from docx import Document
from docx.shared import Pt, Inches, RGBColor
from docx.enum.text import WD_ALIGN_PARAGRAPH

doc = Document()

# --- Page margins ---
from docx.oxml.ns import qn
from docx.oxml import OxmlElement
section = doc.sections[0]
section.top_margin    = Inches(1)
section.bottom_margin = Inches(1)
section.left_margin   = Inches(1.25)
section.right_margin  = Inches(1.25)

# --- Default Normal style ---
normal = doc.styles["Normal"]
normal.font.name = "Times New Roman"
normal.font.size = Pt(12)

# ── TITLE ──────────────────────────────────────────────────────────────────
title_p = doc.add_paragraph()
title_p.alignment = WD_ALIGN_PARAGRAPH.CENTER
run = title_p.add_run("Pacemaker Placement in Heart Disease")
run.bold = True
run.font.size = Pt(14)
run.font.name = "Times New Roman"

# ── INTRODUCTION ───────────────────────────────────────────────────────────
h = doc.add_heading("Introduction", level=1)
h.runs[0].font.size = Pt(12)
h.runs[0].font.name = "Times New Roman"
h.runs[0].bold = True

intro = (
    "Cardiac pacing has been one of the most transformative developments in modern cardiology. "
    "Since the first implantable pacemaker was placed in 1958, devices have evolved from bulky "
    "external stimulators to miniaturized, leadless, and physiologically adaptive systems. Heart "
    "disease encompasses conditions such as sinus node dysfunction, atrioventricular (AV) block, "
    "heart failure with conduction delay, and structural valvular disease - many of which produce "
    "clinically significant bradycardia or conduction disturbances requiring permanent pacing. "
    "This essay draws on five peer-reviewed articles to examine indications, device advances, "
    "complications, and future directions in pacemaker therapy."
)
p = doc.add_paragraph(intro)
p.alignment = WD_ALIGN_PARAGRAPH.JUSTIFY
p.paragraph_format.first_line_indent = Inches(0.3)

# ── LITERATURE REVIEW ──────────────────────────────────────────────────────
h = doc.add_heading("Literature Review", level=1)
h.runs[0].font.size = Pt(12)
h.runs[0].font.name = "Times New Roman"
h.runs[0].bold = True

lit = (
    "Mulpuru et al. (2017) provided a foundational clinical framework for pacemaker indications, "
    "implant complications, programming, and remote monitoring (PMID: 28081829). Sidhu and Marine "
    "(2020) reviewed bradycardia evaluation and highlighted the 2018 ACC/AHA/HRS guideline shift "
    "toward symptom-driven decision-making over rigid rate thresholds (PMID: 31311698). Nuche et al. "
    "(2024) examined conduction disturbances following transcatheter aortic valve replacement (TAVR), "
    "offering updated epidemiology and a fast-track pacemaker management protocol (PMID: 39603774). "
    "Saleem-Talib et al. (2025) reviewed the rapid evolution of leadless pacemaker (LPM) technology, "
    "demonstrating lower device-related complication rates versus transvenous pacemakers (PMID: 40105878). "
    "Finally, Whinnett et al. (2025) reviewed physiological pacing strategies - including His-bundle and "
    "left bundle branch pacing - that preserve normal ventricular activation and reduce pacing-induced "
    "cardiomyopathy (PMID: 40679612)."
)
p = doc.add_paragraph(lit)
p.alignment = WD_ALIGN_PARAGRAPH.JUSTIFY
p.paragraph_format.first_line_indent = Inches(0.3)

