elevated total cholesterol (TC), high triglycerides (TG), low high-density lipoprotein cholesterol (HDL), and elevated low-density lipoprotein cholesterol (LDL) (66). A growing number of studies have reported a high prevalence of lipid abnormalities and the use of lipid-lowering medications among TGCT survivors (17, 21, 24, 26, 53, 55, 58). Haugnes et al. reported that all treatment groups had increased odds of using lipid-lowering medications compared to the healthy male population, with the highest odds observed in the chemotherapy plus radiotherapy group (odds ratio [OR] = 2.59) and the chemotherapy group (OR = 2.07) (21). Another more recent study also showed that the prevalence of lipid-lowering medication use was significantly higher in TGCT survivors compared to healthy controls (44% vs. 18%) (26). Interestingly, in a large study by Lubberts et al., the prevalence of dyslipidemia ranged from 84% to 88% and did not significantly differ among the chemotherapy, radiotherapy, and orchiectomy-only groups (p = 0.507) (24). However, Willemse et al. reported a higher prevalence of dyslipidemia among patients treated with combination chemotherapy compared to those who underwent surgery alone and to healthy controls (20.1% vs. 12.3% vs. 10%) (58). In our recent study (67) of a Slovak population of long-term TGCT survivors (N = 154) with a median follow-up of 10 years (range, 4–32), 57.8% had elevated total cholesterol, 42.9% had elevated triglycerides, 10.4% had suboptimal HDL, 72.1% had elevated LDL, and 42.9% had elevated VLDL levels. While lipid profiles did not significantly differ across treatment groups, patients treated with chemotherapy had the highest levels of total cholesterol, triglycerides, LDL, and VLDL, as well as the lowest HDL levels. Moreover, survivors who received cumulative cisplatin doses ≥ 400 mg/m² demonstrated higher total cholesterol, triglycerides, LDL, and VLDL levels, and lower HDL compared to the surveillance group. Despite the lipid abnormalities, the use of lipid-lowering medications in our population was surprisingly low (only 3.9%).

Diabetes mellitus has been observed particularly in long-term TGCT survivors treated with radiotherapy to the retroperitoneal lymph nodes (16, 21). In a study by Haugnes et al. (21), the overall prevalence of diabetes was 7.3% at a median follow-up of 19 years (range, 13–28), with the highest rates seen in the radiotherapy group (10.2%) and the combined chemotherapy plus radiotherapy group (15.6%). Compared to the surgery-only group, the odds ratios were 2.3 (95% CI, 1.5–3.7) for radiotherapy alone and 3.9 (95% CI, 1.4–10.9) for combined treatment. The authors noted that standard dog-leg and para-aortic radiation fields often include most of the pancreatic gland, suggesting that radiation-induced pancreatic dysfunction, including diabetes, may be a long-term complication of infradiaphragmatic radiotherapy (68, 69). Lauritsen et al. (16) reported an increased risk of diabetes more than 10 years after radiotherapy, with HR of 1.4 (95% CI, 1.0–2.0).

People living with overweight or obesity are at increased risk for cardiovascular morbidity and mortality (70). In a recent study (24) of 304 TGCT survivors with a median follow-up of 21.8 years (range, 7.9–39.0), the prevalence of overweight and obesity was 64.5% and 11.5%, respectively. Furthermore, obesity at the time of testicular cancer diagnosis was identified as a significant risk factor for developing CVD after treatment (HR 4.7; 95% CI, 2.4–9.3). The authors noted that, in addition to being an established independent cardiovascular risk factor, adipose tissue may serve as a long-term reservoir for platinum. This suggests that obesity at diagnosis could be associated with prolonged circulating platinum levels following chemotherapy (24). Willemse et al. (58) reported that TGCT survivors had a significantly higher prevalence of obesity and dyslipidemia compared with age-matched healthy controls. Notably, those treated with combination chemotherapy had the highest prevalence (OR 1.7; 95% CI, 1.1–2.6). Interestingly, in a cohort of 455 TGCT survivors treated with cisplatin (median follow-up 26 months; IQR 16–59 months), a higher visceral-to-subcutaneous fat ratio - measured using pre-chemotherapy CT scans - was significantly associated with an increased risk of developing cardiometabolic conditions such as hypertension, dyslipidemia, or diabetes among obese men (age-adjusted HR 3.14; 95% CI, 1.02–9.71). The study also found that post-chemotherapy weight gain was primarily due to visceral fat accumulation, which correlated with higher estimated cardiovascular risk, especially in younger men. These findings support central obesity as a key predictor of cardiometabolic complications in this population (71).

