Certain diuretics (such as thiazide diuretics), are considered photosensitive drugs and can increase the risk of skin cancer associated with ultraviolet (UV) light by damaging DNA (57). Thiazide diuretics are associated with insulin resistance, a recognized risk factor for breast cancer (58).

Two large studies from Denmark and Iceland have shown that hydrochlorothiazide is significantly associated with an increased risk of skin cancer, possibly in a dose-dependent relationship (59, 60). However, other studies have shown no significant relationship between hydrochlorothiazide and the risk of skin cancer, which may be due to individual sensitivity to UV light, which led to different results (61). Since 1980, many studies have shown that diuretics are positively correlated with the risk of breast cancer. The incidence of breast cancer increases by 16% in using diuretics for more than 10 years, and the use of diuretics is highly correlated with the poor prognosis of breast cancer patients (62). A case-control study of hypertensive and non-hypertensive patients on antihypertensive drugs showed that methotrexate, thiazide, and loop diuretics increased the risk of renal cell carcinoma by 40%, with women at a higher risk than men (63, 64). However, high blood pressure itself can cause kidney damage, so more clinical studies are needed to confirm this statement.

To date, available data suggest that CCBs increase the tumors incidence by inhibiting apoptosis or interfering with cell differentiation through calcium triggering signals. Moreover, CCBs reduce intracellular calcium levels and impair the process of programmed cell death. The body is prevented from destroying damaged cells to prevent malignancy, leaving them to replicate when desired (65, 66).

A meta-analysis combining 11 related studies showed that long-term (>9 years) treatment with CCBs increased the incidence of malignancy (67). Rothschild's large population-based study and meta-analysis showed a slightly increased risk of lung and prostate cancer in calcium antagonist users, both in a time-dependent manner (68–70). CCBs were associated with a 1.6-fold increased risk of breast cancer in those who used CCBs for more than 2 years, especially invasive ductal carcinoma and invasive lobular carcinoma of the breast thant hose who had never used antihypertensive drugs (71, 72).

In recent years, several studies have found that selective beta 2 blockers (β2 blockers) may reduce the recurrence and metastasis of cancer and thus increase overall survival in cancer patients. Selective beta 1 blockers have been shown to have no beneficial effect on cancer (73). Epinephrine and norepinephrine can induce tumor cell invasion and migration, thereby affecting lymph node invasion and metastasis, and this effect is mediated by the β-adrenergic pathway, especially the β2 receptors (74–77). Therefore, beta-blockers compete with epinephrine and norepinephrine for effective beta-adrenergic receptors to reduce the migratory activity of cancer cells and can also alter tumor growth, invasion, apoptosis, and angiogenesis to prevent tumor metastasis (78). Furthermore, the selective β2 receptor blocker propranolol can reduce the expression of the proliferative antigen Ki-67 and increase the phosphorylation of the tumor suppressor gene P53 in early breast cancer, thus slowing down cell proliferation and inducing cell apoptosis, which has a positive effect on breast cancer pateints (79).

Barron suggested that women who took propranolol in the years before breast cancer diagnosis were significantly less likely to develop T4 tumors in a large population study, with positive lymph nodes (N2/N3), or metastases and significantly lower mortality rate than women who did not take propranolol. Besides, prolonged use of propranolol may reduce T4 tumorigenicity (73). Moreover, propranolol has a protective effect on head and neck cancer, stomach, colon, and prostate cancer, especially when used for more than 1,000 days (46). Inhibition of angiogenesis reduces bacterial translocation; thus, non-selective beta-blockers have been shown to reduce the incidence of liver cancer in patients with cirrhosis (80).

RAS is well known for its control over the body's internal environment stability. Recently, there have been many studies reported RAS involvement in the complex carcinogenic mechanism. It is associated with proliferation signaling, resistance to cell death, induction of angiogenesis, energy metabolism reprogramming, inflammation, cell migration, invasion, and metastasis, thereby promoting vascular endothelial growth factor-mediated angiogenesis in malignant tumors and increasing proliferation of malignant tumor cells (81, 82). Therefore, using drugs that inhibit the RAS (mainly ACEI and ARB) can slow the rate of tumor growth. Furthermore, the risk of most cancers also decreases by using for long time (83).