# ── BODY ───────────────────────────────────────────────────────────────────
h = doc.add_heading("Body", level=1)
h.runs[0].font.size = Pt(12)
h.runs[0].font.name = "Times New Roman"
h.runs[0].bold = True

body_text = (
    "The primary indication for permanent pacing remains symptomatic bradycardia from sinus node "
    "dysfunction or AV block. As Sidhu and Marine (2020) stress, pathological significance depends "
    "on symptom correlation rather than rate alone; treatment should not be triggered solely by an "
    "arbitrary cutoff. Beyond bradycardia, structural heart disease creates additional indications. "
    "Mulpuru et al. (2017) describe how cardiac resynchronization therapy (CRT) uses biventricular "
    "pacing to restore ventricular synchrony in heart failure patients with bundle branch block, "
    "improving ejection fraction and survival. TAVR has generated a distinct pacing indication: "
    "Nuche et al. (2024) document that conduction disturbances after TAVR remain in the double-digit "
    "percentage range, driven by mechanical injury to the His-Purkinje system, with prior right bundle "
    "branch block being the strongest predictor of post-procedural pacemaker need.\n\n"
    "Device technology has advanced considerably. Traditional transvenous pacemakers carry risks of "
    "lead dislodgement, venous occlusion, and pocket infection. Saleem-Talib et al. (2025) show that "
    "leadless pacemakers, delivered percutaneously via the femoral vein and fixed directly to the "
    "right ventricular endocardium, significantly reduce these complications. Newer LPM generations "
    "support AV-synchronized pacing, atrial stimulation, and dual-chamber pacing, with future "
    "integration alongside defibrillators anticipated.\n\n"
    "Conventional right ventricular apical pacing produces non-physiological ventricular activation "
    "and can cause pacing-induced cardiomyopathy. Whinnett et al. (2025) describe conduction system "
    "pacing (CSP) - including His-bundle pacing and left bundle branch pacing - as a means of "
    "delivering near-normal activation, preserving cardiac function, and potentially expanding "
    "pacing indications to previously untreatable conduction diseases. Complications reviewed by "
    "Mulpuru et al. (2017) include pneumothorax, cardiac perforation, lead failure, and infection, "
    "all of which are mitigated by careful technique, remote monitoring, and advances in device design."
)
p = doc.add_paragraph(body_text)
p.alignment = WD_ALIGN_PARAGRAPH.JUSTIFY
p.paragraph_format.first_line_indent = Inches(0.3)

# ── CONCLUSION ─────────────────────────────────────────────────────────────
h = doc.add_heading("Conclusion", level=1)
h.runs[0].font.size = Pt(12)
h.runs[0].font.name = "Times New Roman"
h.runs[0].bold = True

conc = (
    "Pacemaker placement in heart disease has evolved from a narrow intervention for complete heart "
    "block into a broad therapeutic strategy encompassing bradycardia, CRT, post-TAVR conduction "
    "injury, and physiologically optimized pacing. Evidence-based, symptom-driven decision-making "
    "remains the cornerstone of appropriate device implantation. Leadless pacing and conduction system "
    "pacing represent the most significant recent advances, offering improved safety and physiological "
    "fidelity respectively. As device technology continues to improve, pacemaker therapy will become "
    "safer, less invasive, and more precisely tailored to individual patient physiology."
)
p = doc.add_paragraph(conc)
p.alignment = WD_ALIGN_PARAGRAPH.JUSTIFY
p.paragraph_format.first_line_indent = Inches(0.3)

# ── REFERENCES ─────────────────────────────────────────────────────────────
h = doc.add_heading("References", level=1)
h.runs[0].font.size = Pt(12)
h.runs[0].font.name = "Times New Roman"
h.runs[0].bold = True

refs = [
    "1. Mulpuru SK, Madhavan M, McLeod CJ, Cha YM, Friedman PA. Cardiac Pacemakers: Function, "
    "Troubleshooting, and Management: Part 1 of a 2-Part Series. J Am Coll Cardiol. 2017;69(2):189-210. "
    "doi:10.1016/j.jacc.2016.10.061. PMID: 28081829.",