Metabolic syndrome is defined as a combination of abdominal obesity, hypertension, dyslipidemia, and insulin resistance that together significantly increase the risk of CVD (72–75). Over the past decades, several studies have evaluated the risk of metabolic syndrome among TGCT survivors (21, 55, 57, 58, 60, 76–78). Furthermore, several studies have reported an association between low testosterone levels and the development of metabolic syndrome in this population (55, 60, 76). However, reported prevalence rates vary due to differences in the definition of metabolic syndrome, characteristics of control groups, and length of follow-up. While many studies have demonstrated an increased prevalence of individual components of metabolic syndrome in TGCT survivors, the overall evidence remains inconclusive regarding an increased prevalence of metabolic syndrome itself after cancer treatment. Some studies have found an association with cisplatin-based chemotherapy (55, 58, 76), whereas others have not (57, 60, 78).

In aging men, hypogonadism, or testosterone deficiency, is associated with a range of complications, including an increased risk of osteoporosis, metabolic syndrome, obesity, diabetes, and CVD. In addition, it is also associated with decreased quality of life (79, 80). In testicular cancer patients, hypogonadism may develop following any treatment modality (10). There is strong evidence that chemotherapy, higher cumulative doses of cisplatin, infradiaphragmatic radiotherapy, and combination of chemotherapy and radiotherapy are associated with an increased risk of testosterone deficiency in TGCT patients compared to those treated with orchiectomy alone. The risk appears to be highest among patients who received higher doses of cisplatin and combination of chemotherapy and radiotherapy (81). A recent study by Fosså et al. reported that 40% of TGCT survivors over the age of 60 had low testosterone levels, compared to 10% of age-matched healthy controls, after a median follow-up of 27 years (range 24–31 years). Nearly three decades after testicular cancer diagnosis, the probability of biochemical hypogonadism was significantly associated with advancing age and higher treatment intensity (82). As mentioned earlier, several studies have identified low testosterone levels a potential risk factor of metabolic syndrome in TGCT survivors (55, 60, 76). Bogefors et al. reported that testicular cancer survivors with hypogonadism had significantly higher insulin levels compared to eugonadal patients. Additionally, the hypogonadal group had an increased risk of metabolic syndrome (OR = 4.4; p = 0.01) (60). Results from the Platinum Study (83) showed that among 491 testicular cancer survivors with median age 38.2 years (range 18.7 - 68.4 years), 38.5% had hypogonadism. Compared to survivors without hypogonadism, those with hypogonadism were more likely to use lipid-lowering medications (20.1% vs. 6.0%; p < 0.001) or antihypertensive medications (18.5% vs. 10.6%; p = 0.013). A marginally significant trend was also observed for increased use of medications for diabetes (5.8% vs. 2.6%; p = 0.07).

To summarize, the available evidence indicates that testicular cancer survivors, especially those treated with cisplatin-based chemotherapy or radiotherapy, show a consistently higher prevalence of cardiovascular risk factors. These include hypertension, dyslipidemia, diabetes, and obesity. Hypertension and lipid abnormalities are among the most frequent findings, often linked to higher cumulative cisplatin doses. Diabetes is more common in survivors treated with retroperitoneal radiotherapy, likely due to pancreatic exposure. Obesity - particularly central obesity - and weight gain after treatment are also key contributors and may be related to persistent platinum exposure. Importantly, hypogonadism has emerged as a significant and prevalent long-term complication, affecting over a third of survivors, and is strongly associated with many of the adverse health outcomes. Testosterone deficiency contributes to the development of metabolic syndrome, insulin resistance, obesity, and dyslipidemia, and it may further exacerbate CVD risk in this population.