**Acknowledgements**

mutation, skipthe exon—thatis holding the genetic alteration inDMDto express a shorterform of DYSTROPHIN corresponding to BMD—or bring in shortened *DYSTROPHIN* variants by viralorcell‐basedtherapy.Severalofthesetherapiesalreadymadeitintoclinicaltrialswithsome undergoing phase III trials. However, as skeletal muscle complications are the most prominent, effects on the heart have not been taken up into the expected outcomes of these trials. This also because in most preclinical treatments beneficial effects on the heart were absent. Novel approaches were necessary to deliver constructs to the cardiac muscle and some preclinical studies have shown DYSTROPHIN expression in the heart together with functional improve‐ ments in small and large animal models. Emerging literature is also showing that IPSC‐derived myogenic progenitors from patients with dystrophy provide an attractive model to get new insights on gene‐editing treatments. This novel technology offers possibilities for autologous therapy and eventually targeting both cardiac and skeletal dystrophic muscles with a single myogenic progenitor population. It is assumed that all these preclinical therapies will make it into clinical studies and hopefully subsequently into dystrophinopathy therapies. However, many issues still exist and need to be addressed such as immunogenic reactions toward the administered cells or viruses, the need for high‐dosing regimens and bodywide delivery.

DYSTROPHINfunctionsasalinkagerodbetweentheactincytoskeletonandthecellmembrane, where it is connected to β‐DYSTROGLYCAN, which in turn associates with the extracellular matrix via LAMININ. The SARCOGLYCAN complex is in close proximity to β‐DYSTROGLY‐ CAN and is important in signaling, which occurs through SYNTROPHIN and DYSTROBRE‐ VIN. Together these proteins are part of the dystrophin‐glycoprotein complex (DGC). DYSTROPHIN also accommodates a neuronal nitric oxide synthase (nNOS)‐binding site.

The 24 spectrin‐like repeats within DYSTROPHIN neutralizes contraction‐induced stress. The absence of DYSTROPHIN leads into a loss of muscle structural integrity, which generates membrane microruptures, leading to elevated CK levels in the serum and a high intracellu‐ lar Ca2+ concentration that subsequently activates calcium‐dependent proteases [81]. Because of the lack of experimental proof, researchers have started questioning this theory. It became evident that activation of stretch‐induced Ca2+ channels corresponds with elevated intracellu‐ lar Ca2+ levels, although the responsible channel has still to be found [82]. Repeated contraction‐ induced damage leads to a continuous muscle breakdown and regeneration, with an increased build‐up of fatty and fibrotic tissue, followed by an eventual loss of muscle contractility.

A reading frame consists out of codons—three nucleotide‐based sequences—which translate into a specific amino acid. A shift of the reading frame basically means that the reading frame

**Appendix**

302 Cardiomyopathies - Types and Treatments

*Appendix 1: The dystrophin-glycoprotein complex*

*Appendix 3: The reading-frame concept*

*Appendix 2: The molecular mechanisms of dystrophin deficiency*

We would like to apologize to all authors whose work has not been reported here due to space limitations. This work has been supported with the contribution of "Opening The Future" Campaign [EJJ‐OPTFUT‐02010] CARIPLO 2015\_0634, FWO (#G088715N, #G060612N, #G0A8813N), GOA (EJJ‐C2161‐GOA/11/012), IUAP‐VII/07 (EJJ‐C4851‐17/07‐P) and OT#09‐053 (EJJ‐C0420‐OT/09/053) grants. We thank Christina Vochten and Vicky Raets for professional administrative assistance. We would also like to thank Rondoufonds voor Duchenne Onder‐ zoek for kind donations.

## **Author details**

Jordi Camps1 , Enrico Pozzo1,2, Tristan Pulinckx1 , Robin Duelen1 and Maurilio Sampaolesi1,2\*

\*Address all correspondence to: maurilio.sampaolesi@kuleuven.be

1 Translational Cardiomyology Lab, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, Leuven, Belgium

2 Division of Human Anatomy, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, Italy

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**Provisional chapter**

### **Cardiomyopathies in Sub-Saharan Africa: Hypertensive Heart Disease (Cardiomyopathy), Peripartum Cardiomyopathy and HIV-Associated Cardiomyopathy Hypertensive Heart Disease (Cardiomyopathy), Peripartum Cardiomyopathy and HIV-Associated Cardiomyopathy**

**Cardiomyopathies in Sub-Saharan Africa:** 

Okechukwu S. Ogah and Ayodele O. Falase Okechukwu S. Ogah and Ayodele O. Falase

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67023

#### **Abstract**

Cardiomyopathy is an important cause of cardiac-related morbidity and mortality in sub-Saharan Africa. Dilated cardiomyopathy is responsible for 20–30% of adult heart failure (HF) in the region. It is only second to hypertensive heart disease as etiological risk factor for HF in many parts of the continent. The aim of the chapter is to review the current epidemiology, clinical features, management, and prognosis of hypertensive heart disease, peripartum cardiomyopathy, and HIV-associated cardiomyopathy in sub-Saharan Africa.

**Keywords:** cardiomyopathy, heart muscle disease, hypertensive heart disease, peripartum cardiomyopathy, HIV-associated cardiomyopathy, heart failure

### **1. Introduction**

Cardiomyopathies are common in Africa. Common causes of myocardial diseases in the region are hypertensive heart disease, endemic cardiomyopathies such as dilated cardiomyopathy, endomyocardial fibrosis, and peripartum cardiomyopathy and most recently heart diseases due to HIV/AIDS and ischemic cardiomyopathy. They are often associated with high morbidity and mortality due to late presentation, lack of modern day treatment available in high-income countries, as well poverty, which limits access to healthcare. **Figure 1** shows the common causes of heart failure (HF) in sub-Saharan Africa (SSA) based on a recent survey of acute HF in the region [1]. The chapter deals with hypertensive heart disease (hypertensive cardiomyopathy) peripartum cardiomyopathy and HIV-associated cardiomyopathy.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Figure 1.** Etiological risk factors for heart failure in sub-Saharan Africa. (Adapted from Damasceno et al. HHF = Hypertensive heart failure, DCM = Dilated cardiomyopathy, RHD = Rheumatic heart disease, IHD = Ischemic heart disease, PPCM = Peripartum cardiomyopathy, PDX = Pericardial diseases, HIV\_CM = HIV associated cardiomyopathy, EMF = Endomyocardial fibrosis.

### **2. Hypertensive heart disease (hypertensive cardiomyopathy)**

#### **2.1. Epidemiology**

More than 30% of adults in SSA have hypertension. The prevalence rate is among the world highest. Worse still, the region has some of the world's lowest rates of hypertension awareness, treatment, and control. About 66% of the people are not aware, 82% are not treated and 93% are uncontrolled. In the year 2010, the age standardized prevalence of hypertension in adults aged 20-years and above was estimated as 36.9 and 36.3% for men and women, respectively (this is compared to 20.9 and 20.3%, 10 years earlier). This translates to 64.8 and 63.8 million men and women with elevated blood pressure in 2010 (compared to 25.5 and 24.9 million hypertensive men and women in the year 2000).

