Cancer and Heart Disease





Introduction


At the intersection of oncology and cardiology, the field of cardio-oncology is growing primarily with the aim of recognizing, monitoring, and treating cardiovascular complications resulting from cancer-related treatments. With advances in cardiac imaging technologies, we now have a much better understanding of the cardiac effects of cancer and cancer therapies; and are refining therapies in the subspecialty of heart failure (HF).


Although a number of different measures are recognized as capable of evaluating systolic function, the left ventricular ejection fraction (LVEF) continues to be the most widely utilized. In the clinical setting and in multiple research protocols, cardiotoxicity has been defined as a decline of LVEF ≥5% to final ejection fraction (EF) <55% with symptoms of congestive HF, or an asymptomatic decline of LVEF ≥10% to a final EF <55%. As controversial and arbitrary as this definition might be considered, special attention is given to LVEF quantification in cardio-oncology oriented practices.


Quantification of Systolic Function in Cardio-oncology


In clinical practice, the most commonly accepted definition of cardiac toxicity comes from the independent Cardiac Review and Evaluation Committee’s (CREC) retrospective review of patients enrolled onto a variety of trastuzumab clinical trials. Echocardiography is the most used test for sequential measurement of LVEF in the assessment of potential cardiotoxicity from chemotherapy or immune therapy in patients with malignancies. In most oncology practices, the LVEF is followed closely, and the EF value is given significant clinical importance.


In practice, given the use of singular numbers for any particular cardiotoxicity definition used, it has been common for echocardiography clinicians in this field to report single numbers and avoid range EF reporting. It is understandable that it would be confusing for our oncology colleagues who make critical clinical decisions based on a 5% or 10% EF change, or a drop to under 50% or 55%, when, for example, the value reported from one study to the next is 55%–60% followed by 50%–55%.


The decisions that oncologists are faced with include the possibility of cessation of further anticancer therapy, which could have significant clinical consequences. We also need to understand the history of single digit measure from the historic perspective in oncology. In this field, cardiac imaging was established in the late 70s and early 80s when a number of publications supported the different available modalities, and over a short period, measurement of LVEF by nuclear methods (multiple-gated acquisition scan [MUGA]) became the established practice and was considered the gold standard for left ventricular function assessment during chemotherapy. LVEF by radionuclide imaging proved to be sensitive, specific, and reproducible and was reported as a single measure. Clearly, measurement of LVEF as a sole indicator of cardiotoxicity has significant limitations. These include image quality, the technical realities of the measurement that may include the single beat selection, operator experience, and volume drawing styles. In addition, the EF—the relative volume ejected in systole—can be load dependent.


It is important that our EF measurements are accurate with the lowest variability possible. The most commonly used LVEF methods in routine practice are the two-dimensional (2D) methods. Among the 2D options, the most commonly used method for volume calculations is the biplane method of disks summation (modified Simpson’s rule). This is the recommended 2D echocardiographic method according to consensus and current published left ventricular quantification guidelines. The literature is clear that among the 2D methods, using biplane volumes with the use of microbubble enhancement offers the best results in terms of intra- and interobserver variability; and contrast agents are recommended when there is a need to improve endocardial border delineation, particularly when two or more contiguous LV endocardial segments are poorly visualized in apical views. It is important to remember that microbubble-enhanced images provide larger volumes than unenhanced images. Volumes obtained in this fashion are closer to those obtained with cardiac magnetic resonance (CMR).


Three-dimensional echocardiography (3DE) has been shown to be more accurate than 2D for both ventricular volume and EF measurements when compared with CMR imaging, and therefore it is an attractive modality in this field and should be used when available. , This method, while not routinely available in most centers, has been shown to offer the lowest temporal variability for EF and ventricular volumes on the basis of multiple echocardiograms performed over 1 year in women with breast cancer receiving chemotherapy.


