*3.1.4 Histopathology and cytopathology*

Dilated cardiomyopathy is a progressive, diffuse process involving cardiomyocytes from the right and left ventricles, resulting in both chambers becoming dilated and dysfunctional. As the myocardium relaxes, it becomes stretchy and thinner. Consequently, the ventricular chamber widens. Since this condition's histologic features are nonspecific, it is a microscopic diagnosis of exclusion. Previous studies have also established such findings, but only in the myocardium of patients with end-stage disease (**Figure 12**).

• Microscopic description: Myocytes have normal architectural distribution but changes in numbers, sizes, and shapes, as well as in the cytoplasm and nucleus. With regards to the size of myocytes, there are significant large variations, as these are a combination of hypertrophic, atrophic, and normal myocardiocytes or are associated with degenerative changes. Due to the atrophy of the myocytes, they have an appearance of long and thin fibers, with a sinuous path and a characteristic appearance of "corrugated fibers" (**Figure 13A**). These fibers are separated from each other by loose spaces, a suggestive aspect of edematous infiltration of the interstitia. The typical atrophy is presented with zonal characters, rarely with extensive or focal elements.

Fibrosis is diffuse or focal in the interstitial or perivascular topography. In interstitia, the fibrillar collagen's presence in intermuscular spaces normally devoid of collagen is noticed. The distribution pattern can vary from a fine peri-myocyte distribution to massive scars. In the case of perivascular fibrosis, collagen has

*Molecular Histopathology and Cytopathology in Cardiovascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.110503*

accumulated in the adventitia of intramedullary coronary arteries and arterioles, otherwise remains untouched (**Figure 13B**). The presence of fatty tissue infiltrates (lipomatosis) with focal characters. (**Figure 13C**). Collagen has individually surrounded the myocardial fibers with a "ragged" appearance due to the corrugated cell membrane (**Figure 13D**).

#### **3.2 Hypertrophic cardiomyopathy**

#### *3.2.1 Abstract*

Hypertrophic cardiomyopathy (HCM) is a congenital or acquired disorder characterized by marked ventricular hypertrophy and diastolic dysfunction but no increased afterload. Symptoms include difficulty breathing, chest pain, fainting, and even sudden death. HCM is diagnosed based on echocardiography and CMR. The initial therapy is beta-blockers, verapamil, disopyramide, alcohol septal ablation, or surgical removal of outlet obstruction [23].

#### *3.2.2 Pathophysiology*

Cardiac muscle abnormalities with fibrous tissue and not specific to HCM. The most common is marked hypertrophy and thickening of the anterior septum and the adjacent

**Figure 13.** *Microscopic diagnosis dilated cardiomyopathy.*

anterior free wall below the aortic valve, with little or no LV posterior wall hypertrophy. Occasionally, isolated apical hypertrophy occurs; most cases are asymmetric hypertrophy, and a few cases of symmetrical hypertrophy have been reported [24].

Two-thirds of patients present with "congestion" at rest or with exercise; obstruction results from mechanical resistance to the LV outflow tract during systole due to the mitral valve's forward motion (SAM). During this period, the mitral valve and valvular structures are drawn into the LV outflow tract due to the Venturi effect of high-velocity blood flow, resulting in flow obstruction and decreased cardiac output. Mitral regurgitation can also occur due to the deformed movement of the leaflets. This blockage and regurgitation cause symptoms associated with heart failure. Less commonly, left midventricular hyperplasia causes elevation of pressure gradient at the site of the papillary muscles [23, 25].

Initially, contractility is completely normal, resulting in a normal ejection fraction (EF). Thereafter, EF increases because the ventricular volume is small and empties almost completely to maintain cardiac output. Hypertrophy leads to a rigid, elastic ventricular chamber that interferes with diastolic filling, increasing end-diastolic pressure and increasing pulmonary venous pressure. As filling resistance and cardiac output decrease, the condition is worsened by any output gradient. Tachycardia allows less time to fill, so symptoms tend to appear mainly with exercise or a rapid heart rate.

Coronary blood flow may be impaired, causing angina, syncope, or arrhythmia in the absence of epicardial coronary artery injury. Impaired flow due to inadequate capillary versus muscle cell density (capillary/muscle imbalance) or narrowing of the lumen of the coronary arteries in the myocardium due to hyperplasia and hypertrophy endothelium and mesothelium. A mismatch between supply and demand can also

arise due to increased oxygen demand, hypertrophy, and adverse loading conditions [23]. In some situations, myocytes die due to ischemia, will be replaced by diffuse fibrosis. Subsequently, the ventricles become enlarged with pre-existing diastolic dysfunction and progressive systolic dysfunction.