In a recent systematic analysis of population-based studies of hypertension in SSA, the pooled prevalence in the region rose from 19.7% in 1990 to 30.8% in 2010. It is estimated that there were about 54.6 million people with hypertension in Africa in 1990. This rose to 130.2 million cases in 2010. It is also projected that by the year 2030, there will be about 216.8 million cases of hypertension in the region [2].

Hypertension is the commonest and strongest risk factor for cardiovascular disease (CVD) in SSA [3]. It is also the commonest cause of disability and death from non-communicable diseases (NCDs) in the region [4]. The condition often manifests in young and middle aged adults in their productive years [4]. It is estimated to cause over 500,000 adult deaths annually and about 10-million years of life lost. Over 50% of heart disease and HF in the region is attributed to elevated blood pressure.

According to the African Union, hypertension is one of the greatest health challenges in adults in Africa after HIV/AIDS [4]. Recent data indicate that hypertension is rising in SSA at a faster rate compared to other regions of the world [5, 6]. This has been attributed to that adoption of western lifestyle, diet and culture, urbanization, urban migration from rural areas, ageing of the population, and increasing use of cigarettes and alcohol [3, 5–7].

It has been demonstrated that a chronic hyperadrenergic state is common among African hypertensives and may be responsible for the high prevalence of hypertension observed in Africans [8].

### **2.2. Clinical features**

Heart disease secondary to elevated blood pressure (hypertensive heart disease), which may manifest in the following ways:

### *2.2.1. LV diastolic dysfunction*

LV diastolic dysfunction is common in hypertensive subjects in the region [9–12]. About 62% of hypertensive individuals have various degrees of LV diastolic dysfunction compared to 12% of normal subjects [9, 13]. Diastolic dysfunction is worse in those with concentric LV geometry [9] as well as in individuals at risk of obstructive sleep apnea [14]. Diastolic dysfunction also occurs in offspring of hypertensive subjects [15–17].

### *2.2.2. RV diastolic dysfunction*

**2. Hypertensive heart disease (hypertensive cardiomyopathy)**

million hypertensive men and women in the year 2000).

of hypertension in the region [2].

More than 30% of adults in SSA have hypertension. The prevalence rate is among the world highest. Worse still, the region has some of the world's lowest rates of hypertension awareness, treatment, and control. About 66% of the people are not aware, 82% are not treated and 93% are uncontrolled. In the year 2010, the age standardized prevalence of hypertension in adults aged 20-years and above was estimated as 36.9 and 36.3% for men and women, respectively (this is compared to 20.9 and 20.3%, 10 years earlier). This translates to 64.8 and 63.8 million men and women with elevated blood pressure in 2010 (compared to 25.5 and 24.9

**Figure 1.** Etiological risk factors for heart failure in sub-Saharan Africa. (Adapted from Damasceno et al. HHF = Hypertensive heart failure, DCM = Dilated cardiomyopathy, RHD = Rheumatic heart disease, IHD = Ischemic heart disease, PPCM = Peripartum cardiomyopathy, PDX = Pericardial diseases, HIV\_CM = HIV associated cardiomyopathy,

In a recent systematic analysis of population-based studies of hypertension in SSA, the pooled prevalence in the region rose from 19.7% in 1990 to 30.8% in 2010. It is estimated that there were about 54.6 million people with hypertension in Africa in 1990. This rose to 130.2 million cases in 2010. It is also projected that by the year 2030, there will be about 216.8 million cases

**2.1. Epidemiology**

EMF = Endomyocardial fibrosis.

314 Cardiomyopathies - Types and Treatments

Right ventricular systolic dysfunction has been reported in about 62% of a cohort of hypertensive patients [18, 19]. RV diastolic dysfunction may be an early clue to the development of hypertensive heart disease in Africans [19].

### *2.2.3. Atrial function and dysfunction*

Absolute and indexed left atrial diameter, area, or volume is increased in African hypertensive subjects [20, 21]. Compared to their age- and sex-matched controls, hypertensive Africans show statistically significant left atrial structural and functional alterations [21].

### **2.3. Left ventricular hypertrophy**

Electrocardiographic LVH occurs in 18–56% of hypertensive Africans depending on the criteria employed for the diagnosis. Sokolow-Lyon criteria appear to have the best sensitivity, while Estes score and Cornell criteria have the best specificity. Some workers in the region have proposed new criteria for ECG diagnosis of LVH in Africans especially in obese subjects [22–28]. ECG LVH with strain pattern is associated with worse LV structure and function in hypertensive Africans [29, 30].

The prevalence of echocardiographic LVH ranges from 30.9 to 74%. This, however, depends on the threshold used for the indexation of LV mass. Adebiyi et al. report 61–74% prevalence of abnormal LV geometry in hospital patients at the University College Hospital, Ibadan, Nigeria [31].

In a similar study in Northern Tanzania [32], 70% of the hypertensive subjects have abnormal LV geometry. The distribution of the abnormal LV geometric patterns is 19.8, 28.2, and 22% for concentric remodeling, concentric hypertrophy, and eccentric LVH, respectively. The best yield appears to be when LV mass is indexed to height raised to the power of 2.7 (allomeric growth rate of the heart). Age, systolic blood pressure, and duration of hypertension are independent predictors of LVH.

### *2.3.1. LV systolic dysfunction*

LV systolic dysfunction (LVSD) occurs in 18.1% (9.6, 3.7, and 4.8% for mild, moderate, and severe LVSD, respectively) of hypertensive Africans [33]. The independent predictors of LVSD are LV mass, body mass index, and male gender. Ojji et al. [34] report LVSD in 6.7% (mild—3.5%, moderate—2.3%, and severe—0.9%) of 1943 hypertensive subjects and LV dysfunction is associated with older age, male sex, presence of diabetes mellitus, and some indices of the LV structure.

The Tei index (index of global myocardial performance) is significantly higher in hypertensive Africans compared to controls. The index increases with severity of LVSD. It is negatively related to the LVEF.

#### *2.3.2. RV systolic dysfunction*

RV systolic dysfunction occurs in about in 32% of hypertensive subjects seen in tertiary centers in the region [18, 35, 36]. RVSD is worse in subjects with eccentric LV geometry. LVEF appears to be the main determinant of RVSD. Recently, Ojji et al. [37] reported RVSD in 44.5% of 611 hypertensive subjects. RVSD estimated by TAPSE <15mm is associated with worse prognosis. LVEF and right atrial area are the main determinants of RVSD.