Diastolic Function and Detection of Cardiotoxicity


Measurements of diastolic function by Doppler echocardiography could represent a marker for the early detection of toxicity. One study found that the isovolumetric relaxation time was significantly prolonged after a cumulative doxorubicin dose of 100 to 120 mg/m 2 . Any increase of more than 37% in volumetric relaxation time was 78% (7 of 9) sensitive and 88% (15 of 17) specific for predicting the ultimate development of doxorubicin-induced systolic dysfunction. The myocardial performance (Tei) index is another important Doppler-derived tool. This index expresses the ratio of the sum of the isovolumetric contraction time and the isovolumetric relaxation time divided by the ejection time. This formula combines systolic and diastolic myocardial performance without geometrical assumptions and correlates well with the results of invasive measurements. The value is appealing for use with cancer patients because it appears to be independent of heart rate, mean arterial pressure, and degree of mitral regurgitation. It has also been found to be sensitive and accurate in detecting subclinical cardiotoxicity associated with anthracycline therapy.


Studies using the Tei index show that this index is better than the EF in detecting anthracycline-induced deterioration in LV function among adults; it detects this deterioration earlier in the course of treatment and is more likely to detect statistically significant differences. However, the results regarding the value of diastolic dysfunction as an indicator of this diagnosis have been inconsistent. Because of the influence of hypertension and other risk factors on diastolic function, this signal appears to be nonspecific.


Cardiac Mechanics in Cardio-oncology


Earlier detection of cardiotoxicity allows for a time advantage in risk stratification. New techniques are aimed at detecting cardiotoxicity before the onset of a measurable decrease in LVEF or symptoms. These methods include echocardiographic assessment for strain using speckle-tracking imaging, as well as testing for elevations in cardiac biomarkers, including troponin. Speckle tracking takes full advantage of a new capacity for image acquisition at higher frame rates. Several reports regarding cancer populations receiving cardiotoxic agents and the use of this particular technology in the realm of cancer therapeutics–related cardiac dysfunction have been very exciting, particularly regarding the use of longitudinal deformation measures and the global longitudinal strain (GLS) value.


It was first reported in 2009 that changes in tissue deformation, assessed by myocardial strain and strain rate, were able to identify left ventricular dysfunction earlier than LVEF in women undergoing treatment with trastuzumab for breast cancer. Following this, two reports resulted in comparable findings. , A multicenter collaboration reported on the use of troponin and longitudinal strain measures to predict the development of cardiotoxicity in patients treated with anthracyclines and trastuzumab. Patients who demonstrated decreases in longitudinal strain measures or elevations in hypersensitive troponin had a ninefold increase in risk for cardiotoxicity at 6 months compared with those with no changes in either of these markers. Furthermore, diastolic function parameters and LVEF alone did not help predict cardiotoxicity.


In a review including over 30 studies, it was reported that although the best GLS value to predict cardiotoxicity is not clear, an early relative change between 10% and 15% appears to have the best specificity. Similar studies, however, have found a stronger correlation with ventricular-arterial coupling and circumferential strain than longitudinal measures. A consensus statement on the evaluation of adult patients during and after cancer therapy published by the American Society of Echocardiography and the European Association of Cardiovascular Imaging also reports that a relative percentage reduction in GLS of >15% is very likely to be abnormal, whereas a change of <8% appears to be of no clinical significance.


Cardiac Dysfunction and the Heart Failure Spectrum


Cancer therapy–related cardiac dysfunction (CTRCD) is one of the most feared and undesirable side effects of chemotherapy despite occurring only in a small minority of cases.


Despite widespread screening recommendations, a clear universal definition of cardiotoxicity is lacking in the current literature. While there are different definitions of CTRCD presented by clinical trials and guideline statements, there is no universal consensus at this time. The first publication defining mild cardiotoxicity as a decline in EF by >10% and moderate cardiotoxicity as EF decline by >15% to a value less than 45% was by Alexander and colleagues in 1979. In 1987 a large clinical trial defined CTRCD as a decline in EF by >10% to a final value <50%. Both of these studies used MUGA scans as the method of screening and only included patients who had been treated with anthracycline. In 2002, after review of the trastuzumab trials, the CREC defined CTRCD as asymptomatic decline of LVEF ≥10% to a final EF <55%. Over a decade later (in 2014), the American Society of Echocardiography and European Association of Cardiovascular Imaging (ASE/EACI) chose a cutoff value of <53%.


Controversy still persists regarding the definitions of cardiac toxicity, the true incidence, detection, monitoring, and treatment of the late effects in survivors of cancer of all ages. There are multiple explanations for the lack of consensus regarding clinical guidelines in CTRCD. Most importantly, there is a lack of large-scale randomized clinical trial data to support any evidence-proven, effective long-term treatment and/or surveillance strategies. Furthermore, there has been minimal success at showing the cost-effectiveness of aggressive cardiac surveillance and treatment to providers.


