**5. MRI field strength**

**4. T1 mapping with Modified Look-Locker Inversion "MOLLI" recovery**

Currently, the most evaluated sequence for myocardium T1 mapping is a modified Look‐ Locker inversion recovery (MOLLI) sequence [13, 14]. The T1 mapping identifies a significant variation between normal and abnormal myocardium. It demonstrates the myocardial fibrosis among different myocardial disorders include ischemia [15], acute/chronic infraction [16], amyloidosis [17], diabetic [18], dilated and hypertrophic cardiomyopathy [19], and heart

MOLLI is a CMR pulse sequence that is used for accurate T1 mapping of myocardium with high spatial resolution. MOLLI is an ECG‐gated pulse sequence scheme and uses three prepared Look–Locker experiments consecutively within one breath‐hold over 17 heartbeats to reconstruct 11 images with different inversion times. Three successive ECG‐triggered LL experiments (LL**1**, LL**2**, and LL**3**) are carried out with three, three, and five single‐shot readouts, respectively, at end diastole of consecutive heartbeats to sample the recovery of longitudinal magnetization after the inversion pulse. MOLLI pulse sequence scheme is illustrated in **Figure 1**. T1 maps can be generated any time before or after contrast agent (e.g., gadolinium)

**Figure 1. T1 map of a healthy volunteer**: Using 17 heartbeats to reconstruct 11 images with different inversion times at end of diastole phase. By merging these images into one data set, T1 values are computed for every pixel with three parameters curve fitting. A reconstructed T1 map with parametric color scale is produced for these pixel values and

The MOLLI sequence has been described, optimized, tested, and retested in phantoms and in large cohorts of healthy volunteers [12, 14] as well as being applied in cardiomyopathies [8, 15, 17, 19, 20]. In addition, the T1 mapping with MOLLI has been validated against histopa‐ thology for assessment of myocardial fibrosis. It demonstrated that the precontrast "native T1" has a linear correlation with the percentage of myocardial fibrosis as measured histologically on invasive myocardial biopsy. T1 times postcontrast administration (10–15 min) had an inverse linear relationship with collagen content in myocardial fibrosis subjects [8, 21, 22].

**•** Precontrast "Native" T1 = predominant signal from *myocytes* (replacement fibrosis or

**•** Postcontrast T1 = predominant signal from *interstitial* space (interstitial fibrosis)

failure [8].

350 Cardiomyopathies - Types and Treatments

administration [12].

the segmental and global T1 times can be estimated.

intracellular accumulation, e.g., Fabry disease)

At 1.5 T, the pre‐ and postcontrast (10 mins) T1 times of normal myocardium are 980 ± 53 ms and 470 ± 26 ms, respectively [14]. Precontrast T1 values of myocardial fibrosis (Infarction scar) are significantly longer than those of normal myocardium (1060 ± 61 ms vs. 987 ± 34 ms) [20]. The postcontrast T1 times (10 mins) were significantly shorter in chronic infarct scar compared with normal myocardium at 0.15 mmol/kg (390 ± 20 ms vs. 483 ± 23 ms, respectively) [20].

**3 T**: T1 mapping at higher magnetic field (3 T) has been reported in a few studies of interstitial myocardial fibrosis, but minimal data exist for ultra‐high field at 7 T. 3 T data are similar to 1.5 T, the precontrast T1 was longer, and postcontrast T1 was shorter in myocardial fibrosis patients compared with normal myocardium. Puntmann et al. [30] reported higher precontrast T1 values for hypertrophic and nonischemic dilated cardiomyopathies at 3 T compared with controls (Hypertrophic 1.254 ± 43 ms, and nonischemic dilated cardiomyopathy 1.239 ± 57 ms vs. healthy 1.070 ± 55 ms). Also, the postcontrast T1 values (10 mins) at 3 T were shorter in hypertrophic and dilated cardiomyopathies compared with healthy (hypertrophic: 307 ± 47 ms, dilated cardiomyopathies: 296 ± 43 ms vs. controls: 402 ± 58 ms) [30].

There are studies published for normal and diffuse myocardial fibrosis of myocardium T1 values, as described comprehensively in **Tables 2** and **3**:


Note: NA, not applicable; srTFL, saturation recovery turboFLASH; LL, Look‐Locker; MOLLI, modified Look–Locker inversion recovery sequence; VAST, inversion recovery gradient echo sequence with Variable Sampling of the k‐space in Time; GRE, gradient pulse sequence; shMOLLI, short modified Look‐Locker sequence.