#### **2.4. Hypertensive heart failure**

Hypertensive HF (HHF) is a common and major form of presentation of HF in Africa. **Table 1** shows the contribution of hypertension in the etiology of HHF in SSA. In the Heart of Soweto study [38], 54% of hypertensive patients visit the hospital on account of this disorder. This devastating form of HHD is often associated with concurrent LVH, renal dysfunction, and anemia. In a study of 180 HHF patients in Ghana, the mean age of presentation is 63.6 years (range-24–88 years) and seen more often in women. The mean systolic blood pressure at presentation is 162.4 mmHg. Shortness of breath, easy fatigability, and palpitation are common symptoms while pulmonary edema and displaced apex beat are the common signs.


**Table 1.** Summary of contribution of hypertension to HF in recent SSA studies.

have proposed new criteria for ECG diagnosis of LVH in Africans especially in obese subjects [22–28]. ECG LVH with strain pattern is associated with worse LV structure and function in

The prevalence of echocardiographic LVH ranges from 30.9 to 74%. This, however, depends on the threshold used for the indexation of LV mass. Adebiyi et al. report 61–74% prevalence of abnormal LV geometry in hospital patients at the University College Hospital, Ibadan,

In a similar study in Northern Tanzania [32], 70% of the hypertensive subjects have abnormal LV geometry. The distribution of the abnormal LV geometric patterns is 19.8, 28.2, and 22% for concentric remodeling, concentric hypertrophy, and eccentric LVH, respectively. The best yield appears to be when LV mass is indexed to height raised to the power of 2.7 (allomeric growth rate of the heart). Age, systolic blood pressure, and duration of hypertension are inde-

LV systolic dysfunction (LVSD) occurs in 18.1% (9.6, 3.7, and 4.8% for mild, moderate, and severe LVSD, respectively) of hypertensive Africans [33]. The independent predictors of LVSD are LV mass, body mass index, and male gender. Ojji et al. [34] report LVSD in 6.7% (mild—3.5%, moderate—2.3%, and severe—0.9%) of 1943 hypertensive subjects and LV dysfunction is associated with older age, male sex, presence of diabetes mellitus, and some

The Tei index (index of global myocardial performance) is significantly higher in hypertensive Africans compared to controls. The index increases with severity of LVSD. It is negatively

RV systolic dysfunction occurs in about in 32% of hypertensive subjects seen in tertiary centers in the region [18, 35, 36]. RVSD is worse in subjects with eccentric LV geometry. LVEF appears to be the main determinant of RVSD. Recently, Ojji et al. [37] reported RVSD in 44.5% of 611 hypertensive subjects. RVSD estimated by TAPSE <15mm is associated with worse

Hypertensive HF (HHF) is a common and major form of presentation of HF in Africa. **Table 1** shows the contribution of hypertension in the etiology of HHF in SSA. In the Heart of Soweto study [38], 54% of hypertensive patients visit the hospital on account of this disorder. This devastating form of HHD is often associated with concurrent LVH, renal dysfunction, and anemia. In a study of 180 HHF patients in Ghana, the mean age of presentation is 63.6 years (range-24–88 years) and seen more often in women. The mean systolic blood pressure at presentation is 162.4 mmHg. Shortness of breath, easy fatigability, and palpitation are common symptoms while pulmonary edema and displaced apex beat are the common signs.

prognosis. LVEF and right atrial area are the main determinants of RVSD.

hypertensive Africans [29, 30].

316 Cardiomyopathies - Types and Treatments

pendent predictors of LVH.

*2.3.1. LV systolic dysfunction*

indices of the LV structure.

*2.3.2. RV systolic dysfunction*

**2.4. Hypertensive heart failure**

related to the LVEF.

Nigeria [31].

Cardiomegaly on chest radiography is present in 75.6%. ECG-LVH or ECHO-LVH occur in 75.6 and 83.3%, respectively. About 62% have heart failure with preserved ejection fraction HFpEF [39].

In Nigeria, HHF is more common in men (56%). The mean age of presentation is 58.4 and 60.6 years in men and women, respectively. Over 80% present in NYHA class III and IV. HFpEF is present in about 35% of cases. The median length of hospital stay is about 9-days while 3.4% die while on admission. A 30-, 90-, and 180-day mortality rates of 0.9, 3.5, and 11.7%, respectively have been reported. Renal dysfunction appears to be the main independent predictor of mortality [40].

**Table 2** shows the characteristics of African patients with HHF compared with similar patients in other parts of the world.

### **2.5. Possible pathophysiologic mechanism of hypertensive heart disease in SSA**

Hypertension is a common cause of pressure overload of the left ventricle. LVH develops as an adaptation to this overload. Hypertensive patient with ECG LVH has 10-fold higher risk


Abbreviation: HOS = Heart of Soweto Study, EHFS II = European Heart Failure Survey II, AHEAD = Acute Heart Failure Database, HF = Heart Failure, NYHA = New York Heart Association, MI = Myocardial Infarction, CAD = Coronary Artery Disease, COPD = Chronic Obstructive Pulmonary Disease, TIA = Transient Ischemic Attack, BP = Blood Pressure, LVEDD = Left Ventricular End-Diastolic Diameter, LA = Left Atrium, LOS = Length of Hospital Stay

**Table 2.** Comparison of our findings with similar studies in other parts of the world.

of developing HF [41]. There is increased wall thickness at the expense of chamber volume in LVH due to hypertrophy of the myocyte and by a parallel alignment of the sarcomere [42]. Specific hypertensive cardiomyopathy has been proposed. This cardiomyopathy has been divided into four stages: in stage 1, there is diastolic dysfunction, which is present in 20–30% of patients. This is common in elderly women, hypertensive diabetics, and ischemic heart disease patients [43]. LV diastolic dysfunction precedes systolic HF and is therefore a more common mechanism of HF in hypertension. Stage 2 is hypertension with impaired LV relaxation abnormalities, while grade 4 is dilated cardiomyopathy with LV systolic dysfunction. It has been shown that apoptosis may be responsible for the reduction of myocyte mass that accompanies progression from compensated hypertrophy to HF.

Several theories have been proposed to explain the relationship between LVH and HF. This includes changes in the coronary microcirculation, which leads to poor myocardial perfusion, impaired cardiac function, loss of contractile protein, and thus reduced cardiac contractility [44]. The second theory is increased LV pressure overload, which leads to ventricular dilatation and reduced cardiac output [45].

Finally, LVH in hypertension is governed by different loading conditions, which involve both hormonal and paracrine factors such as the sympathetic nervous system and reninangiotensin-aldosterone axis [46].