In this chapter, discussion of CTRCD will be limited to the proper management of the cardiac effects of anthracycline therapy in cancer survivors. The antitumor actions include inhibition of topoisomerase II, an enzyme that regulates the uncoiling of DNA strands and in doing so induces breaks in DNA and ultimately cell death. Anthracycline therapy results in the formation of toxic reactive oxygen species (ROS) and interferes with macromolecule synthesis with a subsequent increase in cardiac oxidative stress-associated apoptosis. In addition, a relationship between topoisomerase IIβ activity in the heart and cardiac toxicity was reported, potentially opening a new avenue for future therapies.


Clinical presentations of toxicity can include arrhythmias, heart block, HF, pericarditis-myocarditis syndrome, and cardiac ischemia. Late toxicity is almost universally limited to myocardial systolic dysfunction. There are several known clinical risk factors associated with toxicity such as pre-existing cardiovascular disease (CVD), hypertension, the use of other cardiotoxic nonanthracycline agents (trastuzumab, taxanes), and exposure to mediastinal radiotherapy. It is also important to recognize that children are at particular risk for development of anthracycline-induced cardiomyopathy, but there is also increased incidence of systolic dysfunction with age, particularly in the elderly population. Although there is an accepted direct relationship between cardiotoxicity and cumulative anthracycline dose, cardiotoxicity has been reported in patients who have received doses under 100 mg/m² of doxorubicin, and there are patients who have received doses >550 mg/m 2 and never developed cardiotoxicity.


Biomarkers have been an exciting area of investigation in this arena, and there is increasing evidence that using a biomarker or a panel of them could significantly contribute to the clinical monitoring and surveillance of these patients in the future. The traditional tests have been troponin T/I, B-type natriuretic peptide (BNP), or N-terminal pro-BNP (NT-proBNP). However, new markers in the mRNA category such as miR-208b, miR-34a, and miR-150 have been recently reported, particularly for breast cancer patients receiving anthracyclines and/or trastuzumab.


There is no specific therapy for systolic dysfunction in CTRCD. If a reduction in LVEF is detected, patients should be treated in accordance with established guidelines for the management of HF. Drug antiremodeling therapy should include agents approved with appropriate indications such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and beta blockers as tolerated. There are no quality or long-term outcome data to guide treatment of CTRCD.


It is critical to consider alternate causes of LV dysfunction beyond chemotherapy, particularly in patients who present after low levels of anthracycline exposure or nonanthracycline regimens. It is always clinically mandatory to consider common causes such as coronary disease, hypertension, infiltrative conditions, and alcohol excess depending on the individual clinical picture.


Among patients who are still candidates for active cancer therapy, a multidisciplinary discussion, including the cardiologists and oncology providers, is usually beneficial. The risks and benefits of further chemotherapy should be carefully considered in planning subsequent treatments. It should be noted that there is some evidence that LVEF by echocardiography could be used to improve patient selection for enrollment in clinical trial–based regimens. One study suggests that it is safe to treat patients with LVEF between 35% and 50%. However, in general, it is recommended to avoid further exposure to regimens containing known toxic agents in the presence of ongoing LV dysfunction. See Figs. 6.1 and 6.2 .




Fig. 6.1


A female with breast cancer treated with Herceptin has a GLS value of −19.6% at baseline. GLS , Global longitudinal strain.



Fig. 6.2


The same patient with a GLS of −14.6, 3 months later. This preceded a 14% decrease in LVEF that was noted in her 6-month follow-up echocardiogram. GLS , Global longitudinal strain; LVEF , left ventricular ejection fraction.