**Table 2.** Healthy clinical studies using T1 and T2\*.


**First author (Ref.#) Sample** 

352 Cardiomyopathies - Types and Treatments

**size**

T2\* gradient echo pulse

Sebastian et al. [32] 12 LL T1 = 1033 ± 126 ms

Messroghli et al, [33] 15 MOLLI T1 = 980 ± 53 ms

Messroghli et al. [34] 20 MOLLI T1 = 939 ± 63 ms

Sparrow et al, [35] 15 MOLLI T1 = 980 ± 53 ms

Iles et al. [8] 20 VAST T1 = 975 ± 62 ms

Li et al. [36] 13 2 echo times GRE T1 = NA

Reeder et al. [37] 5 Multi echo GRE T1 = NA

Anderson et al. [38] 15 Multi echo GRE T1 = NA

Positano et al. [39] 15 Multi echo GRE T1 = NA

Messroghli et al. [40] 20 Multi echo GRE T1 = NA

Piechnik et al. [28] 342 shMOLLI T1 = 962 ± 25 ms

in Time; GRE, gradient pulse sequence; shMOLLI, short modified Look‐Locker sequence.

**Table 2.** Healthy clinical studies using T1 and T2\*.

Note: NA, not applicable; srTFL, saturation recovery turboFLASH; LL, Look‐Locker; MOLLI, modified Look–Locker inversion recovery sequence; VAST, inversion recovery gradient echo sequence with Variable Sampling of the k‐space

Wacker et al. [31] 5 srTFL, segmented

**T1/T2\* mapping sequence Result of T1 or**

**T2\* mapping (ms)**

T1 = 1219 ± 72 ms T2\* = 35 ± 3 ms

T2\* = NA

T2\* = NA

T2\* = NA

T2\* = NA

T2\* = NA

T2\* = 33 ± 6.5 ms

T2\*= 38 ± 6 ms

T2\*= 52 ± 16 ms

T2\* = 38 ± 9.2 ms in endocardial sectors, and 33.1 ± 8.4 ms in epicardial sectors

T2\* = 27.9 ± 3.4 ms in anteroseptal and 23.1 ± 5.2 ms

Heart rate only physiologic

in inferolateral

factors effect on myocardial T1 values

T2\* = NA


**Table 3.** Clinical studies using T1 mapping for myocardial diffuse fibrosis in clinical patients.

### **6. Limitations of T1 mapping**

Challenges remain with myocardial relaxometry for T1 mapping. These include technical challenges such as variations of T1 times at different field strength and across different vendors, and the rapidity in growth of pulse sequences being released as product and as works‐in‐ progress (WIP), calling into question both the inherent accuracy and the level agreement between these techniques. Furthermore, the variations in T1 relaxometry values with different contrast doses and image timing require further investigation to establish the test–retest and intersite reproducibility of this technique. Next, the challenges to application of T1 mapping to clinical practice include establishment of robust normal ranges in large cohorts across multiple ethnic groups and the observation that T1 mapping appears to be a highly sensitive technique, with the ability to discriminate healthy normal myocardium and identify very early changes in substrate. However, this technique lacks specificity; a wide variety of conditions prolong native T1 and/or shorten postcontrast myocardial T1. Therefore, further clinical data are required in order to establish the use of these parameters in relation to disease (e.g., early detection of target organ damage in systemic conditions such as hypertension or diabetes), to inform treatment decisions, and their ability to predict or alter clinical outcomes.

### **7. Conclusions**

**First author (Ref. #)**

Flacke and Sebastian [32]

Sparrow et al.

Iles et al. [8] Chronic heart

Maceira 2005 Cardiac

failure

amyloidosis

**6. Limitations of T1 mapping**

[35]

**Cardiac disease category**

354 Cardiomyopathies - Types and Treatments

Acute and chronic myocardial infarction

Myocardial Fibrosis in Chronic Aortic Regurgitation

**Patient sample size**

**T1 mapping method**

22 Segmented inversion recovery sequence

**Table 3.** Clinical studies using T1 mapping for myocardial diffuse fibrosis in clinical patients.

Challenges remain with myocardial relaxometry for T1 mapping. These include technical challenges such as variations of T1 times at different field strength and across different vendors, and the rapidity in growth of pulse sequences being released as product and as works‐in‐ progress (WIP), calling into question both the inherent accuracy and the level agreement between these techniques. Furthermore, the variations in T1 relaxometry values with different contrast doses and image timing require further investigation to establish the test–retest and intersite reproducibility of this technique. Next, the challenges to application of T1 mapping to clinical practice include establishment of robust normal ranges in large cohorts across multiple ethnic groups and the observation that T1 mapping appears to be a highly sensitive technique, with the ability to discriminate healthy normal myocardium and identify very early changes in substrate. However, this technique lacks specificity; a wide variety of conditions prolong native T1 and/or shorten postcontrast myocardial T1. Therefore, further clinical data are required in order to establish the use of these parameters in relation to disease (e.g., early

**Summary of findings**

respectively.

respectively).