### **3. Peripartum cardiomyopathy (PPCM)**

### **3.1. Definition**

**Characteristics Ogah et al.** 

Previous history of hypertension

318 Cardiomyopathies - Types and Treatments

Body mass index (kg/m2

12 months (%)

Hospitalization for HF within last

(%)

**[40] (***n* **= 320)**

**Stewart et al. [41] (***n* **= 281)**

Female (%) 42.5 61 39.6 65.4 33.3 Mean age (yrs) 59.3 61 69.8 74.8 65.5 Denovo HF (%) 85.6 NA 37.3 74.3 66.7 NYHA III+IV (%) 82.2 29 NA 34.0 NA

Diabetes mellitus (%) 12.2 14 34.5 43.1 33.3 Previous MI or CAD (%) 0.3 1.0 53.8 26.4 46.7 COPD (%) 2.5 NA 18.0 17.8 26.7 Stroke or TIA in history (%) 0.3 12 16.0 26.4 20 Atrial fibrillation (%) 12.8 9 37.7 19.0 46.7 Mean systolic BP(mmHg) 144 140 NA 198 NA Mean diastolic BP(mmHg) 91 80 NA 100 NA Heart rate (beats/min) 96 NA NA 93 NA

Renal failure (%) 14.4 27 18.7 NA NA Anemia (%) 11.5 10 11.3 NA NA Infection (%) 63.4 NA 15.6 NA 13.3 Noncompliance with therapy (%) 74.1 NA 21.9 NA 66.7 ACE inhibitors (%) 99.1 NA NA 71.3 NA Beta-blockers (%) 2.7 NA NA 77.0 NA Calcium antagonists (%) 30.6 NA NA 51.1 NA Diuretics (%) 86.9 NA NA 88.5 NA Spironolactone (%) 81.3 NA NA 36.2 NA Digoxin (%) 73.1 NA NS 13.8 NA LVEDD (mm) 55 46 56 NA 50\* Mean ejection fraction 42.7 53 44 55 50.5 LA (mm) 47 NA 45 NA 42\* Mitral regurgitation (%) 79.1 7 77.6 NA 100 Tricuspid regurgitation (%) 60.8 6 53.7 NA 93.3 LOS days, median 9 NA 8 NA 13 Intrahospital mortality (%) 3.4 NA 1.5 2.2 6.6

**Nieminen et al. [59] (***n* **= 200)**

90.6 100 94.6 94.3 100

) 24.2 NA NA 28.0 33.9

Abbreviation: HOS = Heart of Soweto Study, EHFS II = European Heart Failure Survey II, AHEAD = Acute Heart Failure Database, HF = Heart Failure, NYHA = New York Heart Association, MI = Myocardial Infarction, CAD = Coronary Artery Disease, COPD = Chronic Obstructive Pulmonary Disease, TIA = Transient Ischemic Attack, BP = Blood Pressure,

LVEDD = Left Ventricular End-Diastolic Diameter, LA = Left Atrium, LOS = Length of Hospital Stay

**Table 2.** Comparison of our findings with similar studies in other parts of the world.

82.2 NA NA 45.1 46.6

**Spinar et al. [60] (***n* **= 179)** **Venskutonyte et al. [61] (***n* **= 65)**

> Peripartum cardiomyopathy (PPCM) is a form of heart disease characterized by "the development of HF in the last month of pregnancy or within the first 5 months postpartum in the absence of any other determinable cause for cardiac failure and in the absence of demonstrable heart disease before the last month of pregnancy, and bears echocardiographic evidence of left ventricular systolic dysfunction" [62]. In addition, the diagnosis of the condition requires evidence of impaired LV systolic function by echocardiography (LVEF < 45% or LVFS < 30%). LV dilation is common although in some patients, LV dimension may be normal but the LV systolic function is impaired [62, 63].

### **3.2. Epidemiology**

In terms of epidemiology, PPCM is common in developing and poor communities. The incidence is 1/1000 in most parts of low- and middle-income countries [64]. However, very high incidence has been reported from Northern Nigeria (1/100 live births) [65–69] and Haiti (1/300 live births) [70, 71]. The incidence in high-income countries is in the range of 1/3000–1/4000 deliveries [64]. There has been an increase in the awareness of the disease worldwide with the establishment of a global registry.

PPCM is responsible for about 1.5% cases of HF in the Heart of Soweto study [41], 1.3% in the Abeokuta HF registry [44] and 3.2% in the Abuja Heart Study [42]. It is still the most prevalent form of cardiomyopathy (54.6%) in Northern Nigeria [45].

### **3.3. Risk factors**

Risk factors for the development of this cardiac disorder include low socioeconomic status, women of African descent (although PPCM is a global disease), young pregnant women, multiparity, multiple pregnancy, and longer period of breast feeding [64]. However, recent prospectively collected data on PPCM do not support strong association with older age of pregnancy, multiparity, twin pregnancy, gestational hypertension, and the use of tocolytic agents [72].

### **3.4. Clinical features**

Shortness of breath is common form of presentation. Other common clinical features include, cardiomegaly, tachycardia, pulmonary rales, high blood pressure and dysrhythmias. Dyspnea, cough, orthopnea, palpitation, hemoptysis, chest pain, and abdominal pain are other common features. Most patients in SSA present in NYHA class III/IV [68, 72]. Thromboembolic complications are common in the form of pulmonary embolism and stroke from mural thrombus [73, 74].

There are some differences between PPCM and hypertensive heart failure of pregnancy (HHFP). Patients with HHFP are more likely to present in the last trimester, while PPCM patients are more likely to present within the first month of the postpartum period. Family history of hypertension and history of hypertension in previous pregnancy is commoner in HHFP. Twin pregnancy and presence of leg edema are more common in PPCM. Blood pressures are generally higher in HHFP and they are also more likely to have basal rales. Furthermore, functional murmurs (tricuspid and mitral regurgitation) occur more often in PPCM compared to HHFP [75].

#### **3.5. Laboratory findings**

Arrhythmias are also common. In severe cases, anemia and renal dysfunction may be present. The liver enzymes may be normal or mildly raised from hepatic congestion. Some authors in Benin republic, Mali and Nigeria have reported the association of PPCM with micronutrient deficiencies, e.g., selenium, ceruloplasmin [76–78]. LV function and mortality in PPCM patients with HIV infection and those without have been found not to differ significantly [79].

The 12-leads ECG often show sinus rhythm, ST-T changes are common, which resolves after the postpartum. Ventricular arrhythmia occurs in about 20% [80–83].

Echocardiography is the diagnostic procedure of choice. Useful for the evaluation of LV systolic function (*EF* < 45%), and diastolic function as well as assessment for presence of intramural thrombus formation. The mean LV internal dimension in diastole is often about 6 cm; however, some patients have nondilated LV. Where available in SSA, magnetic resonance imaging helps in the detection of myocardial fibrosis with late enhancement imaging. It also helps in the assessment function, shape, size, as well as contents. Immunohistochemistry of biopsy specimen from patient with PPCM is not different from that of idiopathic DCM. Similar viral particles, e.g., coxsackie, encephalomyelocarditis, parvovirus B19, adenoviruses, herpes simplex virus, Ebstein-Burr virus, and cytomegalovirus DNA. Inflammatory markers such as tumor necrosis factor alpha (TNF-alpha) and C-reactive protein levels are raised in both conditions and cannot be used to differentiate one from the other. However, peculiar to PPCM are some immune activation processes, e.g., elevated levels of marker of apoptosis-FAS/APO 1. This has been shown to predict prognosis [84].