A recent retrospective study of 73,170 patients with breast cancer patients using ARB improved patient's survival rate and reduced mortality. Patients who used other antihypertensive drugs also had reduced mortality, but cannot rule out it is due to blood pressure control or have positive effects on cancer (84). Similarly, compared with other antihypertensive drugs, patients on ACEI have a lower incidence of prostate cancer; hence, ACEI may improve their survival rate (85, 86). RAS inhibitors slow the progression of gastrointestinal cancer. Using ACEI over 3 years was associated with a 29% reduction in the risk of esophageal adenocarcinoma, and high daily doses were associated with a 45% risk reduction (87). RAS inhibitors have been linked to a protective effect against pancreatic cancer, with a 39% risk reduction after 1–3 years of use, but no significant effect on long-term use (88). A case-control study of patients with hypertension suggested that RAS inhibitors reduced the incidence of colon cancer, with long-term use decreasing the risk by 16 and a 25% reduction after 5 years of use. The greater the dose, the more significant the positive effect (89). The dose of ACEI is inversely proportional to the size of adenomatous polyps.

However, ACEI increases the incidence of lung cancer in patients with hypertension. The existing research points out that bradykinin (BK, a 9-peptide substance with cardioprotective effects) was found in lung cancer tissue and substance P. Many tumor cells expressed higher levels of BK and the related receptors that directly release vascular endothelial growth factor that stimulate the growth of cancer cells and angiogenesis, leading to increased risk of lung cancer. Additionally, ACEI promotes the buildup of these two chemicals in the lungs (90, 91).

Hicks et al. (92) in 2018 conducted a study, which included more than 90,000 patients with hypertension, was followed for 13 years to compare ACEI use and lung cancer incidence. This study confirmed that ACEIs could lead to an increased incidence of lung cancer. Lin et al. (93) further compared lung cancer incidence in hypertensive patients using ACEIs vs. ARBs and found that lung cancer incidence was significantly higher in patients using ACEIs than in those using ARBs. Moreover, they found that the higher the dose and longer the duration of ACEI use, the higher the incidence of lung cancer. Kumar et al. (94) and Hsu et al. (95) subsequent studies support this view. There are different conclusions, a 2021 study by Lee et al. (96) concluded that there was no significant difference in the effect of ACEI and ARB on lung cancer. Similarly, a meta-analysis, enrolled 13 observational studies with 458,686 ACEI users, conducted by Batais et al. (97) suggested that ACEIs were not associated with an increased risk of lung cancer. Although most studies reported a negative effect of ACEIs on lung cancer, more prospective studies are needed to confirm the effect of antihypertensive drugs on cancer incidence and progression.

Different cancer stages or different types of cancer have different responses to RAS blockers. As the only antihypertensive drugs that have definite effects on cancer, RAS blockers should be used carefully in clinical practice to achieve treatment optimization.

In patients with antineoplastic therapy-induced congestive heart failure, a reduction in LVEF of more than 10% and <50% is diagnostic of cancer therapy-induced cardiac insufficiency (cancer therapy drug-associated cardiac insufficiency/CTRCD). CTRCD usually appears months to years after treatment and is reversible in 75% of patients after withdrawal; however, it may affect long-term prognosis in 25% of patients, especially in patients with left bundle branch block. Most of these patients have no obvious symptoms, left ventricular dysfunction was diagnosed in some patients, while only a small number of patients develop symptomatic heart failure (117).

The most common anti-cancer drug that causes heart failure is anthracycline, the main treatment drug for many lymphomas, soft tissue sarcomas, and breast cancer, causing about 43% of those at risk (118). The main mechanism is the irreversible damage of cardiomyocytes with a high density of mitochondria, which induces myocardial remodeling and leads to cardiomyopathy (119). This is followed by TKI and immunotherapy, but the damage to the heart muscle is temporary and reversible. Previous studies suggested that the targeted drug trastuzumab may also increase the risk of cardiomyopathy by four times, and that when combined with anthracyclines, the risk increases by seven times (120, 121).

Women receiving anthracyclines are less likely than men to have cardiac insufficiency secondary to chemotherapy (122). The mechanism of cardiac insufficiency caused by anthracyclines is mainly due to oxidative stress-mediated oxidative damage in cardiomyocytes and abnormal mitochondrial function (123), which is less reported in female individuals (122). Notably, the occurrence of cardiac insufficiency complications in pediatric cancer patients does not appear to be significantly correlated with gender, as pediatric and postmenopausal females are more likely to develop cardiac insufficiency from antineoplastic therapy, suggesting that estrogen modulates abnormal oxidative stress in cancer patients receiving anthracyclines (124, 125). Estrogen enhances myocardial resistance to ischemia/reperfusion injury, i.e., attenuates abnormal oxidative stress and apoptosis (126). Thus, estrogens are cardioprotective. Sex differences in cardiotoxicity are not only present in anthracycline treatment but also cardiotoxicity caused by paclitaxel and tyrosine kinase inhibitors. The cardiotoxicity produced by different drugs differed concerning age and gender (Table 2). Sex-related genes are also involved in regulating the development of chemotherapy-related cardiac insufficiency (139). However, there are few studies related to the effect of gender on the efficacy and complications of antitumor therapy, and more gender- and age-specific studies are needed in the future to clarify the effectiveness of antitumor therapy and provide more theoretical support for clinical use.