    "2. Sidhu S, Marine JE. Evaluating and managing bradycardia. Trends Cardiovasc Med. "
    "2020;30(5):265-272. doi:10.1016/j.tcm.2019.07.001. PMID: 31311698.",

    "3. Nuche J, Ellenbogen KA, Mittal S, et al. Conduction Disturbances After Transcatheter Aortic "
    "Valve Replacement: An Update on Epidemiology, Preventive Strategies, and Management. "
    "JACC Cardiovasc Interv. 2024;17(23):2714-2730. doi:10.1016/j.jcin.2024.07.032. PMID: 39603774.",

    "4. Saleem-Talib S, Hoevenaars CPR, Molitor N, et al. Leadless pacing: a comprehensive review. "
    "Eur Heart J. 2025;46(21):2009-2024. doi:10.1093/eurheartj/ehaf119. PMID: 40105878.",

    "5. Whinnett Z, Naraen A, Vijayaraman P, Cleland JGF, Keene D. Physiological pacing: mechanisms, "
    "clinical indications, and perspectives. Eur Heart J. 2025. doi:10.1093/eurheartj/ehaf440. PMID: 40679612.",
]

for ref in refs:
    p = doc.add_paragraph(ref, style="Normal")
    p.alignment = WD_ALIGN_PARAGRAPH.JUSTIFY
    p.paragraph_format.left_indent = Inches(0.3)
    p.paragraph_format.first_line_indent = Inches(-0.3)
    p.paragraph_format.space_after = Pt(4)

# ── SAVE ───────────────────────────────────────────────────────────────────
out = "/tmp/workspace/pacemaker-essay/Pacemaker_Placement_Essay.docx"
doc.save(out)
print(f"Saved: {out}")

from docx import Document
from docx.shared import Pt, Inches
from docx.enum.text import WD_ALIGN_PARAGRAPH

doc = Document()

# --- Page margins ---
section = doc.sections[0]
section.top_margin    = Inches(1)
section.bottom_margin = Inches(1)
section.left_margin   = Inches(1.25)
section.right_margin  = Inches(1.25)

# --- Default Normal style ---
normal = doc.styles["Normal"]
normal.font.name = "Times New Roman"
normal.font.size = Pt(12)

# helper: justified paragraph with first-line indent
def add_para(doc, text):
    p = doc.add_paragraph(text)
    p.alignment = WD_ALIGN_PARAGRAPH.JUSTIFY
    p.paragraph_format.first_line_indent = Inches(0.3)
    return p

# helper: section heading
def add_heading(doc, text):
    h = doc.add_heading(text, level=1)
    for run in h.runs:
        run.font.size = Pt(12)
        run.font.name = "Times New Roman"
        run.bold = True
    return h

# ── TITLE ──────────────────────────────────────────────────────────────────
title_p = doc.add_paragraph()
title_p.alignment = WD_ALIGN_PARAGRAPH.CENTER
run = title_p.add_run("Gene Therapy for Inherited Heart Disease")
run.bold = True
run.font.size = Pt(14)
run.font.name = "Times New Roman"

# ── INTRODUCTION ───────────────────────────────────────────────────────────
add_heading(doc, "Introduction")
add_para(doc,
    "Inherited heart diseases represent a diverse group of genetic disorders that collectively "
    "affect millions of people worldwide and account for a significant proportion of sudden cardiac "
    "death, progressive heart failure, and arrhythmia. Conditions such as hypertrophic cardiomyopathy "
    "(HCM), dilated cardiomyopathy linked to Lamin A/C mutations, and Duchenne muscular dystrophy "
    "(DMD)-associated cardiomyopathy share a common feature: they arise from identifiable genetic "
    "mutations for which conventional pharmacotherapy offers only symptomatic relief rather than "
    "disease modification. The emergence of gene therapy - encompassing gene replacement, gene "
    "silencing, exon skipping, and CRISPR-based genome editing - has opened the possibility of "
    "targeting the root molecular cause of these conditions. This essay draws on five peer-reviewed "
    "articles to examine the current state, challenges, and future promise of gene therapy for "
    "inherited heart disease."
)