### **3.6. Recent advances in the pathophysiology**

More recently, Sliwa and her colleagues have shown the role of cleavage of prolactin in the pathogenesis of PPCM. A 16-KDa fragment of prolactin may induce myocardial damage [85]. This has provided a new option of blocking prolactin secretion with bromocriptine in the treatment of PPCM.

### **3.7. Prognosis**

**3.3. Risk factors**

320 Cardiomyopathies - Types and Treatments

agents [72].

[73, 74].

**3.4. Clinical features**

PPCM compared to HHFP [75].

**3.5. Laboratory findings**

Risk factors for the development of this cardiac disorder include low socioeconomic status, women of African descent (although PPCM is a global disease), young pregnant women, multiparity, multiple pregnancy, and longer period of breast feeding [64]. However, recent prospectively collected data on PPCM do not support strong association with older age of pregnancy, multiparity, twin pregnancy, gestational hypertension, and the use of tocolytic

Shortness of breath is common form of presentation. Other common clinical features include, cardiomegaly, tachycardia, pulmonary rales, high blood pressure and dysrhythmias. Dyspnea, cough, orthopnea, palpitation, hemoptysis, chest pain, and abdominal pain are other common features. Most patients in SSA present in NYHA class III/IV [68, 72]. Thromboembolic complications are common in the form of pulmonary embolism and stroke from mural thrombus

There are some differences between PPCM and hypertensive heart failure of pregnancy (HHFP). Patients with HHFP are more likely to present in the last trimester, while PPCM patients are more likely to present within the first month of the postpartum period. Family history of hypertension and history of hypertension in previous pregnancy is commoner in HHFP. Twin pregnancy and presence of leg edema are more common in PPCM. Blood pressures are generally higher in HHFP and they are also more likely to have basal rales. Furthermore, functional murmurs (tricuspid and mitral regurgitation) occur more often in

Arrhythmias are also common. In severe cases, anemia and renal dysfunction may be present. The liver enzymes may be normal or mildly raised from hepatic congestion. Some authors in Benin republic, Mali and Nigeria have reported the association of PPCM with micronutrient deficiencies, e.g., selenium, ceruloplasmin [76–78]. LV function and mortality in PPCM patients with HIV infection and those without have been found not to differ significantly [79]. The 12-leads ECG often show sinus rhythm, ST-T changes are common, which resolves after

Echocardiography is the diagnostic procedure of choice. Useful for the evaluation of LV systolic function (*EF* < 45%), and diastolic function as well as assessment for presence of intramural thrombus formation. The mean LV internal dimension in diastole is often about 6 cm; however, some patients have nondilated LV. Where available in SSA, magnetic resonance imaging helps in the detection of myocardial fibrosis with late enhancement imaging. It also helps in the assessment function, shape, size, as well as contents. Immunohistochemistry of biopsy specimen from patient with PPCM is not different from that of idiopathic DCM. Similar viral particles, e.g., coxsackie, encephalomyelocarditis, parvovirus B19, adenoviruses, herpes simplex virus, Ebstein-Burr virus, and cytomegalovirus DNA. Inflammatory markers such as tumor necrosis factor alpha (TNF-alpha) and C-reactive protein levels are raised in

the postpartum. Ventricular arrhythmia occurs in about 20% [80–83].

Full recovery of LV function occurs in about half of PPCM patients [72]. About 25% recover by the end of 6 months and around 10–15% die within 6 months. Long-term prospective followup studies show that overall recovery occurs in about 25% of patients and this mostly occurs in the first 18–24 months of diagnosis [79].

In recent time, there has been an increased awareness of this condition, and it has been recognized in the guidelines of the American College of Cardiology and European Society of Cardiology. Large global or continental registries of PPCM exist and many centers in SSA are participating. The European society of Cardiology has recently released a position paper on the disorder [62].

### **4. HIV-associated cardiomyopathy**

### **4.1. Prevalence**

SSA contributes about 69 and 90% of the global adult and childhood HIV/AIDS burden. HIVassociated cardiomyopathy is therefore a significant contributor to CVD morbidity and mortality in the region [86, 87].

The true prevalence of HIV-associated cardiomyopathy is unknown. The prevalence of HIVassociated cardiomyopathy in the pre-HAART era was about 50%. The incidence of any cardiac abnormality in HIV-infected individuals was 55% over a 7-year period [88–90]. It was common in young persons with CD4 count of <100 cells/mm3 , lower socioeconomic class, longer duration of the infection, higher viral load, and advanced stage of the disease [89, 91]. In-hospital mortality was 15% [89].

Because of the availability of HAART, the prevalence has reduced by about 50% in highincome countries [92]. However, in low-income countries (where most of the countries in SSA belong to), the prevalence of the condition has increased by 32% due to poor and limited access to HAART as well the impact of malnutrition [93].

Echocardiographic studies have reported prevalence ranging from 5% (in Nigeria) to 57% in Burkina Faso [89, 91, 94]. Differences may be due to study design and lack of common definition of the disorder [95].

In the Heart of Soweto study, about 9.7% of the cohort were HIV infected, 54% of who were on HAART [41, 81]. They were younger, had lower blood pressure and body mass index, and higher heart rate compared to the general cohort. HIV associated HF was the commonest diagnosis. The mean LVEF was 46% and common in women who were also about 6-years younger than the men. HIV patients who had HF had lower CD4 count compared to those who did not have. They were also more likely to have right-heart failure and valve dysfunction [96].

About 2.6% of HF cases in the THESU-HF survey were due to HIV infection. They were younger by 10–15 years and were less often smokers, hypertensive, or diabetic. They had larger LV dimensions but had similar LVEF compared to the general cohort [1]. The findings from the Heart of Soweto and the THESUS-HF survey are similar to more recent observational studies in the region. The prevalence is in the range of 1–5% [67, 73, 74]. It is often diagnosed in the third decade of life and more often in women. Both systolic and diastolic HF are common (about 30%).

### **4.2. Pathophysiologic mechanism**

The proposed mechanism in the pathogenesis of HIV-associated cardiomyopathy include the direct myocardial invasion by the HIV, post-viral autoimmunity, immune system dysregulation, adverse effect of the viral protein, endothelial dysfunction, transcriptional activation of cellular genes, and beta-adrenergic dysregulation. Others include HIVimmunosuppression-related myocarditis due to opportunistic infection with toxoplasmosis, cryptococcus, and mycobacteria. Myocardial dysfunction as a result of systemic effects of sepsis may also play a role. Some of the anti-retroviral medications may play a role in the pathogenesis. Nucleoside reverse transcriptase inhibitors cause mitochondrial damage by inhibiting mitochondrial DNA polymerase. Zalcitabine is thought to exhibit the greatest toxicity among this group [97]. Zidovudine causes cardiac and skeletal myopathy [98].