Considerations in Radiation-Induced Heart Disease


Radiation-induced cardiac changes include a spectrum of pericardial disease, valvular disease, coronary/microvascular disease or dysfunction, and restrictive cardiomyopathy. Most commonly, these are pathologic processes that are late manifestations, becoming clinically significant years after radiation. Pericardial thickening appears as increased echogenicity of the pericardium on 2D echocardiography or M-mode imaging. Correct distinction between normal to thickened pericardium is challenging. Characteristic echocardiographic findings of constrictive pericarditis include a thickened pericardium, prominent respiratory phasic diastolic motion of the interventricular septum, restrictive diastolic filling pattern, and significant inspiratory variation of the mitral E-wave velocity (>25%). Other secondary findings include inferior vena cava dilatation and expiratory diastolic flow reversal in the hepatic veins. Typically, tissue Doppler interrogation of the medial mitral annulus reveals a normal or increased velocity that can be higher than the lateral annulus velocity. Another important consideration is effusive-constrictive pericarditis. This clinical syndrome is characterized by concurrent pericardial effusion and pericardial constriction, with constrictive hemodynamics that persists after the drainage of the pericardial effusion. In effusive-constrictive pericarditis, the visceral layer of the pericardium, rather than the parietal layer, constricts the heart. This is a rare condition; however, effective recognition is important because pericardiectomy is sometimes indicated for management.


In the particular case of valvular disease, manifestations of radiation-induced heart disease (RIHD) include fibrosis and patchy calcification of structures, such as the aortic root, annulus, leaflets, the aorto-mitral intervalvular fibrosa, mitral annulus, and the base and mid-portions of the mitral valve leaflets usually sparing the tips and commissures (a key difference from rheumatic heart disease). Grading the severity of valvular disease should be based on published guidelines. Valve regurgitation is more commonly encountered than stenosis. Stenotic lesions more commonly involve the aortic valve. Reported incidence of clinically significant valve disease is 1% at 10 years, 5% at 15 years, and 6% at 20 years after radiation exposure. Incidence of valve disease increases significantly after >20 years following chest radiation (mild aortic regurgitation [AR] up to 45%, moderate AR up to 15%, aortic stenosis up to 16%, mild mitral regurgitation up to 48%, mild pulmonary regurgitation up to 12%). ,


Cardiac Tumors


Cardiac tumors are rare, and are generally categorized as primary or secondary. Primary cardiac tumors are the rarest, with an autopsy incidence of 0.002%–0.3%. , Primary cardiac tumors include both benign and malignant neoplasms that originate from cardiac tissue. Secondary or metastatic cardiac tumors are around 30 times more common than primary malignancy, with a reported autopsy incidence of 1.7%–14%.


Other possible categories of tumors could include those from the lower body that reach the cardiac cavities by extension through the inferior vena cava, and tumors that extend from the mediastinal space directly invading the pericardial layers. The infradiaphragmatic tumors can occur with almost any cell type, but the large majority of these have been attributed to renal cell carcinoma (RCC) where as much as 10% of patients will have tumor extension into the inferior vena cava. In patients with RCC, involvement of the right atrium (RA) is encountered in up to 5% of cases, and pulmonary artery tumor emboli is rarely observed. Other sources for this route of invasion include uterine malignancies and hepatocellular carcinoma. , Tumors with direct extension in the mediastinal space again can occur with almost any cell type. Thymoma compromises 20%–25% of all mediastinal tumors and is the most commonly described anterior mediastinal tumor ; however, most case reports of direct mediastinal invasion are not from thymic origin. ,


The clinical manifestation of cardiac tumor is variable and not unlikely to be found on routine surveillance echocardiogram examination or other chest imaging modality. In terms of clinical presentation, tumors cause signs and symptoms, depending on location, size, and etiology. Presence of a growing mass inside a contractile and moving cavity can eventually cause hemodynamic compromise of blood flow in the affected or receiving chamber and even disrupt valve coaptation. In this setting, syndromes of congestive failure can be present. This can be further accelerated in the case of myocardial involvement and secondary limitations to contractility. See Table 6.1 .



Table 6.1

Leading Reported Clinical Signs and Symptoms on Presentation for Cardiac Tumors



























Dyspnea
Chest pain, common with malignant and pericardial tumors
Hypotension
Syncope
Edema (secondary to blood flow obstruction)
Cough or hemoptysis
Cardiac tamponade
Pericardial friction rubs
Auscultation: gallop or murmur
Systemic embolization of tumor fragments, stroke
Peripheral arterial occlusion associated with left sided tumors
Right heart failure/pulmonary hypertension as a complication of right-sided tumors

aSystemic emboli from left heart lesions are more frequently seen than pulmonary tumor emboli from right heart lesions


Careful evaluation of segmental ventricular dysfunction is pertinent, as direct occlusive pressure or extension of the tumor into the lumen of the coronary arteries (including the possible embolization of tumor fragments) has also been described. , Repolarization changes in patients with cardiac metastases are believed to occur by myocardial ischemia caused by the tumor’s direct myocardial injury and invasion, as this presentation has been found in subjects without obstructive coronary lesion on angiography.