# ── LITERATURE REVIEW ──────────────────────────────────────────────────────
add_heading(doc, "Literature Review")
add_para(doc,
    "Prondzynski, Mearini, and Carrier (2019) reviewed gene therapy strategies in HCM, detailing "
    "approaches such as genome editing, exon skipping, allele-specific silencing, and gene replacement "
    "with a focus on MYBPC3 mutations (PMID: 29971600). Tuohy et al. (2020) examined the future of "
    "HCM treatment in the European Journal of Heart Failure, covering novel pharmacotherapies that "
    "target sarcomeric dysfunction and emerging gene-based interventions including embryonic gene "
    "editing (PMID: 31919938). Chen et al. (2019) reviewed Lamin A/C cardiomyopathy, one of the most "
    "common causes of dilated cardiomyopathy, discussing siRNA-based gene silencing and genome editing "
    "as future therapeutic avenues alongside ongoing clinical trials (PMID: 31773301). Babbs et al. "
    "(2020) reviewed the full therapeutic landscape of Duchenne muscular dystrophy - a condition "
    "frequently complicated by fatal cardiomyopathy - highlighting CRISPR-Cas9, exon skipping, and "
    "dystrophin minigene delivery as leading genetic strategies entering clinical trials (PMID: 32597486). "
    "Most recently, Abdul-Rahman et al. (2026) provided a comprehensive review of gene editing for "
    "inherited cardiac conditions in Trends in Cardiovascular Medicine, integrating CRISPR/Cas9 "
    "advances with epigenetics, artificial intelligence, and ethical frameworks (PMID: 41237872)."
)

# ── BODY ───────────────────────────────────────────────────────────────────
add_heading(doc, "Body")
add_para(doc,
    "Hypertrophic cardiomyopathy, caused predominantly by mutations in sarcomeric protein genes such "
    "as MYBPC3 and MYH7, is the most common inherited monogenic cardiac condition, affecting "
    "approximately 0.2% of the population (Tuohy et al., 2020). Current treatments - beta-blockers, "
    "calcium channel blockers, and septal reduction procedures - reduce symptoms but do not address "
    "the underlying genetic defect. Prondzynski et al. (2019) describe how allele-specific silencing "
    "can selectively suppress the mutant allele while preserving wild-type expression, and how "
    "AAV-mediated gene replacement of MYBPC3 has shown efficacy in mouse and human induced pluripotent "
    "stem cell models. Genome editing using CRISPR/Cas9 offers the potential to correct the mutation "
    "directly, though off-target effects and delivery efficiency in post-mitotic cardiomyocytes remain "
    "key challenges."
    "\n\n"
    "Lamin A/C (LMNA) cardiomyopathy is an autosomal dominant form of dilated cardiomyopathy "
    "characterized by rapid progression to heart failure, life-threatening arrhythmias, and sudden "
    "cardiac death. Chen et al. (2019) highlight that altered nuclear biomechanics and aberrant "
    "signaling pathways - particularly MAPK and mTOR - represent targetable molecular mechanisms. "
    "Future therapeutic strategies under investigation include siRNA-based silencing of the mutant "
    "LMNA allele and CRISPR-mediated correction, with several in vitro and in vivo studies currently "
    "underway. The complexity of LMNA variants and their variable penetrance make patient stratification "
    "a priority for any future gene therapy trial."
    "\n\n"
    "Duchenne muscular dystrophy, caused by loss-of-function mutations in the dystrophin gene, "
    "invariably causes a progressive and fatal cardiomyopathy in affected patients. Babbs et al. (2020) "
    "review the most clinically advanced genetic strategies: exon skipping using antisense "
    "oligonucleotides to restore the reading frame, delivery of micro-dystrophin minigenes via "
    "adeno-associated viral vectors, and CRISPR-Cas9 deletion of exons flanking mutational hotspots. "
    "While several of these approaches have entered clinical trials with promising early results, "
    "challenges remain in achieving sufficient transduction of cardiac and diaphragmatic muscle and "
    "managing immune responses to viral vectors."
    "\n\n"
    "Abdul-Rahman et al. (2026) place these developments in a broader context, noting that CRISPR/Cas9 "
    "has become the dominant gene editing platform in cardiology research due to its precision, "
    "versatility, and relative ease of delivery. The integration of artificial intelligence in variant "
    "classification and off-target prediction is accelerating the path from bench to bedside. However, "
    "the authors stress that ethical considerations - including equitable access, germline editing "
    "concerns, and long-term genomic safety - must be addressed through rigorous regulatory frameworks "
    "before these therapies can be widely adopted."
)