Malnutrition especially selenium deficiency is another possible mechanism. Selenium has an antioxidant property and protects against endothelial dysfunction. Its deficiency is associated with cardiac dysfunction. Due to soil composition and agricultural practices in the region, selenium deficiency is common and 285 of the SSA population are at risk of selenium deficiency. Selenium deficiency has been demonstrated in HIV patients [99]. Selenium supplementation has also been shown to improve cardiac function in some studies [100].

Heavy alcohol use and smoking have also been implicated especially in high-income countries [101]. This was not demonstrated in a Rwandan study [101].

The role of genetic factor has not been demonstrated in Africa. " The mitochondrial DNA T16189C polymorphism, with a homopolymeric C-tract of 10-12 cystosines—a putative genetic risk factor for idiopathic dilated cardiomyopathy in the African and British populations—was not associated with HIV-associated cardiomyopathy in a South-African case control study" [102].

### **Author details**

In the Heart of Soweto study, about 9.7% of the cohort were HIV infected, 54% of who were on HAART [41, 81]. They were younger, had lower blood pressure and body mass index, and higher heart rate compared to the general cohort. HIV associated HF was the commonest diagnosis. The mean LVEF was 46% and common in women who were also about 6-years younger than the men. HIV patients who had HF had lower CD4 count compared to those who did not have. They were also more likely to have right-heart failure and valve

About 2.6% of HF cases in the THESU-HF survey were due to HIV infection. They were younger by 10–15 years and were less often smokers, hypertensive, or diabetic. They had larger LV dimensions but had similar LVEF compared to the general cohort [1]. The findings from the Heart of Soweto and the THESUS-HF survey are similar to more recent observational studies in the region. The prevalence is in the range of 1–5% [67, 73, 74]. It is often diagnosed in the third decade of life and more often in women. Both systolic and diastolic HF

The proposed mechanism in the pathogenesis of HIV-associated cardiomyopathy include the direct myocardial invasion by the HIV, post-viral autoimmunity, immune system dysregulation, adverse effect of the viral protein, endothelial dysfunction, transcriptional activation of cellular genes, and beta-adrenergic dysregulation. Others include HIVimmunosuppression-related myocarditis due to opportunistic infection with toxoplasmosis, cryptococcus, and mycobacteria. Myocardial dysfunction as a result of systemic effects of sepsis may also play a role. Some of the anti-retroviral medications may play a role in the pathogenesis. Nucleoside reverse transcriptase inhibitors cause mitochondrial damage by inhibiting mitochondrial DNA polymerase. Zalcitabine is thought to exhibit the greatest toxicity among this group [97]. Zidovudine causes cardiac and skeletal myop-

Malnutrition especially selenium deficiency is another possible mechanism. Selenium has an antioxidant property and protects against endothelial dysfunction. Its deficiency is associated with cardiac dysfunction. Due to soil composition and agricultural practices in the region, selenium deficiency is common and 285 of the SSA population are at risk of selenium deficiency. Selenium deficiency has been demonstrated in HIV patients [99]. Selenium supplementation has also been shown to improve cardiac function in some stud-

Heavy alcohol use and smoking have also been implicated especially in high-income coun-

The role of genetic factor has not been demonstrated in Africa. " The mitochondrial DNA T16189C polymorphism, with a homopolymeric C-tract of 10-12 cystosines—a putative genetic risk factor for idiopathic dilated cardiomyopathy in the African and British populations—was not associated with HIV-associated cardiomyopathy in a South-African case con-

tries [101]. This was not demonstrated in a Rwandan study [101].

dysfunction [96].

322 Cardiomyopathies - Types and Treatments

are common (about 30%).

athy [98].

ies [100].

trol study" [102].

**4.2. Pathophysiologic mechanism**

Okechukwu S. Ogah\* and Ayodele O. Falase

\*Address all correspondence to: osogah56156@gmail.com

Division of Cardiology, Department of Medicine, University College Hospital, Ibadan, Nigeria

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#### **Chapter 17 Provisional chapter**

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Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/65060

#### **Abstract**

A wide variety of animal models in cardiomyopathy have been established for the discovery of pathophysiological mechanisms, diagnosis, and treatment of human myocardial disease. Experimentally, several species including rodents, rabbit, canine, pig, and sheep have been involved in the fundamental research in medical field. However, knowledge about naturally occurring myocardial disease in animals is limited in the veterinary medicine. Among small and large animals that develop myocardial disease, to the best of authors' knowledge, naturally occurring cardiomyopathy in canine and feline is commonly encountered in veterinary clinical setting. Their pathophysiology is not fully described; specific pathophysiology is documented in both species, which resembles those of humans. These conditions are hypertrophic cardiomyopathy (HCM) in feline and dilated cardiomyopathy (DCM) in canine. Each has distinct etiology and pathophysiology. In order to translate new findings from naturally occurring cardiomyopathies in small and large animals into medical applications, knowledge gained through animals with cardiomyopathies becomes a necessary approach. The purpose of this chapteris to introduce the overview of findings on small and large animals with naturally occurring cardiomyopathies already investigated.

**Keywords:** animal model, canine dilated cardiomyopathy, feline hypertrophic cardio‐ myopathy, naturally occurring cardiomyopathies

### **1. Introduction**

Several animal models in cardiomyopathy have been established for the discovery of patho‐ physiological mechanisms, diagnosis, and treatment of human myocardial disease. Experi‐ mentally, rodents, rabbit, canine, pig, sheep, and other species have been involved in the

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

fundamental research in medical field [1–7]. Although anatomic and biochemical differences betweenspecies are critical, eachexperimentally inducedanimalmodelplays animportantrole for translation to clinical practice in human. In addition to experimentally induced animal models, naturally occurring cardiomyopathies in small and large animals offer an excellent opportunity to evaluate novel therapies for those of human. However, knowledge about naturally occurringmyocardialdisease inanimals is limitedinthe veterinarymedicine.Among animals that develop myocardial disease, to the best of authors' knowledge, cardiomyopathy in canine and feline is commonly encountered in veterinary clinical setting [8–12]. Their pathophysiology isnot always clearlydescribedyet;however, specific features aredocumented in both canine and feline. Briefly, naturally occurring myocardial disease is one of the most common heart diseases in canine and feline. A number of remarkable similarities have been reported between these animals and humans [13, 14]. Several causes concerning genetic, metabolic, inflammatory, nutritional, infectious, and drug‐induced myocardial disease have beenreportedascanineandfelineidiopathicor secondarymyocardialdisease[15,16].Generally speaking, treatment strategy of these naturally occurring diseases in veterinary clinical setting is based on those of humans. Therefore, this chapter provides pathophysiological aspects of these diseases.