#### *3.2.3 Clinical diagnostic criteria*

The diagnosis of HCM is suspected based on murmurs and other typical symptoms, especially if the patient has unexplained syncope or a family history of sudden death. HCM must be differentiated from aortic stenosis and coronary artery disease because they have similar clinical symptoms.


#### *3.2.4 Histopathology*

Myocyte hypertrophy is correlated with heart size. The disarray of the overall architecture of the hypertrophied myocytes characterizes histopathology in patients with HCM. It notes that whether myocytes may be obviously or barely noticeably enlarged depends on their relative heart size.

The increase in myocytes and interstitial tissue leads to increased myocardial mass. Meanwhile, the heart may or may not increase in overall size due to the hypertrophy of myocytes may or may not be associated with dilation. Dilation is a prominent feature in response to volume overload rather than pressure overload. Regarding pressure overload, the walls may be thick with no dilation, and the chamber volume ratio to wall thickness decreases; this is also known as "concentric hypertrophy". Although the ventricular wall thickness is measured as a reflection of the degree of hypertrophy, such measurement does not accurately reflect the myocardial mass in hypertrophy with dilation (**Figure 14**).

#### **Figure 14.**

*Very large heart size (18 x 15 cm). Cross section of hypertrophic heart in an adult: The right ventricular free wall thickness is 1,5 cm, the LV is 3,5 cm, and the septum 3 cm.*

**Figure 15.**

*In Myocardial hypertrophy cardiocyte diameter is up to 25 μm and in severe hypertrophy is usually between 25 and 30 μm.*

The diameter of the myocardial cell is also an indicator that predicts different levels of hypertrophy. Under normal conditions, the myocardial cell ranges from 5 to 12 μm in diameter. In cases of mild and moderate hypertrophy, it can go up to 20 μm and 25 μm, respectively. Diameters between 25 and 30 μm usually indicate moderate to severe hypertrophy. And when diameters are greater than 30 μm, severe hypertrophy must be suspected. HCM almost always presents with cell hypertrophy. Hypertrophic myocardial cells show nuclear enlargement, bizarre nuclei, and binucleation (**Figure 15**).

The typical histologic description of hyperchromatic nuclei is like a rectangular shape, or "box-car" nuclei (**Figure 16A**). Myocardial fibrosis can be comprised of three main categories: interstitial, perivascular, and replacement-type fibrosis. In interstitial diffuse fibrosis, bundles of collagen surround the cardiomyocytes individually (**Figure 16B**). Perivascular fibrosis spreads radially around capillary and small arteries. Replacement by adipose tissue is often seen in the terminal stage of fibrosis (**Figure 16C**). Replacement fibrosis is characterized as areas of fibrosis not large enough to be considered an infarct, typically less than 3 mm in size (**Figure 16D**).

*Molecular Histopathology and Cytopathology in Cardiovascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.110503*

**Figure 16.** *A: Hyperchromatic nuclei. B: interstitial fibrosis. C: Perivascular fibrosis. D: Replacement fibrosis.*

#### **3.3 Restrictive cardiomyopathy**

#### *3.3.1 Abstract*

Restrictive cardiomyopathy is the least common form of cardiomyopathy. It is characterized by noncompliant ventricular walls that resist diastolic filling; the right or left ventricle or both may be affected. Symptoms include fatigue and shortness of breath, especially with exertion. Restrictive cardiomyopathy is diagnosed based on echocardiography and cardiac catheterization. The medication is often less effective. Surgery is sometimes beneficial [27]. It classifies as non-obstructive (infiltration of the myocardium by an abnormal substance) and fibrosis (fibrosis of the endocardium and subendocardium).

#### *3.3.2 Pathophysiology*

Endocardial thickening or myocardial infiltration (with possible myocardial cell death, papillary infiltration, myocardial hypertrophy, and fibrosis) occurs on one side, typically the left or both ventricles. Thus, causing mitral or tricuspid regurgitation. If the nodal and conduction tissues are affected, the sinus node and the atrioventricular node become less functional, sometimes causing varying degrees of SA and AV block. The hemodynamic consequences are diastolic dysfunction with ventricular stiffness, loss of elasticity, impaired diastolic filling capacity, and increased filling pressure,

leading to increased pulmonary venous pressure. The systolic function may worsen. A cardiac chamber thrombus can form, leading to systemic embolism [27].

#### *3.3.3 Clinical diagnostic criteria*

Restrictive cardiomyopathy should be suspected in patients with heart failure and preserved ejection fraction, particularly in the presence of systemic disease. An electrocardiogram, chest x-ray, and routine echocardiography are required.