With the increasing number of cancer survivors, vascular toxicity has become the second most widely concerned disease after cardiac toxicity. In addition to the high incidence of venous thromboembolism, arterial toxicity has also attracted attention due to the increase of cancer patients, the prolonged life span, and the continuous progress of cancer treatment. A case study of children's study points out that had not been treated for cancer patients with systemic inflammation and increased risk of atherosclerosis, and a diagnosis of age is smaller, the higher their risk of dying from heart disease, 2 years after another child study, points out that accepting radiotherapy or chemotherapy and survival over the age of 35 patients compared with a normal person five times the risk of myocardial infarction (AMI) (140, 141). However, the overall incidence of myocardial infarction is not high. Arterial thromboembolism is also common in pancreatic, gastric, and lung cancer patients, like venous thromboembolism. Among all patients with vascular complications, lung cancer patients have the highest mortality rate and colon cancer patients have the highest bleeding risk (142, 143). Patients with metastatic cancer complicated with acute myocardial infarction have a poor prognosis, and the cause of death is usually associated with hemorrhage and reinfarction (144).

Ischemic heart disease is critical cardiotoxicity in patients treated with 5-fluorouracil during antitumor therapy. Vascular endothelial growth factor inhibitors can cause coronary spasms and even acute myocardial infarction due to endotheliotropic and erosion of monolayer vascular endothelial cells (145, 146). Paclitaxel can cause acute coronary spasms and even myocardial infarction (147). In such patients, the ST segment elevation rapidly reduces after immediate administration of nitrates. Due to its endothelial toxicity, which is not easy to eliminate, cisplatin can also cause coronary artery diseases, and the toxicity increases with the increase of its dose (148). Existing findings show that radiation therapy can change vascular reactivity and vascular spasm and possible acute severe endothelial injury and acute myocardial infarction (MI). The prolonged radiation exposure time is proportional to the risk of myocardial infarction. Due to the cancer patients own existence of cardiovascular risk factors and the role of anti-cancer treatment, prolonged endothelial cells to rebuild (149, 150). Protecting the heart from radiation may significantly reduce the risk of coronary atherosclerotic heart disease (151).

Various arrhythmias may occur in cancer patients during anti-cancer treatment. Inflammatory infiltration of the heart may result in pericarditis or cardiomyopathy that involves the cardiac conduction system and results in the atrioventricular block, prolonged QT interval, and AF. Radiotherapy causes radiation injury and promotes myocardial fibrosis, resulting in an atrioventricular block and AF, but rarely causes ventricular arrhythmias (152), so it may become an alternative therapy for invasive ventricular ablation of ventricular arrhythmias. The arrhythmias induced by antitumor therapy may also be related to drug interactions, drug accumulation, and electrolyte disturbance. The common arrhythmias in cancer patients mainly include AF, prolonged QT interval, ventricular arrhythmias, and cardiac arrest (152).

In 1993, the first arrhythmia caused by antineoplastic therapy was proposed, about 30% of patients who used chemotherapy drug paclitaxel developed asymptomatic bradycardia (104). Later studies suggested that thalidomide, palazonib, sunitinib, and crizotinib may also cause bradycardia. About 72% of patients treated with the chemothermic arsenic trioxide extended their QT interval from baseline by more than 30 ms, with half of those exceeding 60 ms (153). Many targeted drugs cause prolongation of the QT interval (154, 155). Generally, the prolonged QT interval resolves gradually as the drugs are metabolized. However, if the upper limit is exceeded, antitumor drugs should be discontinued to avoid torsade de points ventricular tachycardia. AF is closely linked to cancer, and they share the same risk factors: obesity and inflammation. A study showed a 20% increase in the incidence of cancer within 1 year of AF onset. AF occurred as a cardiotoxic complication of antitumor therapy with anthracycline, ibrutinib, melphalan, and paclitaxel (156, 157).

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is second only to disease progression as the leading cause of death in cancer patients. Pulmonary embolism occurred in half of untreated DVT patients. About one-third of untreated pulmonary embolism patients die, most of whom have recurrent thromboembolism (158, 159). Compared with normal people, the incidence of VTE in cancer patients is at least 4 times higher, and a higher risk of VTE often indicates a poor prognosis of the cancer patients. A previous study showed that cancer of the pancreas, bile duct, and liver is associated with a higher risk of VTE (160).