Dilated cardiomyopathy (DCM) was first reported in 1970, as congestive heart failure (CHF). It is characterized by chamber dilation and myocardial systolic and diastolic dysfunction. DCM appears to be common in canine, which has been suspected to be inherited defects and mainly affects the certain large‐ to giant‐sized pure‐bred such as English Cocker Spaniels, Doberman Pinschers, Irish Wolfhounds, Newfoundlands, Boxers, German Short‐ haired Pointers, Portuguese Water Dog, Airedale Terriers, St. Bernards, Standard Poodles, Scottish Deerhounds, Afghan Hounds, and other breeds [8, 15–17]. Myocardial dysfunction results from ischemia, tachycardia, and trauma in canine myocardial disease. An underlying disease associated with neoplasia, renal disease, immune‐mediated hemolytic anemia, acute pancreatitis, disseminated intravascular coagulopathy (DIC), myocardial infarction, mitral insufficiency, and other disease results in ischemic myocardial disease. Atrioventricular nodal‐reciprocating tachycardias can lead to the tachycardia‐induced cardiomyopathy in several breeds. However, hypertrophic cardiomyopathy (HCM) occurs less often in canine [15–17].

On the other hand, HCM is being the most commonly diagnosed cardiomyopathy in feline [10, 18, 19]. It is prevalent in certain populations. The disease is known to be inherited in some breeds, most notably The Domestic Shorthair, Turkish Van, Maine Coon, Persian, Ragdoll, Sphynx, Scottish Fold Cats, Chartreux, British Shorthair, Norwegian Forest Cat, Persian, and other breeds [14–16, 18]. The pathogenic mechanisms responsible for the development of HCM remain unclear; however, causal genetic mutations in genes encoding the sarcomere protein myosin‐binding protein C (MYBPC3) have been identified in specific breeds such as Maine Coons and Ragdolls [14, 19–21].

Limited information exists on naturally occurring cardiomyopathies in large animals such as swine, cattle, and other species. Generally, these large animals are classified as farm animals and treated under group control. Compared with small animal veterinary practice, which mainly treats canine and feline, large animals are not potentially therapeutic objec‐ tives. From this circumstance, few opportunities exist for veterinarian to treat the disease. Even though numerous anatomic and biochemical differences exist, naturally occurring disease in large animal species can provide significant advantages for understanding those human conditions.

### **2. Canine DCM**

fundamental research in medical field [1–7]. Although anatomic and biochemical differences betweenspecies are critical, eachexperimentally inducedanimalmodelplays animportantrole for translation to clinical practice in human. In addition to experimentally induced animal models, naturally occurring cardiomyopathies in small and large animals offer an excellent opportunity to evaluate novel therapies for those of human. However, knowledge about naturally occurringmyocardialdisease inanimals is limitedinthe veterinarymedicine.Among animals that develop myocardial disease, to the best of authors' knowledge, cardiomyopathy in canine and feline is commonly encountered in veterinary clinical setting [8–12]. Their pathophysiology isnot always clearlydescribedyet;however, specific features aredocumented in both canine and feline. Briefly, naturally occurring myocardial disease is one of the most common heart diseases in canine and feline. A number of remarkable similarities have been reported between these animals and humans [13, 14]. Several causes concerning genetic, metabolic, inflammatory, nutritional, infectious, and drug‐induced myocardial disease have beenreportedascanineandfelineidiopathicor secondarymyocardialdisease[15,16].Generally speaking, treatment strategy of these naturally occurring diseases in veterinary clinical setting is based on those of humans. Therefore, this chapter provides pathophysiological aspects of

Dilated cardiomyopathy (DCM) was first reported in 1970, as congestive heart failure (CHF). It is characterized by chamber dilation and myocardial systolic and diastolic dysfunction. DCM appears to be common in canine, which has been suspected to be inherited defects and mainly affects the certain large‐ to giant‐sized pure‐bred such as English Cocker Spaniels, Doberman Pinschers, Irish Wolfhounds, Newfoundlands, Boxers, German Short‐ haired Pointers, Portuguese Water Dog, Airedale Terriers, St. Bernards, Standard Poodles, Scottish Deerhounds, Afghan Hounds, and other breeds [8, 15–17]. Myocardial dysfunction results from ischemia, tachycardia, and trauma in canine myocardial disease. An underlying disease associated with neoplasia, renal disease, immune‐mediated hemolytic anemia, acute pancreatitis, disseminated intravascular coagulopathy (DIC), myocardial infarction, mitral insufficiency, and other disease results in ischemic myocardial disease. Atrioventricular nodal‐reciprocating tachycardias can lead to the tachycardia‐induced cardiomyopathy in several breeds. However, hypertrophic cardiomyopathy (HCM) occurs less often in canine

On the other hand, HCM is being the most commonly diagnosed cardiomyopathy in feline [10, 18, 19]. It is prevalent in certain populations. The disease is known to be inherited in some breeds, most notably The Domestic Shorthair, Turkish Van, Maine Coon, Persian, Ragdoll, Sphynx, Scottish Fold Cats, Chartreux, British Shorthair, Norwegian Forest Cat, Persian, and other breeds [14–16, 18]. The pathogenic mechanisms responsible for the development of HCM remain unclear; however, causal genetic mutations in genes encoding the sarcomere protein myosin‐binding protein C (MYBPC3) have been identified in specific breeds such as Maine

Limited information exists on naturally occurring cardiomyopathies in large animals such as swine, cattle, and other species. Generally, these large animals are classified as farm animals and treated under group control. Compared with small animal veterinary practice,

these diseases.

332 Cardiomyopathies - Types and Treatments

[15–17].

Coons and Ragdolls [14, 19–21].

#### **2.1. Etiology and pathogenesis**

The canine DCM can be divided into two categories: idiopathic and secondary (**Table 1**). The exact underlying molecular and biochemical mechanisms for canine DCM are generally not established in all cases. However, the etiology concerning genetic, nutritional, infectious, metabolic, inflammatory, drug‐ or toxin‐induced myocardial hypokinesis have been proposed in canine DCM [17]. In idiopathic cases, genetic basis is thought to exist especially in certain breeds with high prevalence or familial occurrence of disease [15–17]. Large and giant breeds such as Great Danes, Scottish Deerhounds, Boxers, St. Bernards, Newfound‐ lands, Dalmatians, Doberman Pinschers, Irish Wolfhounds, and other breeds have been documented [8, 15, 16]. Newfoundlands, Irish Wolfhounds, Boxers, and Doberman Pinschers appear to have an autosomal dominant mode of transmission pattern of inheritance [8, 22, 23]. An autosomal recessive transmission has been documented in the inherited form of DCM in juvenile Portuguese Water Dogs [24, 25]. The disease is rapidly progressive and fatal in puppies. In some German Short‐haired Pointer littermates, DCM appears to be an X‐linked disorder caused by mutations in the Duchenne muscular dystrophy (DMD) gene [8, 26]. This gene codes for dystrophin, which is thought to strengthen muscle fiber membranes.