# ── CONCLUSION ─────────────────────────────────────────────────────────────
add_heading(doc, "Conclusion")
add_para(doc,
    "Gene therapy for inherited heart disease has transitioned from a theoretical concept to a rapidly "
    "advancing clinical frontier. Across HCM, LMNA cardiomyopathy, and DMD-related heart disease, "
    "strategies including CRISPR genome editing, AAV-mediated gene delivery, exon skipping, and RNA "
    "silencing are demonstrating efficacy in preclinical models and early clinical trials. Key obstacles "
    "including delivery efficiency, immune responses, and off-target effects are progressively being "
    "overcome through vector engineering and improved editing tools. With continued interdisciplinary "
    "collaboration and responsible ethical governance, gene therapy holds the potential to transform "
    "inherited heart disease from a life-limiting condition into a curable one."
)

# ── REFERENCES ─────────────────────────────────────────────────────────────
add_heading(doc, "References")

refs = [
    "1. Prondzynski M, Mearini G, Carrier L. Gene therapy strategies in the treatment of hypertrophic "
    "cardiomyopathy. Pflugers Arch. 2019;471(5):683-697. doi:10.1007/s00424-018-2173-5. PMID: 29971600.",

    "2. Tuohy CV, Kaul S, Song HK, Nazer B, Heitner SB. Hypertrophic cardiomyopathy: the future of "
    "treatment. Eur J Heart Fail. 2020;22(2):228-240. doi:10.1002/ejhf.1715. PMID: 31919938.",

    "3. Chen SN, Sbaizero O, Taylor MRG, Mestroni L. Lamin A/C Cardiomyopathy: Implications for "
    "Treatment. Curr Cardiol Rep. 2019;21(12):160. doi:10.1007/s11886-019-1224-7. PMID: 31773301.",

    "4. Babbs A, Chatzopoulou M, Edwards B, Squire SE, Wilkinson IVL, Wynne GM. From diagnosis to "
    "therapy in Duchenne muscular dystrophy. Biochem Soc Trans. 2020;48(3):1185-1197. "
    "doi:10.1042/BST20190282. PMID: 32597486.",

    "5. Abdul-Rahman T, Roy P, Garg N, et al. Gene editing for inherited cardiac conditions: A new "
    "frontier in cardiology. Trends Cardiovasc Med. 2026;36(4):247-258. "
    "doi:10.1016/j.tcm.2025.11.002. PMID: 41237872.",
]

for ref in refs:
    p = doc.add_paragraph(ref, style="Normal")
    p.alignment = WD_ALIGN_PARAGRAPH.JUSTIFY
    p.paragraph_format.left_indent = Inches(0.3)
    p.paragraph_format.first_line_indent = Inches(-0.3)
    p.paragraph_format.space_after = Pt(4)

# ── SAVE ───────────────────────────────────────────────────────────────────
out = "/tmp/workspace/pacemaker-essay/Gene_Therapy_Inherited_Heart_Disease.docx"
doc.save(out)
print(f"Saved: {out}")