10 LL Mean T1 values of the normal myocardium postcontrast

8 Molli There is a significant difference in segmental averaged T1

25 VAST Postcontrast myocardial T1 times were shorter in heart

than remote areas (1197 ± 76 vs. 1011 ± 66). The hyper‐ enhanced in acute is higher than chronic infarction.

was 536 **±** 66 ms, chronically infracted precontrast and postcontrast was 1000 ± 67 ms and 408 ± 43 ms,

relaxation between in abnormal wall motion vs. Normal control segments in 10, 15, and 20 min after administration Gd: (510 vs. 476 ms, 532 vs 501 ms, and 560 vs. 516 ms,

failure subjects than in controls (383 ± 17 ms vs. 564 ± 23 ms) even when excluding areas of regional fibrosis. T1 15‐min postcontrast values correlated significantly with collagen volume fraction on myocardial biopsies (*R* = −0.7).

Subendocardial T1 in amyloid patients was shorter than in controls (at 4 min: 427 ± 73 vs. 579 ± 75 ms; *p* < 0.01).

Myocardial T1 mapping using quantitative relaxometry is an emerging and important tool in the assessment of global myocardial fibrosis. It is a highly sensitive marker of disease, but is not specific, with changes in myocardial T1 occurring in many different conditions. Never‐ theless, the high sensitivity and excellent reproducibility of the technique offer a tool for the early detection of myocardial damage, over‐and‐above techniques such as the CMR LGE technique and other modalities such as speckle tracking echocardiography, pulse wave velocity, and tissue tagging. Native T1 mapping is proving to be a robust indicator of early myocardial disease in many conditions, and normal ranges and guidelines for postprocessing have been published by the Society of Cardiovascular Magnetic Resonance [41]. Myocardial T1 mapping is a rapidly evolving technique, now with longitudinal prognostic data emerging, and normal ranges established at 1.5 and 3.0 T in healthy humans and in aging persons. Further questions remain as to the standardization of pulse sequences across field strengths and between vendors, the affect of contrast type, dose and timing, the postprocessing software, and the interpretation of T1 mapping results to inform clinical practice.

### **Acknowledgements**

The author acknowledges the contribution of Dr Qurain Alshammari's to the background work.

### **Abbreviations**


### **Author details**

Christian R. Hamilton‐Craig1,2\*, Mark W. Strudwick3 and Graham J. Galloway1,4

\*Address all correspondence to: c.hamiltoncraig@uq.edu.au


3 Medical Imaging and Radiation Science, Monash University, Australia

4 Translational Research Institute, Brisbane, Australia

### **References**


[9] Amano Y, Takayama M, Kumita S. Contrast‐enhanced myocardial T1‐weighted scout (Look–Locker) imaging for the detection of myocardial damages in hypertrophic cardiomyopathy. Journal of Magnetic Resonance Imaging 2009;30:778–784.

**Author details**

356 Cardiomyopathies - Types and Treatments

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### **Hypertrophic Cardiomyopathy: Treatment, Risk Stratification, and Implantable Defibrillators Hypertrophic Cardiomyopathy: Treatment, Risk Stratification, and Implantable Defibrillators**

Peter Magnusson Peter Magnusson

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

http://dx.doi.org/10.5772/65392

#### **Abstract**

Hypertrophic cardiomyopathy (HCM) affects 1:500 individuals, and in majority of cases, a mutation in sarcomere proteins can explain the disease. Phenotype is hetero‐ geneous and thus the prognosis. Many patients suffer from dyspnoea, especially at exercise. Unfortunately, sudden cardiac death (SCD) does occur at all ages and is a major cause of death in young adults. There is no proven pharmacological treatment to reduce hypertrophy or fibrosis, but beta‐blockers are first‐line treatment. In patients with obstruction, myectomy is preferred in the young, but in older patients, alcohol septal ablation is tried to reduce symptoms and possibly prognosis. Risk stratification of sudden cardiac death is challenging. The major established risk factors are extreme myocardial thickness, non‐sustained ventricular tachycardia, unexplained syncope, abnormal exercise blood pressure response, and family history of sudden cardiac death. In 2014, a novel risk calculator was developed that also takes age, outflow gradient, and left atrial seize into account. Implantable defibrillator treatment is effective in HCM, but complications requiring surgery and inappropriate shocks remain a problem.