Myocardial function can impair result from a variety of causes including infections, inflam‐ mation, nutritional deficiencies, metabolic abnormalities, certain drugs, and other factors. These factors can lead to canine secondary myocardial disease. The antineoplastic drug doxorubicin and ethyl alcohol can cause severe myocardial damage and death. Plant toxins (e.g., *Taxus*, foxglove, black locust, buttercup, gossypol), cocaine, cobalt, catecholamines, and anesthetic drug can also affect the myocardial function [8, 15–17]. Carnitine and taurine deficiencies have been described in canine DCM [8]. L‐Carnitine deficiency is not a primary cause of canine DCM; however, in Boxers, Doberman Pinschers, American Cocker Spaniels, Irish Wolfhounds, Newfoundlands, and Great Danes, low myocardial L‐carnitine concentra‐ tion has been reported [15]. L‐Carnitine is an essential component of the long‐chain fatty acids, which is an important energy‐producing substrate of the myocardium. Taurine is known to regulate calcium influx across membranes in heart muscle. However, most cases with canine DCM are not taurine deficient; a reversible canine DCM associated with low plasma taurine concentration was reported in Cocker Spaniels [27]. Low plasma taurine level has also been described in Golden Retrievers, Labrador Retrievers, St. Bernards, Dalmatians, and other breeds with DCM.


**Table 1.** Possible factors of naturally occurring canine DCM.

### **2.2. Pathophysiology**

Dilation of all cardiac chambers is typical in canine DCM [8, 15, 16, 28]. Decreased ventricular contractility is the major functional defect. Compensatory mechanisms become activated as progressive cardiac chamber dilation and remodeling develop as cardiac output worsens. Development of higher end‐diastolic pressure, venous congestion, and congestive heart failure occurs in response to increased diastolic stiffness. Valve insufficiency also occurs because of cardiac enlargement and papillary muscle dysfunction. Arterial fibrillation (AF) is typical in canine DCM [15].

### **2.3. Histologic description**

Gross anatomically, canine idiopathic DCM reveals marked dilation of all four cardiac chambers and/or predominantly dilation of the left chambers [8, 29–31]. Generally, myocardial hypertrophy is evident in the lesion. Distinct two histological forms of canine DCM have been reported: the fatty infiltration‐degenerative type observed in specific breeds such as Boxers and Doberman Pinschers, and the attenuated wavy fiber type reported in medium‐, large‐, and giant‐sized breed (**Table 2**). Histological forms such as vacuolar degeneration of myofib‐

ers, atrophic myofibers, lipid deposits, and fatty infiltration replacing myofibers are evident for the fatty infiltration‐degenerative type. On the other hand, the attenuated wavy fiber type seems to be a major histological form of canine DCM. The myofibers are stretched and thinner than normal with wavy appearance. The morphological alterations including myofiber atrophy, impairing wavy appearance to the fibers, and diffuse infiltration of subendocardial fibrosis were reported [8]. These lesions were most abundant in the lateral wall of the left ventricle (LV) [32, 33].


**Table 2.** Two distinct histological forms of canine idiopathic DCM.

#### **2.4. Survival and prognosis**

**Etiology/pathogenesis Breed References**

Dystrophin German Short‐haired Pointers Schatzberg et al. [47] Desmin Doberman Pinschers Stabej et al. [48] Titin‐cup Irish Wolfhounds Philipp et al. [49] α‐actinin Doberman Pinschers O'Sullivan et al. [50] Striatin Boxers Cattanach et al. [51]

L‐Carnitine Doberman Pinschers, Boxers Keene et al. [52]

Anti‐mitochondrial antibodies English Cocker Spaniel Day [57]

**Table 1.** Possible factors of naturally occurring canine DCM.

Canine adenovirus type 1 Crossed breed Maxson et al. [58]

Dilation of all cardiac chambers is typical in canine DCM [8, 15, 16, 28]. Decreased ventricular contractility is the major functional defect. Compensatory mechanisms become activated as progressive cardiac chamber dilation and remodeling develop as cardiac output worsens. Development of higher end‐diastolic pressure, venous congestion, and congestive heart failure occurs in response to increased diastolic stiffness. Valve insufficiency also occurs because of cardiac enlargement and papillary muscle dysfunction. Arterial fibrillation (AF) is typical in

Gross anatomically, canine idiopathic DCM reveals marked dilation of all four cardiac chambers and/or predominantly dilation of the left chambers [8, 29–31]. Generally, myocardial hypertrophy is evident in the lesion. Distinct two histological forms of canine DCM have been reported: the fatty infiltration‐degenerative type observed in specific breeds such as Boxers and Doberman Pinschers, and the attenuated wavy fiber type reported in medium‐, large‐, and giant‐sized breed (**Table 2**). Histological forms such as vacuolar degeneration of myofib‐

Thyroid hormone Great Dane Phillips and Harkin [54]

American Cocker Spaniels Kittleson et al. [53]

Alaskan Malamute Flood and Hoover [55]

Doberman Pinschers Beier et al. [56]

**Idiopathic DCM** *Genetic disorder*

334 Cardiomyopathies - Types and Treatments

**Secondary DCM** *Nutritional disorder*

*Metabolic disorder*

*Immunological disorder*

**2.2. Pathophysiology**

canine DCM [15].

**2.3. Histologic description**

Prognosis in canine DCM varies from weeks to several years. Sudden death may occur before the development of disease. Survival rate of Doberman Pinschers with fatty infiltration‐ degenerative type of DCM is shorter than attenuated wavy fiber type of those with DCM [8].

### **3. Cardiomyopathy in Boxers**

Inherited cardiomyopathy in Boxers has similar features to arrhythmogenic right ventricular cardiomyopathy (ARVC) [15, 23]. Three forms were originally described by Harpster in 1983 including the cases with asymptomatic arrhythmias, ventricular tachyarrhythmias, cardiac arrhythmias, and congestive heart failure [34]. The disease appears to have an autosomal dominant inherited pattern. The Boxers with cardiac arrhythmias and congestive heart failure is considered to be a form of canine DCM, which is characterized by left and right ventricular myocardial systolic dysfunction [15, 23]. Histologic form of the disease includes myofibers atrophy, fibrosis, and fatty infiltration in the right ventricular wall. Deletion in the desmosomal striatin gene is associated with the disease developed in Boxer with ARVC [23]. The prognosis is varied in the forms of disease but survival is less than 6 months in case of CHF. Sudden death is common in asymptomatic cases.