Cancer patients release pro-inflammatory factors and pro-coagulation active substances, thereby promoting the adhesion between blood cells and blood vessels, resulting in a high coagulation state. The main factors of cancer patients that predispose to VTE include the type of cancer, central venous catheter chemotherapy, radiotherapy, surgical treatment, and related drug side effects (161).

Hypertension is closely related to the occurrence of tumors. High blood pressure and cancer have some common risk factors (age, active or passive smoking, diabetes, dyslipidemia, overweight or obesity, low physical activity, unhealthy diet) (162). Vascular endothelial growth factor (VEGF) possibly plays an important role in the pathogenesis of hypertension and tumor by stimulating angiogenesis (163, 164). Forty-one years after Judah Folkman (165) proposed that tumor growth depends on the formation of new blood vessels by secreting factors, hyperactive angiogenesis is now becoming a therapeutic target for cancer (166). However, given the common biological characteristics of tumors and hypertension, some anti-tumor drugs can increase the incidence of hypertension. At present, it is believed that the anti-tumor drugs that can cause hypertension mainly refer to VEGF signal inhibitors, with a 19–47% incidence of hypertension (167). VEGF signal inhibitors may lead to an imbalance between vasodilators and vasoconstrictors, loss of capillary microcirculation, and altered glomerular function, all of which contribute to hypertension (168, 169). Some scholars believe that hypertension may be related to the effectiveness of anti-cancer treatment. Tanaka et al. (170) found that the development of hypertension in the early stage of treatment is related to the anti-tumor effect and maybe a predictor of treatment effect.

Anti-tumor therapy-related valvular heart disease is mainly caused by radiotherapy, especially involving the left heart valve. The pathological manifestations were valve tip and leaflet thickening, calcification, and retraction. Similarly, radiotherapy over 2 years can lead to pericarditis in up to 20% of tumor patients, so it is recommended that radiotherapy doses of <10 Gy should be limited to patients without prior cardiac disease during radiotherapy for thoracic tumors (171).

Cardiac metabolic syndrome is a condition caused by various metabolic disorders that affect about one in four adults. Saxena et al. (172) proposed that cardiac metabolic syndrome is associated with various cancers, especially pancreatic and rectal cancer in females and prostate cancer in males.

The diagnostic criteria for hypertension in cancer patients are the same as those in the general population.

The diagnosis of arrhythmia and acute ST-segment elevation myocardial infarction in cancer survivors can be confirmed by paying close attention to the dynamic changes of ECG. For paroxysmal arrhythmia, a dynamic ECG is feasible to make a clear diagnosis. Aggressive electrophysiological tests can be used to diagnose suspected arrhythmias, but the necessity of these tests depends on the patient's general state and life expectancy (176).

Echocardiography is the first choice for cancer patients to monitor cardiac function (i.e., LVEF) and diagnose valvular heart disease. 3D echocardiography is recommended as the first choice so that the endocardial boundary can be seen more clearly (177). Cardiac magnetic resonance imaging (CMR) has become the clinical gold standard for measuring left ventricular volume and ejection fraction, followed by radionuclide ventricular angiography (RVG)/ multigate cardiac pool imaging (multigate acquisition, MUGA). An endomyocardial biopsy can determine the extent of myocardial injury in cancer patients, but due to its invasive nature, the diagnosis is usually confirmed by the patient's symptoms and imaging examination (178, 179).

Arterial and venous ultrasound of bilateral lower extremities is preferred for VTE diagnosis. Computed tomography pulmonary angiography (CTPA) is recommended to confirm PE after DVT is diagnosed. CTPA is the preferred imaging modality for diagnosing PE. When patients have symptoms highly suspicion of PE, such as dyspnea, chest pain, hemoptysis, and cough, accompanied by hypoxemia, along with DVT, as suggested by arterial and venous ultrasound of lower limbs, the CTPA should be performed timely to make a confirmed diagnosis. CTPA is contraindicated in patients with contrast hypersensitivity, renal insufficiency, hypotension, advanced heart failure, or unable to perform CT scanning due to complex comorbid conditions or difficulty lying flat (159).

Biomarkers play an important role in the prevention and diagnosis of CVD (Table 3). However, a single biomarker has certain limitations, and many factors can lead to abnormal results, so a definite diagnosis generally requires imaging findings and lab tests.

In addition to the patient's symptoms and vital signs, coronary angiography is the gold standard for diagnosing coronary artery disease (CAD) and evaluating vascular status. Diagnosis of CAD can be challenging in cancer patients, and some of the anti-tumor drugs mentioned earlier can cause transient coronary spasms that mimic the symptoms of a heart attack.

For patients at low risk for CAD, CCTA can be considered. Indications for coronary angiography are that the patient is suitable for coronary revascularization and that acute coronary syndrome or angina is not adequately controlled by optimal medication (185).