Due to its noninvasive nature, availability, relative portability, and affordability (when compared with other modalities), echocardiography is the most widely used diagnostic modality for the evaluation of cardiac tumors. As indicated earlier, this technology has advanced to include mechanical function analysis, which may increase our sensitivity to recognize subtler wall motion defects.


A great complement to transthoracic echocardiogram (TTE) is the use of transesophageal echocardiography, which provides a significant upgrade in spatial resolution and overall image clarity compared to transthoracic imaging. This technique has also demonstrated impressive and rapidly improving quality of three-dimensional images. The use of echo contrast has also added a significant degree of confidence and accuracy to transthoracic echo; and is also frequently used for mass characterization. See Fig. 6.3 .




Fig. 6.3


A young woman with sarcoma. On echocardiogram, we see a mass at the base of the right ventricle. The mass is easily visible in the echo-contrast enhanced image (A), which the unenhanced image at the same angle fails to demonstrate clearly (B).


However, when it comes to more detailed characterization of a malignant lesion infiltrating the myocardium, CMR and cardiac computerized tomography (CCT) can give a more complete view of the mediastinum, extra cardiac structures, and the possible attachments of a mass outside of the cardiac cavities. This is considered critical information for the surgeon when planning resection. These modalities also have well-known advantages when it comes to tissue characterization. They do not suffer from the acoustic “window” limitations that often make transthoracic echocardiographic examination technically difficult, particularly in obese patients, subjects with history of previous chest surgery, and those with chronic lung disease.


Cardiac interventional procedures described in the diagnosis of cardiac tumors, both primary and secondary, include endomyocardial biopsy and pericardiocentesis. The latter has been frequently used to confirm malignant cells within the fluid or as a palliative tool for patients with increased intrapericardial pressures secondary to progressive disease. Echocardiography (TEE) is often helpful for imaging guidance during these procedures.


Tumor Types, Physiology, and Treatment Considerations


There are limited detailed reports of large series of cardiac tumors in the existing literature. One of the largest reports comes from our institution, a 12-year experience, where we describe that roughly a quarter of cardiac tumors as primary and nearly three-quarters as secondary. We found that dyspnea is the most common symptom described by patients diagnosed with this condition. The large majority (>80%) of primary cardiac tumors are benign; myxoma being the most common , ; the remaining 20% are malignant primary cardiac tumors. The most common malignant primary tumor to be described unanimously in every large series is sarcoma. In our series, this was followed by paraganglioma and myxoma. Most sarcomas in our series were angiosarcomas. The most common location was the RA. This closely resembles the findings of other reported series. From an echocardiography, perspective angiosarcomas are predominantly found on the right side, while osteosarcomas and unclassified sarcomas are predominantly found on the left side of the heart. , Pericardial angiosarcomas are rare. It is important to know that about 29% of cardiac sarcomas have metastatic disease at the time of presentation.


Secondary cardiac tumors were, in large majority, metastases from renal cell carcinoma. These patients were generally older than those diagnosed with sarcoma. Again, the RA was the most frequent location affecting patients. The most common presenting symptom was, as expected, dyspnea. In our series, the majority of all secondary cardiac tumors were metastases from renal cell carcinoma, whereas in most other series metastasis from lung carcinoma appears to the commonest cause. For secondary tumors in our experience, the second most common site was the left atrium, followed by right ventricle, right atria and right ventricle combined, left atria, mitral valve, an instance of left atria/right atria/mitral valve involvement, and an intrapericardial case. Almost half of the subjects (44%) died within 12 months of diagnosis; hence early recognition with imaging is considered critical.


Despite melanoma being described in a few reports as a neoplasm with a propensity to metastasize to the heart, this represented a minority of cases in our series. Recognition of cardiac lesions in these cases can yield a significant change in prognosis since once metastasized to other organs; melanoma is by definition stage IV, and associated with poor survival rates. The reported 5-year survival in these cases is 15% to 20%. Of note, sarcomas that metastasize to the myocardium are frequently high grade and progress quickly. Myocardial infiltration, outflow obstruction, and distant metastasis result in death within a few weeks to 2 years of onset of symptoms, with median survival ranging from 6 to 12 months. Different series have documented the metastatic rate to be 26%–43% at presentation and 75% at the time of death. , , In comparison to older series, there is a significant increase in the incidence of cardiac metastases in cancer patients after 1970. This is possibly in an era of improved and more available cardiac imaging modalities.