**Keywords:** complications, hypertrophic cardiomyopathy, implantable defibrillator, in‐ appropriate shock, risk stratification, risk markers, sudden cardiac death

### **1. Diagnosis**

Hypertrophic cardiomyopathy (HCM) implies increased ventricular thickness that is not only a response to hypertension, aortic stenosis, or any other loading condition with abnormal loading of the ventricle [1]. In adults, a wall thickness of ≥15 mm is typically required for

© 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.

diagnosis. In borderline cases (≥13 mm), a thorough evaluation including family history is needed [1, 2]. In siblings, parents or children of a HCM patient, 13‐mm thickness is enough for diagnosis [1, 2]. In children and adolescents, a wall thickness more than two standard deviations in the corresponding age group should raise suspicion of the diagnosis of HCM [3]. An ultrasound of the heart, echocardiography, typically reveals the diagnosis of HCM. Echocardiography is usually readily available, but occasionally other imaging techniques are needed. Cardiac magnetic resonance (CMR), computed tomography (CT) or rarely positron emission tomography (PET) is sometimes used for diagnostic purposes or to gain additional information for optimal disease management [4]. The hypertrophied segment is almost always affecting the left ventricle even though right wall involvement does occur [1, 2]. Typically, the septal part is enlarged, eitherthe basal part orthe middle part, but could affect lateral, posterior and apical part, or a combination thereof [1]. A concentric hypertrophic is often associated with secondary causes of hypertrophy but does occur as HCM entity. If an isolated hypertro‐ phy solely involves the basal part of the septal wall in an elderly and no other signs or family history of HCM is found, often an explanation such as hypertension is the major cause [1, 2]. Even though the diagnosis of most cases of HCM is straight forward, careful attention to other causes and robust imaging techniques, including a cardiologist with expertise in the field, is warranted. Because HCM is a life‐long disease with consequences not only for the patient but also for relatives, a correct diagnosis is indeed important.

### **2. Symptoms and signs**

Dyspnoea is the predominant symptom of HCM that leads to evaluation with an echocardio‐ gram. Shortness of breath is pronounced at exertion due to relaxation disturbance of the left ventricle during diastole and/or outflow tract obstruction. This latter form is called hypertro‐ phic obstructive cardiomyopathy, and the obstruction is often dynamic with regard to filling pressure, heart rate and body position and affected by medications with effect on the cardio‐ vascular system. Often the patient has an adopted life style to decreased physical stamina, and often the diagnostic presentation is rather vague including tiredness. The HCM diagnosis is often delayed or sometimes misclassified from the initial diagnostic work‐up.

A progressive HCM may sometimes lead to deterioration of the systolic function of the left ventricle. The ventricle dilates and hypertrophic segments remodel into dilatation, which sometimes can make it difficult to discern from other cardiomyopathies with dilated mor‐ phology. This condition is called end stage and indicates a worse prognosis [5–8].

Chest pain without coronary disease may also lead the physician to evaluate alternative diagnosis, and sometimes HCM is revealed. Microvascular dysfunction and fibrosis are part of the disease progression; biopsies show myocardial disarray, and modern PET imaging techniques confirm structural and functional abnormalities, which explain symptoms. However, biopsies are not indicated as part of routine evaluation as the same information would be gained non‐invasively [2, 4]. Syncope evaluation is sometimes the initial work‐up that leads to the diagnosis of HCM. The mechanisms could be either hemodynamic or cardiac arrhythmias [9]. Less specific symptoms such as pre‐syncope, near‐syncope or vertigo will often include ECG and that in turn will lead to suspicion of morphological disease.

Atrial fibrillation is common among HCM, and thus, the risk of embolization stroke warrants effective anticoagulants even without other risk factors [10, 11]. The CHADSVASC score is not validated for HCM patients, and current guidelines recommend warfarin/dual oral anticoa‐ gulants if no contraindication is present [2].

Unfortunately, the first manifestation of HCM could be sudden cardiac death (SCD). In such cases, the autopsy confirms or at least suspects HCM even though the microscopy and post‐ mortem genetic evaluation will aid. A conclusive diagnosis of HCM is of uttermost importance because of the inheritance pattern and relatives need to be evaluated.