ECG presentation is less specific and may show ST segment and T wave abnormalities and sometimes low voltage. Pathological Q wave, not due to previous myocardial infarction. LV hypertrophy due to compensatory myocardial hypertrophy or both atrioventricular block, and sinoatrial block may be present.

On a chest X-ray, the heart is usually normal in size but may be enlarged in amyloidosis or hemochromatosis. Echocardiography showed a normal LV ejection fraction. Tissue Doppler imaging often shows increased LV filling pressure, and longitudinal decline in contractile function despite normal ejection fraction. In addition, other nonspecific signs such as atrial dilatation and myocardial hypertrophy. In amyloidosis, abnormal echogenic tissue can be observed from the myocardium, and identification of the amyloid type has implications for treatment, genetic counseling, and prognosis [27, 28].

#### **3.4 Some other diseases**

In addition to the three common types mentioned above, there may also be other forms such as arrhythmogenic right ventricular cardiomyopathy, Takotsubo cardiomyopathy, peripartum cardiomyopathy, spongiform cardiomyopathy, or secondary cardiomyopathies. Consequences of endocrine, metabolic, neurological, nutritional, autoimmune, toxicological diseases... For each of these diseases, there are separate pathophysiological mechanisms and different diagnostic procedures. Histopathology is diverse, but all have in common that is, leading to cardiovascular mortality or severe cardiac dysfunction.

#### **4. Pulmonary embolism**

#### **4.1 Abstract**

Pulmonary embolism is caused by the thrombus moving through, most commonly from the large veins of the lower extremities or pelvis. Risk factors for PE are venous stasis, endothelial damage, and disorders associated with hypercoagulability [29]. Symptoms of PE include dyspnea, chest pain, and in more severe cases syncope, respiratory failure, and cardiac arrest. Physical examination may tachypnea, tachycardia, and, in more severe cases, hypotension. Computed tomographic pulmonary angiography is considered the gold standard diagnostic modality for PE with a sensitivity of 83% and specificity of 96%, although ventilation/perfusion is sometimes required. Treatment of PE with anticoagulants and thrombolytics is systemic or directly through the catheter, thrombectomy with mechanical and surgical instruments. When anticoagulation is contraindicated, an inferior vena cava filter should be placed. Preventive measures include

anticoagulation and/or the use of compression stockings and lower extremity decompression devices [30].

#### **4.2 Pathophysiology**

As deep vein thrombosis develops, the clots can move through the venous system to the right heart and the pulmonary arteries, where they partially or completely obstruct one or more arterial branches of the pulmonary vessels. The severity depends on the size and amount of the thrombosis, the underlying lung condition, right ventricular function, and the fibrinolytic system's ability to dissolve the clot. The death occurred due to right ventricular failure [29, 30].

Small emboli may have no physiological effects, dissolve immediately, and resolve spontaneously within hours or days. Larger emboli can cause reflex hyperventilation, hypoxia due to inadequate ventilation/perfusion (V/Q), and low venous mixed oxygen due to decreased cardiac output. Low blood pressure, atelectasis due to decreased alveolar CO and surfactant abnormalities, and increased pulmonary vascular resistance due to mechanical obstruction and vasoconstriction lead to tachycardia and hypotension. Endogenous lysis reduces most thrombi, even moderate-sized ones, and physiological changes subside after hours or days. Some emboli are resistant to lysis and can organize and persist, subsequently causing chronic pulmonary hypertension [31, 32]. PE can be classified according to risk:


In 1 to 4% of cases, chronic residual obstruction leads to pulmonary hypertension. This condition can progress and lead to chronic right-sided heart failure [34]. When a large embolus blocks the major pulmonary arteries, or many smaller emboli combine to occlude >50% of the more distal vessels, RV pressure increases, induce in acute RV failure. The risk of death depends on the degree and rate of elevation of RV pressure and the patient's baseline cardiopulmonary status. Patients with pre-existing cardiopulmonary disease are at increased risk of mortality, but young and/or otherwise healthy patients may survive after thrombosis occluding >50% of the pulmonary vascular bed [30, 35].

Pulmonary infarction (ischemia of lung tissue) occurs in <10% of patients with a diagnosis of PE. This low incidence is attributed to the dual blood supply to the lungs (i.e, bronchi and lungs). In general, pulmonary infarctions are caused by emboli. Smaller occlusions lodge in the more distant pulmonary arteries and are almost completely reversible; pulmonary infarction is detected early by highly sensitive radiographic criteria, often before necrosis occurs.