The pericardium is most often involved due to direct invasion by the thoracic malignancies. The myocardium or epicardium is believed to be most involved through lymphatic spread and endocardial metastases through hematogenous spread.


Review of previous reports shows that lung cancer is the most common cause of cardiac metastasis followed by hematologic malignancy. Only a couple of reports show a different trend. ,


Last, in contrast, in the pediatric population, rhabdomyosarcoma is the most common form of cardiac sarcoma. Leiomyosarcoma, synovial sarcoma, osteosarcoma, fibrosarcoma, myxoidsarcoma, liposarcoma, mesenchymal sarcoma, neurofibrosarcoma, and malignant fibrous histocytoma are the other cardiac sarcomas observed. , A recent systematic review of the literature reported a cumulative 30-day mortality rate of 6.7%.


Cardiac Tumor Therapies


For treatment purposes, cardiac sarcomas are divided into three groups: right heart sarcomas, left heart sarcomas, and pulmonary artery sarcomas. The treatment for right heart and left heart sarcomas is chemotherapy and surgical resection. Direct cardiac radiotherapy is avoided in patients, as it may cause myocardial injury. In brief, the history of cardiac tumor surgery dates back to the late 1550s when a case of primary cardiac neoplasm was first described. The first series of cases was published in 1845 with six arterial tumors consistent with myxoma. A further 86 years later in 1931, Yater reported a postmortem series of nine cases of cardiac tumors, and a classification system that is still in use today.


The surgical treatment of cardiac tumors began in the late 1930s with the removal of an intrapericardial cystic teratoma that extended to the right ventricle. Surgery radically changed and progressed after the introduction of cardiopulmonary bypass in 1953. This allowed controlled access to the interior chambers of the heart and led to multiple reports of successful cardiac mass excisions, mostly myxomas. , Cardiac tumor resection, however, has continued against challenges related to inherent technical difficulties of any major cardiac resection and the aggressive biology of these tumors. Against the challenges, survival has been shown to improve with surgical resection. In addition, a major catalyst for the surgical treatment of cardiac tumors was the growth in cardiac imaging, specifically echocardiography. This allowed noninvasive, easy visualization of the interior and exterior of the heart. Over time, innovation has flourished in this field and novel approaches allowing a more complete tumor resection, such as cardiac autotransplantation, have been successful. ,


Unlike other sarcomas, cardiac sarcomas have a very poor prognosis with a median survival rate of 6–25 months after diagnosis. , Presence of tumor necrosis and metastases is associated with a poor prognosis. , A recent study showed that 14.8% of the resected tumors were low grade and all the patients were alive at follow-up. This underlies the importance of tumor grade in survival of postoperative patients. Sarcomas other than angiosarcomas, sarcomas on the left heart, and completely resected sarcomas have a better prognosis. , Angiosarcomas grow faster, infiltrate widely, and metastasize early; they therefore have a poor prognosis.


Treatment of metastatic cardiac tumors is usually palliative. Different series have shown that the median survival is 17–24 months for patients who can undergo complete resection, and 6–10 months for patients unable to undergo complete resection. , Surgery with postoperative chemotherapy and/or radiotherapy to prevent local recurrence is indicated in patients with better prognosis and when they only have cardiac metastasis without disseminated disease. Orthotopic heart transplantation is an option in selected patients, with improved survival. , In patients with disseminated disease, limited life expectancy, and poor performance status, radiotherapy might still represent a choice. Chemotherapy is recommended for tumors that are chemosensitive. In these patients, end-of-life care should be discussed, and all efforts should be made to improve patient quality of life.


Acute Coronary Syndromes


Rudolf Virchow postulated that three features predispose to thrombus formation, namely abnormalities in vessel wall, blood constituent, and blood flow. Although originally Virchow was referring to venous thrombosis, the concept also relates to arterial thrombosis. A number of patients with cancer show abnormalities in each component of Virchow’s triad leading to a prothrombotic or hypercoagulable state. Exposure to radiation and various chemotherapy agents predisposes to the development of cardiovascular disease. Radiation damages the endothelium, predisposing to vascular disease and ischemic heart disease in a relatively younger patient population. , Of all chemotherapeutic agents, 5-flurouracil (and its analogue capecitabine) is particularly known to cause ischemic heart disease. , In addition to 5-fluorouracil, other medications, such as paclitaxel, docetaxel, bevacizumab, erlotinib, and sorafenib, are also implicated in the development of ischemic heart disease.


In patients with cancer, in addition to underlying coronary atherosclerosis, there are multiple other etiologies and predisposing factors for cardiovascular abnormalities, including cardiac metastasis/coronary compression, tumor-related coagulation disorder (especially in patients with leukemia), coronary embolization from tumor or endocarditis, radiation, and chemotherapy, for example, 5-fluorouracil. In terms of incidence and overall prognosis, there are limited reports available in the literature. However, a recent report from a national US database with more than 6 million patients showed a prevalence of acute myocardial infarction (AMI) of 9% in patients with cancer in the decade after 2004. A very recent analysis on a large AMI population revealed that patients with active cancer have a 50% increased risk of major in-hospital adverse cardiac events than those without cancer. In a 2017 study of more than 48,000 patients admitted with ST segment elevation myocardial infarctions, those with cancer had a significantly higher in-hospital and 1-year mortality than those without. In summary, we have few observational, mainly retrospective studies comparing the clinical outcomes of patients with and without cancer and acute coronary syndromes. These analyses consistently report that patients with cancer are at higher risk of both in-hospital and long-term morbidity and mortality than those without.


Clinical Presentation and Diagnosis


Most patients with cancer and AMI usually have chest pain and dyspnea. Clinically a myocardial infarction denotes the presence of acute myocardial injury detected by abnormal cardiac biomarkers in the setting of evidence of acute myocardial ischemia. The diagnosis of myocardial infarction in cancer patients is based on the universal definition of myocardial infarction. Myocardial infarction is further subclassified into various types.


Type 1 myocardial infarction is caused by atherothrombotic coronary artery disease and usually precipitated by atherosclerotic plaque disruption (rupture or erosion), whereas type 2 myocardial infarction is due to any condition causing a mismatch between oxygen supply and demand, leading to ischemic myocardial injury. Majority of the cases in the intensive care unit setting are due to type 2 myocardial infarction, as some common conditions causing mismatch between oxygen supply and demand and resultant troponin are frequently seen in this setting, for example, tachycardia/arrhythmias, hypotension/shock, respiratory failure, severe hypertension, and HF/cardiomyopathy.


Treatment


Treatment of myocardial infarction in the cancer population is similar to the general population, which includes primary percutaneous intervention (in appropriate patients) antiplatelets, statin, and beta blockers.


Due to a lack of well-controlled trials, substantial data on cancer population are lacking. Nevertheless, current available evidence suggests that aspirin and beta blockers reduce mortality in these patients. Primary percutaneous interventions should be considered as method of reperfusion, as a 1-year survival rate of 83% has been shown with this approach in the cancer population with ST elevation myocardial infarctions.


The presence of thrombocytopenia poses special problems for management, but even in these patients aspirin should not be withheld, as one study amongst this subset of population showed that aspirin reduces mortality with no significant increase in bleeding. The management of myocardial infarction in the cancer population, including those with thrombocytopenia, is outlined in an expert consensus statement.


Acute Pericarditis


Acute pericarditis is acute inflammation of the pericardium resulting in a clinical syndrome consisting of pleuritic/positional chest pain, electrocardiogram changes, and a pericardial frictional rub. A pericardial effusion may or may not develop. , Malignancy is a common cause of pericardial disease in cancer, and in one study of 100 consecutive patients hospitalized with acute pericarditis, malignancy was found in 7% of the patients, with lung carcinoma being the commonest primary tumor.


Acute pericarditis presents with retrosternal chest pain, which is typically worse on inspiration and in supine position and improves with sitting and on leaning forward. In some cases, it may radiate to the shoulder due to irritation of the phrenic nerve. On physical examination, the classic finding is a pericardial friction rub. The rub is best heard in end expiration with the patient leaning forward. It is a high-pitched scratchy sound that can have one, two, or all three components. A pericardial friction rub is present in approximately 34% of cases.


Clinical criteria for diagnosis of acute pericarditis include typical chest pain, presence of audible pericardial friction rub, widespread ST-segment elevation on the electrocardiograms, and new or worsening pericardial effusion. , A diagnosis of acute pericarditis is made if at least two of the four criteria are present. ,


Evidence of pericardial inflammation gained through the use of imaging techniques such as computerized tomographic scan or cardiac magnetic resonance, elevation of inflammatory markers, for example, C-reactive protein, white cell count, and erythrocyte sedimentation rate are additional supporting findings. A 12-lead electrocardiogram is the most useful diagnostic test. The classic electrocardiogram finding is concave ST elevation and PR-segment depression in all leads, except AvR, which shows PR-segment elevation, and ST depression. The electrocardiogram changes evolve in stages. In stage 1 the electrocardiogram shows ST-segment elevation and PR-segment depression. In stage 2 the normalization of PR and ST segments occurs. In stage 3 there are widespread T wave inversions and in stage 4 normalization of these T waves occurs.


A chest x-ray is recommended in all patients with pericardial disease. It is usually normal but may show other concomitant pathology such as pneumonia or enlarged cardiac silhouette in patients with associated pericardial effusion. Echocardiography is usually obtained to exclude a large pericardial effusion and tamponade. Small pericardial effusion is present in about 60% of the cases and is responsive to medical therapy. Computed tomography scan and CMR imaging can be used when the first level of investigations are not sufficient for diagnostic purposes or when there are complications related to pericarditis. ,


Treatment


The mainstay of treatment are oral nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and colchicine. , Steroids should not be used as a primary therapy in uncomplicated acute idiopathic pericarditis due to the high rate of relapse when the steroid is tapered or stopped. , Hence steroids should only be used in patients who are refractory and intolerant to aspirin/NSAIDs and colchicine combination or have an underlying condition for which steroids are indicated. For a first episode, aspirin should be given in a dose of 750–1000 mg three times a day, NSAIDs (e.g., ibuprofen) 600 mg three times a day for 1 to 2 weeks, and colchicine 0.5 mg twice daily or 0.5 mg daily in those weighing <70 kg or intolerant to high dose for 3 months. If steroids are used, prednisone in a dose of 0.25–0.5 mg/kg/day is given for 1–2 weeks. For recurrent cases, aspirin and NSAIDs are given for 2–4 weeks, colchicine for 6–12 months, and steroids for 2–4 weeks.


Pericardial Effusion and Cardiac Tamponade


Generally, the pericardial space contains <50 mL of fluid. Accumulation of larger amounts of fluid is usually due to the disease process in the pericardium, which may or may not be related to cancer or a systemic disease. It may range from minimal to moderate and large, with symptoms and signs not only related to the size of effusion but also to the rapidity of fluid collection. In the general population, malignancy is the commonest cause of large pericardial effusion.


The clinical symptoms and signs of pericardial effusion depend on the size, cause, and rate of accumulation of the pericardial fluid. A large but slowly growing effusion, for example, in a patient with malignancy, may lead to fewer symptoms and less-acute presentation, whereas a rapidly accumulating smaller pericardial fluid, for example, a complication of a radiofrequency ablation or cardiac biopsy, may cause acute tamponade. Common symptoms of pericardial effusion include dyspnea on exertion with orthopnea, palpations, chest pain, or tightness. Other nonspecific symptoms include weakness, fatigue, and anorexia. The classic clinical findings in tamponade consist of low blood pressure, distended neck veins, and muffled heart sounds, which is known as Beck’s triad. Claude S. Beck described this in 1935 as two cardiac compression triads: acute cardiac compression (low arterial pressure, high venous pressure, quiet heart) and chronic cardiac compression (ascites, high venous pressure, quiet heart).


A 2D echocardiogram is the most common noninvasive test utilized for the diagnosis of pericardial effusion. It not only provides information on the size but also on the features of increased intrapericardial pressure. As for the general population, in patients with cancer the effusion is categorized into small (≤1 cm), moderate (1–2 cm), and large ( > 2 cm). Signs of hemodynamic compromise and tamponade include the presence of right atrial and right ventricular collapse/compression, respiratory variation in tricuspid and mitral valve inflow velocities, and usually associated with inferior vena cava plethora. See Fig. 6.4 .


Jun 26, 2022 | Posted by in ANESTHESIA | Comments Off on Cancer and Heart Disease
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